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Sample records for hereditary motor neuropathy

  1. Genetics Home Reference: distal hereditary motor neuropathy, type V

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    ... neuropathy, type V Distal hereditary motor neuropathy, type V Printable PDF Open All Close All Enable Javascript ... collapse boxes. Description Distal hereditary motor neuropathy, type V is a progressive disorder that affects nerve cells ...

  2. Chaperonopathies: spotlight on hereditary motor neuropathies

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    Vincenzo Lupo

    2016-12-01

    Full Text Available Distal hereditary motor neuropathies (dHMN comprise a group of rare hereditary neuromuscular disorders characterized by a peroneal muscular atrophy without sensory symptoms. To date twenty-three genes for dHMN have been reported and four of them encode for chaperones: DNAJB2, which encodes a member of the HSP40/DNAJ co-chaperone family, and HSPB1, HSPB3 and HSPB8, which encode three members of the family of small heat shock proteins. Except for HSPB1, with around thirty different mutations, the remaining three genes comprise a much low number of cases. Thus, only one case has been described caused by an HSPB3 mutation, whereas few DNAJB2 and HSPB8 cases are known, most of them caused by a founder c.352+1G>A mutation in DNAJB2 and by mutations affecting the hot spot K141 residue of the HSPB8 chaperone. This low number of cases makes it difficult to understand the pathomechanism underlying the neuropathy. Chaperones can assemble in multi-chaperone complexes forming an integrative chaperone network in the cell, which plays relevant cellular roles in a variety of processes such as the correct folding of newly synthesized proteins, their escort to their precise cellular locations to form functional proteins and complexes and the response to protein misfolding, including the degradation of proteins that fail to refold properly. Despite of this variety of functions, mutations in some of them lead to diseases with a similar clinical picture, suggesting common pathways. This review gives an overview of the genetics of dHMNs caused by mutations in four genes, DNAJB2, HSPB1, HSPB3 and HSPB8, which encode chaperones and show a common disease mechanism.

  3. Hereditary neuropathies: systematization and diagnostics (clinical case of hereditary motor and sensor neuropathy of the IA type

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    Kolokolova A.M.

    2016-09-01

    Full Text Available Aim: to study the value of routine methods (clinical symptoms, electrophysiological findings and results of DNA analysis in diagnostics of hereditary motor sensory neuropathy type IA in outpatient clinics. Material and Methods. The review of foreign literature is represented. The phenotypic polymorphism, genetic heterogeneity and the difficulties of diagnostics are identified. A family with hereditary motor sensory neuropathy of lAtype is presented, which was diagnosed on the base of available methods in outpatient practice (clinical symptoms, genealogical method, electro-physiological findings and DNA analysis results. Results. Routine algorithm (consistent valuation of clinical symptoms, neurophysiologic findings and the results of DNA analysis helped to verify the diagnosis of hereditary motor sensory neuropathy of lAtype in outpatient practice after more than 20 years of the onset of the disease. Conclusion. The neurologists of outpatient clinics and other specialists must be informed about the availability of diagnostics of hereditary diseases of nervous system.

  4. Hereditary Neuropathies

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    ... the appearance of an inverted champagne glass) or scoliosis (curvature of the spine). The symptoms of hereditary neuropathies may be apparent ... the appearance of an inverted champagne glass) or scoliosis (curvature of the spine). The symptoms of hereditary neuropathies may be apparent ...

  5. A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy.

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    Tsai, Pei-Chien; Soong, Bing-Wen; Mademan, Inès; Huang, Yen-Hua; Liu, Chia-Rung; Hsiao, Cheng-Tsung; Wu, Hung-Ta; Liu, Tze-Tze; Liu, Yo-Tsen; Tseng, Yen-Ting; Lin, Kon-Ping; Yang, Ueng-Cheng; Chung, Ki Wha; Choi, Byung-Ok; Nicholson, Garth A; Kennerson, Marina L; Chan, Chih-Chiang; De Jonghe, Peter; Cheng, Tzu-Hao; Liao, Yi-Chu; Züchner, Stephan; Baets, Jonathan; Lee, Yi-Chung

    2017-05-01

    Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A > G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that co-segregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS. © The Author (2017). Published by Oxford University Press on behalf of

  6. Coenzyme Q10 Therapy in Hereditary Motor Sensory Neuropathy Type VI with Novel Mitofusin 2 Mutation

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    Takahashi, Ryoichi; Ikeda, Tokuhei; Hamaguchi, Ayumi; Iwasa, Kazuo; Yamada, Masahito

    2012-01-01

    Hereditary motor sensory neuropathy type VI (HMSN VI) is hereditary neuropathy accompanied by optic neuropathy. The feasibility of Coenzyme Q10 (CoQ10) as a treatment for subacute visual impairment of HMSN VI was examined. A 37-year-old patient with HMSN VI with a novel mitofusin 2 mutation was treated with high dose of CoQ10 (200 mg/day) for eight months. Visual impairment was partially resolved after CoQ10 therapy. High dose CoQ10 therapy may improve the prognosis of subacute visual impairm...

  7. Genetics Home Reference: distal hereditary motor neuropathy, type II

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    ... K, Kremensky I, Van Den Bosch L, Robberecht W, Van Vandekerckhove J, Van Broeckhoven C, Gettemans J, De Jonghe P, Timmerman V. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet. 2004 Jun;36(6):597- ...

  8. Severe fatigue and reduced quality of life in children with hereditary motor and sensory neuropathy 1A

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    Jagersma, Elbrich; Jeukens-Visser, Martine; van Paassen, Barbara W.; Meester-Delver, Anke; Nollet, Frans

    2013-01-01

    Severe fatigue and low quality of life are reported by a majority of adult patients with hereditary motor and sensory neuropathy 1A. In children with hereditary motor and sensory neuropathy 1A, the prevalence and impact of fatigue have not been studied yet. In this questionnaire survey, 55 Dutch

  9. X-linked hereditary motor sensory neuropathy (type 1) presenting with a stroke-like episode

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    Anand, Geetha; Maheshwari, Nitin; Roberts, David; Padeniya, Anuruddha; Hamilton-Ayers, Michele; van der Knaap, Marjo; Fratter, Carl; Jayawant, Sandeep

    2010-01-01

    X-linked hereditary motor sensory neuropathy type 1 (CMTX 1) is caused by mutation in the GJB1 gene that codes for the connexin 32 protein. Central nervous system involvement with or without white matter changes on magnetic resonance imaging (MRI) has rarely been reported in this condition. We

  10. Coenzyme Q10 therapy in hereditary motor sensory neuropathy type VI with novel mitofusin 2 mutation.

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    Takahashi, Ryoichi; Ikeda, Tokuhei; Hamaguchi, Ayumi; Iwasa, Kazuo; Yamada, Masahito

    2012-01-01

    Hereditary motor sensory neuropathy type VI (HMSN VI) is hereditary neuropathy accompanied by optic neuropathy. The feasibility of Coenzyme Q10 (CoQ10) as a treatment for subacute visual impairment of HMSN VI was examined. A 37-year-old patient with HMSN VI with a novel mitofusin 2 mutation was treated with high dose of CoQ10 (200 mg/day) for eight months. Visual impairment was partially resolved after CoQ10 therapy. High dose CoQ10 therapy may improve the prognosis of subacute visual impairment in HMSN VI. To confirm the effectiveness of CoQ10 on HMSN VI, further studies are needed.

  11. [Hereditary optic neuropathies].

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    Milea, D; Verny, C

    2012-10-01

    Hereditary optic neuropathies are a group of heterogeneous conditions affecting both optic nerves, with an autosomal dominant, autosomal recessive, X-related or mitochondrial transmission. The two most common non-syndromic hereditary optic neuropathies (Leber's hereditary optic neuropathy and autosomal dominant optic atrophy) are very different in their clinical presentation and their genetic transmission, leading however to a common, non-specific optic nerve atrophy. Beyond the optic atrophy-related visual loss, which is the clinical hallmark of this group of diseases, other associated neurological signs are increasingly recognized. Copyright © 2012. Published by Elsevier Masson SAS.

  12. Relative Contribution of Mutations in Genes for Autosomal Dominant Distal Hereditary Motor Neuropathies: A Genotype-Phenotype Correlation Study

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    Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, An; De Vriendt, Els; Deconinck, Tine; Merlini, Luciano; Van den Bergh, Peter; Rasic, Vedrana Milic; Robberecht, Wim; Fischer, Dirk; Morales, Raul Juntas; Mitrovic, Zoran; Seeman, Pavel; Mazanec, Radim; Kochanski, Andrzej; Jordanova, Albena; Auer-Grumbach, Michaela; Helderman-van den Enden, A. T. J. M.; Wokke, John H. J.; Nelis, Eva; De Jonghe, Peter; Timmerman, Vincent

    2008-01-01

    Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; "glycyl-tRNA synthetase (GARS)," "dynactin 1 (DCTN1)," "small heat shock 27 kDa…

  13. Genetic heterogeneity of motor neuropathies

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    Bansagi, Boglarka; Griffin, Helen; Whittaker, Roger G.; Antoniadi, Thalia; Evangelista, Teresinha; Miller, James; Greenslade, Mark; Forester, Natalie; Duff, Jennifer; Bradshaw, Anna; Kleinle, Stephanie; Boczonadi, Veronika; Steele, Hannah; Ramesh, Venkateswaran; Franko, Edit

    2017-01-01

    Objective: To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England. Methods: Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex...

  14. Hereditary neuropathies: An update.

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    Stojkovic, T

    2016-12-01

    Hereditary neuropathies are the most common inherited neuromuscular diseases. Charcot-Marie-Tooth (CMT) disease represents the most common form with an average prevalence ranging from 1/2500 to 1/1200, depending on the studies. To date and with the advances of the latest generation sequencing, more than 80 genes have been identified. Although the common clinical phenotype comprises a progressive distal muscle weakness and sensory loss, foot deformities and decreased or absent tendon reflexes, clinical and electrophysiological phenotypes exhibit great variability. Moreover, atypical phenotypes are arising, overlapping with spastic paraplegia, hereditary sensory neuropathies or amyotrophic lateral sclerosis. The causative genes are involved in various biological processes such as myelin development and maintenance, biosynthesis and degradation of proteins, neuronal structural maintenance, axonal transport, endocytosis, membrane dynamics, ion-channel function and the mitochondrial network. An accurate genetic diagnosis is important for appropriate genetic counselling and treatment options. Therapeutic advances, particularly small interfering RNA therapy, are encouraging in hereditary transthyretin amyloid neuropathy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. Hereditary spastic paraplegia and axonal motor neuropathy caused by a novel SPG3A de novo mutation.

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    Fusco, Carlo; Frattini, Daniele; Farnetti, Enrico; Nicoli, Davide; Casali, Bruno; Fiorentino, Francesco; Nuccitelli, Andrea; Giustina, Elvio Della

    2010-08-01

    Mutations in the SPG3A gene (atlastin protein) cause approximately 10% of autosomal-dominant hereditary spastic paraplegia. Most patients with an SPG3A mutation present with a pure phenotype and early-onset disease, although complicated forms with peripheral neuropathy are also reported. We report a new heterozygous S398F mutation in exon 12 of the SPG3A gene causing a very early-onset spastic paraplegia in association with motor axonal neuropathy in a 4-year-old girl resembling diplegic cerebral palsy. Copyright 2009 Elsevier B.V. All rights reserved.

  16. Analysis of primary diagnostics of hereditary motor and sensory neuropathies in the Republic of Bashkortostan

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    E. V. Saifullina

    2017-01-01

    Full Text Available Background. Hereditary motor and sensory neuropathies (HMSN, Charcot–Marie–Tooth disease form genetically heterogenous and clinically polymorphic group of diseases which predominantly affect peripheral nervous system. Correct primary diagnostics of these diseases is a starting point for planning subsequent molecular and genetic diagnostics.Objective. Analysis of primary diagnostics of HMSN for subsequent improvement of specialized medical and genetic help for patients and their families.Materials and methods. We analyzed 260 primary diagnoses of patients referred to a neurogeneticist for consultation and registered in the Genetics Consultation Clinic with the diagnosis of HMSN between 1970 and 2016.Results. A total of 17 variants of referral diagnoses of patients with HMSN were identified. They can be divided into 3 subgroups: hereditary diseases of the nervous and neuromuscular systems, other diseases of the nervous system, diseases of other systems. A correct diagnosis was listed in a little more than half (58.1 % of all cases of primary referrals. The most common (10.8 % erroneous referral diagnosis of patients with HMSN was Friedreich’s ataxia. Most of erroneous referral diagnoses could be confidently ruled out at the stage of primary clinical diagnosis and after electroneuromyography. Altogether, in the observed period percentage of correct referral diagnoses increased while the specter of erroneous diagnoses decreased significantly which attests to increased doctors’ awareness of HMSN.Conclusion. In order to improve HMSN diagnostics doctors should pay more attention to analysis of family medical history and perform a clinical examination of all proband’s available relatives.

  17. Hereditary motor and sensory neuropathies or Charcot-Marie-Tooth diseases: an update.

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    Tazir, Meriem; Hamadouche, Tarik; Nouioua, Sonia; Mathis, Stephane; Vallat, Jean-Michel

    2014-12-15

    Hereditary motor and sensory neuropathies (HMSN) or Charcot-Marie-Tooth (CMT) diseases are the most common degenerative disorders of the peripheral nervous system. However, the frequency of the different subtypes varies within distinct populations. Although more than seventy clinical and genetic forms are known to date, more than 80% of CMT patients in Western countries have genetic abnormalities associated with PMP22, MPZ, MFN2 and GJB1. Given the considerable genetic heterogeneity of CMT, we emphasize the interest of both clinical and pathological specific features such that focused genetic testing could be performed. In this regard, peripheral nerve lesions in GDAP1 mutations (AR CMT1A), such as mitochondrial abnormalities, have been newly demonstrated. Otherwise, while demyelinating autosomal recessive CMT used to be classified as CMT4 (A, B, C …), we propose a simplified classification such as AR CMT1 (A, B, C …), and AR CMT2 for axonal forms. Also, we stress that next generation sequencing techniques, now considered to be the most efficient methods of genetic testing in CMT, will be helpful in molecular diagnosis and research of new genes involved. Finally, while no effective therapy is known to date, ongoing new therapeutic trials such as PXT3003 (a low dose combination of the three already approved drugs baclofen, naltrexone, and D-sorbitol) give hopes for potential curative treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Hereditary motor and sensory neuropathies: Understanding molecular pathogenesis could lead to future treatment strategies.

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    Jerath, Nivedita U; Shy, Michael E

    2015-04-01

    Inherited peripheral neuropathies, like many other degenerative disorders, have been challenging to treat. At this point, there is little specific therapy for the inherited neuropathies other than genetic counseling as well as symptomatic treatment and rehabilitation. In the past, ascorbic acid, progesterone antagonists, and subcutaneous neurotrophin-3 (NT3) injections have demonstrated improvement in animal models of CMT 1A, the most common inherited neuropathy, but have failed to translate any effect in humans. Given the difficulty in treatment, it is important to understand the molecular pathogenesis of hereditary neuropathies in order to strategize potential future therapies. The hereditary neuropathies are in an era of molecular insight and over the past 20 years, more than 78 subtypes of Charcot Marie Tooth disease (CMT) have been identified and extensively studied to understand the biological pathways in greater detail. Next generation molecular sequencing has also improved the diagnosis as well as the understanding of CMT. A greater understanding of the molecular pathways will help pave the way to future therapeutics of CMT. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Genetics of hereditary motor and sensory neuropathy and the Costa Rican contribution

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    Alejandro Leal

    2004-09-01

    Full Text Available Hereditary motor and sensory neuropathy (HMSN or Charcot-Marie-Tooth disease (CMT is the most common hereditary illness of the peripheral nervous system. The genetics and the physiopathological aspects of the disease clarified until know, are here summarized. More than twenty genes and ten additional loci have been related with HMSN. These findings contribute to understand the metabolism of peripheral nerves and give the basis for molecular diagnostics and future therapy. Several Costa Rican families with CMT have been identified, specially with axonal forms. Two families present mutations in the myelin protein zero gene (MPZ. In addition, linkage have been found between the disease and locus 19q13.3 in an extended family, and a mutation segregating with the disease is present in a candidate gene of the critical interval. Costa Rica has several advantages for genetical studies, that can contribute importantly in the generation of knowledge in the neurogenetical field. Rev. Biol. Trop. 52(3: 475-483. Epub 2004 Dic 15.El grupo de neuropatías motoras y sensoriales hereditarias (HMSN o enfermedad de Charcot-Marie-Tooth (CMT es el padecimiento hereditario más común del sistema nervioso periférico. El propósito de este trabajo es resumir los aspectos genéticos y fisiopatológicos más actuales de esta enfermedad. Más de veinte genes y diez loci adicionales han sido relacionados con HMSN. Estos hallazgos han contribuido con la comprensión del metabolismo de los nervios periféricos y sirven de base para el diagnóstico molecular y el diseño de terapias. Diversas familias costarricenses con CMT han sido identificadas: dos de ellas presentan mutaciones en el gen que codifica por la mielina proteína cero (MPZ. Además, un análisis de ligamiento localizó el gen que causa una forma axonal de la enfermedad en el cromosoma 19q13.3 en una extensa familia; también se detectó en esa región una mutación que co-segrega con la enfermedad y que

  20. Hereditary sensory neuropathy type I

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    Auer-Grumbach, Michaela

    2008-01-01

    Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin

  1. Hereditary sensory neuropathy type I

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    Auer-Grumbach Michaela

    2008-03-01

    Full Text Available Abstract Hereditary sensory neuropathy type I (HSN I is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7 identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN, especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra

  2. Hereditary motor and sensory neuropathy with hypertrophy of the cauda equina and concomitant demyelinating white matter lesions

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    Ertl-Wagner, B.B.; Staebler, A.; Reiser, M. [Univ. Muenchen (Germany). Inst. fuer Klinische Radiologie; Helmchen, C. [Univ. Luebeck (Germany). Klinik fuer Neurologie; Fassmann, F. [Zentrum fuer Radiologie und Nuklearmedizin, Erlangen-Nuernberg (Germany)

    2005-07-01

    Hereditary motor and sensory neuropathy (HMSN) is thought to almost exclusively affect the peripheral nervous system. We report the case of a 48-year-old patient with a longstanding history of HMSN type I who developed signs and symptoms of a cauda equina compression and of a central nervous system relapsing-remitting demyelinating white matter disease. Gross enlargement of the cauda equina fibers was detected by MR imaging of the lumbar spine. Cranial MR imaging revealed demyelinating white matter lesions. This case suggests that peripheral neuropathic mechanisms may also affect the central myelin in HMSN type I.

  3. Genetic heterogeneity of motor neuropathies.

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    Bansagi, Boglarka; Griffin, Helen; Whittaker, Roger G; Antoniadi, Thalia; Evangelista, Teresinha; Miller, James; Greenslade, Mark; Forester, Natalie; Duff, Jennifer; Bradshaw, Anna; Kleinle, Stephanie; Boczonadi, Veronika; Steele, Hannah; Ramesh, Venkateswaran; Franko, Edit; Pyle, Angela; Lochmüller, Hanns; Chinnery, Patrick F; Horvath, Rita

    2017-03-28

    To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England. Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients). The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy. Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

  4. Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy.

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    Lupo, Vincenzo; García-García, Francisco; Sancho, Paula; Tello, Cristina; García-Romero, Mar; Villarreal, Liliana; Alberti, Antonia; Sivera, Rafael; Dopazo, Joaquín; Pascual-Pascual, Samuel I; Márquez-Infante, Celedonio; Casasnovas, Carlos; Sevilla, Teresa; Espinós, Carmen

    2016-03-01

    Charcot-Marie-Tooth disease is characterized by broad genetic heterogeneity with >50 known disease-associated genes. Mutations in some of these genes can cause a pure motor form of hereditary motor neuropathy, the genetics of which are poorly characterized. We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy. We validated this diagnostic tool by first testing 11 patients with pathological mutations. A cohort of 33 affected subjects was selected for this study. The DNAJB2 c.352+1G>A mutation was detected in two cases; novel changes and/or variants with low frequency (A mutation was also detected in three additional families. On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event. Our gene panel allowed us to perform a very rapid and cost-effective screening of genes involved in Charcot-Marie-Tooth disease/hereditary motor neuropathy. Our diagnostic strategy was robust in terms of both coverage and read depth for all of the genes and patient samples. These findings demonstrate the difficulty in achieving a definitive molecular diagnosis because of the complexity of interpreting new variants and the genetic heterogeneity that is associated with these neuropathies. Copyright © 2016 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  5. Psychiatric disorders appear equally in patients with myotonic dystrophy, facioscapulohumeral dystrophy, and hereditary motor and sensory neuropathy type I.

    NARCIS (Netherlands)

    Kalkman, J.S.; Schillings, M.L.; Zwarts, M.J.; Engelen, B.G.M. van; Bleijenberg, G.

    2007-01-01

    OBJECTIVES: To study the presence of psychiatric comorbidity assessed by the use of a structured clinical interview and self-reported questionnaires in a large sample of patients with adult-onset myotonic dystrophy (DM), facioscapulohumeral muscular dystrophy (FSHD), and hereditary motor and sensory

  6. [Sudden blindness: consider Leber's hereditary optic neuropathy

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    Schieving, J.H.; Vries, L.B.A. de; Hol, F.A.; Stroink, H.

    2008-01-01

    In 3 young male patients, aged 10, 19 and 21 years respectively, sequential, severe, painless bilateral visual loss occurred. Ophthalmological examination revealed no other abnormalities and this delayed the diagnosis Leber's hereditary optic neuropathy (LHON). LHON is a mitochondrial genetic

  7. Spectrum of sonographic changes in hereditary motor and sensory neuropathy with autosomal dominant and X-linked inheritance

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    E. S. Naumova

    2016-01-01

    Full Text Available Background. In the recent years interest towards nerve sonography has largely increased, specifically in terms of differentiating types of hereditary motor and sensory neuropathy (HMSN. The diagnostic possibilities of high-resolution ultrasound (HRUS compared to standard neurophysiological tools in the peripheral nerve disorders is still a matter of debate.Objectives. Analysis of quantitative and qualitative ultrasound changes of limb nerves in patients with HMSN type 1 and its comparison with anthropometric and nerve conduction study data.Materials and methods. 44 HMSN patients were analyzed: 16 men, mean age 35,9 ± 6,8 years; 16 (37 % with autosomal dominant type 1А, 11 (25 % – with 1В type and 17 (38 % with Х-linked inheritance. Control group included 44 subjects, 16 male; mean age 35,9 ± 6,8 years. HRUS parameters were analyzed bilaterally on the selected levels: cross-sectional area (CSA, visual cross sectional and longitudinal patterns of the median and ulnar nerves, C5, C6, C7 spinal nerves, tibial, peroneal and sciatic nerves. HRUS parameters were compared to standard anthropometric data, nerve conduction velocity and CMAP amplitude.Results. In all HMSN cases CSA was enlarged compared to healthy controls. Greater changes were found in patients with autosomal dominant inheritance. CSA enlargement in С5, С6, С7 spinal nerves was found in patients with HMSN 1A, С6, С7 – in HMSN 1В, С6 – in HMSN 1X, confirming the necessity to include those nerves in the sonographic protocol in patients with HMSN. Three qualitative cross sectional and longitudinal patterns of the investigated arm nerves were identified, distinct for each of the HMSN type. Absence of significant differences in CSA of the upper limb nerves among analyzed types of HMSN makes it unreliable as the differential parameter, opposite to the defined sonographic patterns. Methodological issues and absence of significant quantitative and qualitative data

  8. Demyelinating polyneuropathy in Leber hereditary optic neuropathy.

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    Gilhuis, H.J.; Schelhaas, H.J.; Cruysberg, J.R.M.; Zwarts, M.J.

    2006-01-01

    We report a patient with Leber hereditary optic neuropathy (G11778A mtDNA) and a severe demyelinating neuropathy, for which no other cause except his mitochondrial disorder could be found. The involvement of the peripheral nervous system of patients with LHON, in particular with a 11778 mtDNA, is

  9. Relapsing Acute Axonal Neuropathy in Hereditary Fructose Intolerance.

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    Maitre, Anna; Maw, Anna; Ramaswami, Uma; Morley, Sarah L

    2016-11-01

    A severe neurological abnormality has not been previously described in individuals with hereditary fructose intolerance, which typically presents early in childhood with severe metabolic acidosis and hypoglycemia. We describe a boy who by age five years had required multiple admissions to the pediatric intensive care unit for an aggressive and atypical, relapsing and remitting neuropathy with features of acute motor axonal neuropathy (AMAN). It was later discovered that he also had undiagnosed hereditary fructose intolerance, and the severity and frequency of his neurological episodes diminished following an exclusion diet. His asymptomatic younger brother was diagnosed with hereditary fructose intolerance on screening. He is on a fructose-free diet and has not developed neurological symptoms. Ongoing low-level exposure to fructose prior to diagnosis may have contributed to our patient's neurological dysfunction. Early diagnosis and treatment may prevent neurological complications of hereditary fructose intolerance. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Late-onset Leber hereditary optic neuropathy.

    Science.gov (United States)

    Pfeiffer, Margaret L; Hashemi, Nafiseh; Foroozan, Rod; Lee, Andrew G

    2013-01-01

    While Leber hereditary optic neuropathy typically causes bilateral visual loss in the second through fourth decades, we highlight visual loss from Leber hereditary optic neuropathy in older patients to characterize the clinical features of this cohort. Retrospective case series. Patients seen between January 2003 and July 2012 at Baylor College of Medicine and between April 2010 and July 2012 at The Methodist Hospital in Houston, Texas. Patients with visual loss from genetically confirmed Leber hereditary optic neuropathy were identified via retrospective chart review. Clinical courses of patients. Five patients with visual loss from genetically confirmed Leber hereditary optic neuropathy were greater than 60 years of age at the time of visual loss (range 62-70 years, mean 66.4 ± 3.0). This series reinforces the importance of including Leber hereditary optic neuropathy in the differential diagnosis of patients of any age with optic neuropathy. © 2013 The Authors. Clinical and Experimental Ophthalmology © 2013 Royal Australian and New Zealand College of Ophthalmologists.

  11. Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy-Russe in depth.

    Science.gov (United States)

    Sevilla, T; Martínez-Rubio, D; Márquez, C; Paradas, C; Colomer, J; Jaijo, T; Millán, J M; Palau, F; Espinós, C

    2013-06-01

    Four private mutations responsible for three forms demyelinating of Charcot-Marie-Tooth (CMT) or hereditary motor and sensory neuropathy (HMSN) have been associated with the Gypsy population: the NDRG1 p.R148X in CMT type 4D (CMT4D/HMSN-Lom); p.C737_P738delinsX and p.R1109X mutations in the SH3TC2 gene (CMT4C); and a G>C change in a novel alternative untranslated exon in the HK1 gene causative of CMT4G (CMT4G/HMSN-Russe). Here we address the findings of a genetic study of 29 Gypsy Spanish families with autosomal recessive demyelinating CMT. The most frequent form is CMT4C (57.14%), followed by HMSN-Russe (25%) and HMSN-Lom (17.86%). The relevant frequency of HMSN-Russe has allowed us to investigate in depth the genetics and the associated clinical symptoms of this CMT form. HMSN-Russe probands share the same haplotype confirming that the HK1 g.9712G>C is a founder mutation, which arrived in Spain around the end of the 18th century. The clinical picture of HMSN-Russe is a progressive CMT disorder leading to severe weakness of the lower limbs and prominent distal sensory loss. Motor nerve conduction velocity was in the demyelinating or intermediate range. © 2012 John Wiley & Sons A/S.

  12. DNA testing in hereditary neuropathies.

    LENUS (Irish Health Repository)

    Murphy, Sinéad M

    2013-01-01

    The inherited neuropathies are a clinically and genetically heterogeneous group of disorders in which there have been rapid advances in the last two decades. Molecular genetic testing is now an integral part of the evaluation of patients with inherited neuropathies. In this chapter we describe the genes responsible for the primary inherited neuropathies. We briefly discuss the clinical phenotype of each of the known inherited neuropathy subgroups, describe algorithms for molecular genetic testing of affected patients and discuss genetic counseling. The basic principles of careful phenotyping, documenting an accurate family history, and testing the available genes in an appropriate manner should identify the vast majority of individuals with CMT1 and many of those with CMT2. In this chapter we also describe the current methods of genetic testing. As advances are made in molecular genetic technologies and improvements are made in bioinformatics, it is likely that the current time-consuming methods of DNA sequencing will give way to quicker and more efficient high-throughput methods, which are briefly discussed here.

  13. Salvage procedures in lower-extremity trauma in a child with hereditary motor and sensory neuropathy type I: a case report

    Directory of Open Access Journals (Sweden)

    Gothner Martin

    2012-09-01

    Full Text Available Abstract Introduction Fractures of the lower extremity are a common type of childhood injury and many can be treated without surgery. Dislocated and open fractures are an indication for fracture stabilization via either intramedullary nailing or, in the case of complicated fractures, external fixation. But if complications are likely because of diseases and disabilities (for example, a neuropathy that can complicate the post-operative procedure and rehabilitation, what options does one have? Case presentation We report a nine-year-old Caucasian girl who had hereditary motor and sensory neuropathy type I and who was admitted with a grade I open tibia fracture after a fall from a small height. Plain radiographs showed a dislocated tibia and fibula fracture. An open reduction with internal fixation with a compression plate osteosynthesis was performed, and soft tissue debridement combined with an external fixateur was undertaken. Three months later, she was re-admitted with localized swelling and signs of a local soft tissue infection in the middle of her tibia. Plain radiographs showed a non-union of the tibia fracture, and microbiological analysis confirmed a wound infection with cefuroxime-sensitive Staphylococcus aureus. Because of the non-union, the osteosynthesis was replaced with an Ilizarov external fixateur, and appropriate antibiotic therapy was initiated. Four months after the initial accident, the fracture was consolidated and we removed the external fixateur. Conclusions If there is a pre-existing neuropathy and if disease makes it difficult for a child to follow all post-operative instructions, salvage procedures should be kept in mind in case of complications. There are multiple therapeutic options, including osteosynthesis, intramedullary nailing systems, cast therapy, or an external fixateur like the Ilizarov or Taylor spatial frame system. The initial use of an external fixateur such as an Ilizarov or Taylor spatial frame in

  14. Medical Management of Hereditary Optic Neuropathies

    Science.gov (United States)

    La Morgia, Chiara; Carbonelli, Michele; Barboni, Piero; Sadun, Alfredo Arrigo; Carelli, Valerio

    2014-01-01

    Hereditary optic neuropathies are diseases affecting the optic nerve. The most common are mitochondrial hereditary optic neuropathies, i.e., the maternally inherited Leber’s hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA). They both share a mitochondrial pathogenesis that leads to the selective loss of retinal ganglion cells and axons, in particular of the papillo-macular bundle. Typically, LHON is characterized by an acute/subacute loss of central vision associated with impairment of color vision and swelling of retinal nerve fibers followed by optic atrophy. DOA, instead, is characterized by a childhood-onset and slowly progressive loss of central vision, worsening over the years, leading to optic atrophy. The diagnostic workup includes neuro-ophthalmologic evaluation and genetic testing of the three most common mitochondrial DNA mutations affecting complex I (11778/ND4, 3460/ND1, and 14484/ND6) for LHON and sequencing of the nuclear gene OPA1 for DOA. Therapeutic strategies are still limited including agents that bypass the complex I defect and exert an antioxidant effect (idebenone). Further strategies are aimed at stimulating compensatory mitochondrial biogenesis. Gene therapy is also a promising avenue that still needs to be validated. PMID:25132831

  15. Medical management of hereditary optic neuropathies

    Directory of Open Access Journals (Sweden)

    Chiara eLa Morgia

    2014-07-01

    Full Text Available Hereditary optic neuropathies are diseases of the optic nerve. The most common are mitochondrial hereditary optic neuropathies, i.e. the maternally inherited Leber’s Hereditary Optic Neuropathy (LHON and Dominant Optic Atrophy (DOA. They both share a mitochondrial pathogenesis that leads to the selective loss of retinal ganglion cells and axons, in particular of the papillo-macular bundle. Typically, LHON is an acute/subacute loss of central vision associated with impairment of color vision and swelling of retinal nerve fibers followed by optic atrophy. DOA, instead, is characterized by a childhood-onset and slowly progressive loss of central vision, worsening over the years, leading to optic atrophy. The diagnostic workup includes neuro-ophthalmologic evaluation and genetic testing of the three most common mitochondrial DNA mutations affecting complex I (11778/ND4, 3460/ND1 and 14484/ND6 for LHON and sequencing of the nuclear gene OPA1 for DOA. Therapeutic strategies are limited including agents that bypass the complex I defect and exert an antioxidant effect (idebenone. Further strategies are aimed at stimulating compensatory mitochondrial biogenesis. Gene therapy is also a promising venue that still needs to be validated.

  16. Antiretroviral therapy-induced Leber's hereditary optic neuropathy ...

    African Journals Online (AJOL)

    Nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine and stavudine have known mitochondrial toxicity and can cause mitochondrial myopathies, neuropathies, hyperlactataemia, and can induce mitochondrial genetic disorders. Individuals with the mutation for Leber's hereditary optic neuropathy (LHON), ...

  17. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy

    National Research Council Canada - National Science Library

    Giordano, Carla; Montopoli, Monica; Perli, Elena; Orlandi, Maurizia; Fantin, Marianna; Ross-Cisneros, Fred N; Caparrotta, Laura; Martinuzzi, Andrea; Ragazzi, Eugenio; Ghelli, Anna; Sadun, Alfredo A; d'Amati, Giulia; Carelli, Valerio

    2011-01-01

    Leber's hereditary optic neuropathy, the most frequent mitochondrial disease due to mitochondrial DNA point mutations in complex I, is characterized by the selective degeneration of retinal ganglion...

  18. Antiretroviral therapy-induced Leber's hereditary optic neuropathy

    National Research Council Canada - National Science Library

    Moodley, A; Bhola, S; Omar, F; Mogambery, J

    2014-01-01

    .... Individuals with the mutation for Leber's hereditary optic neuropathy (LHON), a mitochondrial disorder, are usually asymptomatic but develop visual loss when exposed to external triggers such as smoking...

  19. Cuban epidemic optic neuropathy and its relationship to toxic and hereditary optic neuropathy.

    Science.gov (United States)

    Santiesteban-Freixas, Rosaralis; Mendoza-Santiesteban, Carlos E; Columbie-Garbey, Yannara; Quevedo, Alina Gonzalez; Garcia, Alberto Gonzalez; Rodríguez, Ramón Cabal

    2010-07-01

    The similarities and differences between toxic/nutritional and hereditary optic neuropathy and the pathophysiologic mechanisms that they have in common are described. This is based on data from the epidemic suffered in Cuba in 1992, which affected the optic nerves of many individuals and the experience of the authors in dealing with various toxic optic neuropathies, as well as Leber's hereditary optic neuropathy.

  20. Leber hereditary optic neuropathy: current perspectives

    Directory of Open Access Journals (Sweden)

    Meyerson C

    2015-06-01

    Full Text Available Cherise Meyerson, Greg Van Stavern, Collin McClelland Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, MO, USA Abstract: Leber hereditary optic neuropathy (LHON is one of the most common inherited optic neuropathies causing bilateral central vision loss. The disorder results from point mutations in mitochondrial DNA and subsequent mitochondrial dysfunction. The primary cell type that is lost in LHON is the retinal ganglion cell, which is highly susceptible to disrupted ATP production and oxidative stress. Inheritance of LHON follows that of mitochondrial genetics, and it has a highly variable clinical phenotype, as other genetic and environmental factors also play a role. Although LHON usually presents with isolated vision loss, some patients suffer other neurological sequelae. For ill-defined reasons, male LHON mutation carriers are more affected than females. Most LHON patients remain legally blind, but a small proportion can experience spontaneous partial recovery, often within the first year of symptom onset. Unfortunately, at this time there are no established curative interventions and treatment is largely supportive. Patients should be offered low vision services and counseled on mitigating risk factors for additional vision loss, such as smoking and consuming alcohol. Encouraging treatments currently undergoing investigation includes ubiquinone analogs, such as idebenone, as well as gene therapy and stem cells to restore ATP synthesis and provide neuroprotection to surviving retinal ganglion cells. Keywords: Leber hereditary optic neuropathy, mitochondria, neuro-ophthalmology, mitochondrial DNA

  1. Successful outcome in a twin pregnancy with hereditary motor and sensory neuropathy type –II complicated with heart disease and preclampsia superimposed on chronic hypertension

    OpenAIRE

    Debasmita Mondal

    2008-01-01

    Heridetary motor and sensory neuropathy (HMSN TYPE-2) reflects reduction in the number of primary motor and sensory neurons. The occurrence of this disease is rare in pregnancy but may be exaggerated in pregnancy leading to preeclampsia / eclampsia. Here is a 28 years old 2nd gravidae with twin pregnancy at 31 weeks hospitalized with HMSN TYPE-2 disease and was managed successfully with good feto maternal outcome

  2. Leber's Hereditary Optic Neuropathy: A Case Report

    Directory of Open Access Journals (Sweden)

    Chi-Wu Chang

    2003-10-01

    Full Text Available Leber's hereditary optic neuropathy (LHON is a maternally inherited mitochondrial disease that primarily affects the optic nerve, causing bilateral vision loss in juveniles and young adults. A 12-year-old boy had complained of blurred vision in both eyes for more than 1 year. His best-corrected visual acuity was 0.08 in the right eye and 0.1 in the left. Ophthalmologic examination showed bilateral optic disc hyperemia and margin blurring, peripapillary telangiectasis, and a relative afferent pupil defect in his right eye. Fluorescein angiography showed no stain or leakage around the optic disc in the late phase. Visual field analysis showed central scotoma in the left eye and a near-total defect in the right. Upon examination of the patient's mitochondrial DNA, a point mutation at nucleotide position 11778 was found, and the diagnosis of LHON was confirmed. Coenzyme Q10 was used to treat the patient.

  3. Leber hereditary optic neuropathy: current perspectives

    Science.gov (United States)

    Meyerson, Cherise; Van Stavern, Greg; McClelland, Collin

    2015-01-01

    Leber hereditary optic neuropathy (LHON) is one of the most common inherited optic neuropathies causing bilateral central vision loss. The disorder results from point mutations in mitochondrial DNA and subsequent mitochondrial dysfunction. The primary cell type that is lost in LHON is the retinal ganglion cell, which is highly susceptible to disrupted ATP production and oxidative stress. Inheritance of LHON follows that of mitochondrial genetics, and it has a highly variable clinical phenotype, as other genetic and environmental factors also play a role. Although LHON usually presents with isolated vision loss, some patients suffer other neurological sequelae. For ill-defined reasons, male LHON mutation carriers are more affected than females. Most LHON patients remain legally blind, but a small proportion can experience spontaneous partial recovery, often within the first year of symptom onset. Unfortunately, at this time there are no established curative interventions and treatment is largely supportive. Patients should be offered low vision services and counseled on mitigating risk factors for additional vision loss, such as smoking and consuming alcohol. Encouraging treatments currently undergoing investigation includes ubiquinone analogs, such as idebenone, as well as gene therapy and stem cells to restore ATP synthesis and provide neuroprotection to surviving retinal ganglion cells. PMID:26170609

  4. Genotype–phenotype correlations in Leber hereditary optic neuropathy

    National Research Council Canada - National Science Library

    Tońska, Katarzyna; Kodroń, Agata; Bartnik, Ewa

    2010-01-01

    Leber hereditary optic neuropathy (LHON), acute or subacute vision loss due to retinal ganglion cell death which in the long run leads to optic nerve atrophy is one of the most widely studied maternally inherited diseases caused...

  5. Leber's hereditary optic neuropathy and vitamin B12 deficiency

    NARCIS (Netherlands)

    Pott, Jan Willem R.; Wong, Kwok H.

    2006-01-01

    Background: Leber's hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy caused by mutations in mitochondrial DNA (mtDNA). It is also believed that several epigenetic factors have an influence on the development of LHON. Methods: A case series was observed. Results: Three

  6. Hereditary And Acquired Chronic Demyelination Neuropathies : A Clinical, electrophysiological And Histopathological Study

    Directory of Open Access Journals (Sweden)

    Menon A

    1999-01-01

    Full Text Available Differentiating hereditary motor sensory neuropathy (HMSN from chronic inflammatory demyelinating polyneuropathy (CIDP is often difficult especially when the disease starts at an early age and has protracted course. This study compares the clinical, electro, physiological and histopathological features of hereditary and acquired chronic demyelinating neuropathies. Records of 26 patients of chronic demyelinating neuropathy who underwent sural nerve biopsy were reviewed; HMSN 9, CIDP 13, chronic relapsing demyelinating polyneuropathy (CRDP-4, Salient features of the HMSN group were: Consanguineous parentage-4, onset in first decade-9, skeletal markers-7, absence of positive sensory symptoms- 7 and clinically thickened nerves-6. None of the patients with acquired neuropathy had skeletal markers, 11 had positive sensory symptoms and only 4 had nerve thickening. Electrophysiological evaluation in 22 motor nerves in the HMSN group revealed: inexcitable nerves -13, prolonged distal latency - 6, slow conduction velocity-8 and prolonged f wave latency-3. The 44 motor nerves in patients with acquired neuropathy showed: inexcitable nerves- 7, prolonged distal latency-35, slow conduction velocity-34, f wave prolongation-30 and conduction block 9. Elevated CSF protein was noticed only in acquired group (77%. Pathologically in HMSN the fibre loss was always diffuse and onion bulb formation was frequent while endoneural edema and inflammatory infiltration were absent in this group. Selection of patients with chronic demyelinating neuropathies for therapeutic modulation needs comprehensive clinical and laboratory evaluation.

  7. Childhood-onset Leber hereditary optic neuropathy.

    Science.gov (United States)

    Majander, Anna; Bowman, Richard; Poulton, Joanna; Antcliff, Richard J; Reddy, M Ashwin; Michaelides, Michel; Webster, Andrew R; Chinnery, Patrick F; Votruba, Marcela; Moore, Anthony T; Yu-Wai-Man, Patrick

    2017-11-01

    The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m.3460G>A, m.11778G>A or m.14484T>C. In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m.3460G>A and m.14484T>C mutations compared with the m.11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) ≥0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA <0.05 in their better seeing eye. Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  8. Leber's hereditary optic neuropathy: case report and literature review

    Directory of Open Access Journals (Sweden)

    Hélio Afonso Ghizoni Teive

    Full Text Available CONTEXT: Leber's hereditary optic neuropathy is an important cause of progressive painless visual loss among young male patients. OBJECTIVE: To report on a case of a young patient with a clinical and neurophysiological condition suggestive of Leber's hereditary optic neuropathy, confirmed by genetic testing. CASE REPORT: We describe a 17-year-old male with progressive bilateral visual loss. Two maternal uncles had had similar patterns of visual loss. The patient had a history of smoking and alcohol abuse. Neuro-ophthalmological examination revealed visual acuity of 20/800 in both eyes, with decreased direct and consensual pupillary light reflexes. Fundus examination demonstrated pale optic discs. The visual evoked potential test showed signs of conduction disturbances in both optic nerves and campimetric study showed complete visual loss in all fields of both eyes. A diagnosis of bilateral optic neuropathy with a clinical suspicion of Leber's hereditary optic neuropathy was made. A blood sample was submitted to genetic analysis in relation to the principal mutations of this disorder, and homoplasmic mutation in 11778 was detected, thereby confirming the diagnosis of Leber's hereditary optic neuropathy.

  9. Visual Rehabilitation of Persons with Leber's Hereditary Optic Neuropathy.

    Science.gov (United States)

    Rudanko, S.-L.

    1995-01-01

    This article presents results of a noncontrolled clinical study of 20 persons with Leber's hereditary optic neuropathy who were treated from 1976 to 1990 at the Low Vision Centre of the Finnish Federation of the Visually Handicapped. The importance of early functional visual rehabilitation is emphasized, as is the use of low vision aids to help…

  10. Gene-environment interactions in Leber hereditary optic neuropathy

    NARCIS (Netherlands)

    M.A. Kirkman; P. Yu-Wai-Man (Patrick); A. Korsten (Alex); M. Leonhardt (Miriam); K. Dimitriadis (Konstantin); I.F.M. de Coo (René); T. Klopstock (Thomas); P.F. Chinnery

    2009-01-01

    textabstractLeber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to

  11. Genetics Home Reference: hereditary sensory neuropathy type IA

    Science.gov (United States)

    ... hereditary sensory neuropathy type IA typically get open sores (ulcers) on their feet or hands or infections of the soft tissue of the fingertips (whitlows) that are slow to heal. Because affected ... of these sores, they may not seek immediate treatment. Without treatment, ...

  12. On the many faces of Leber hereditary optic neuropathy

    NARCIS (Netherlands)

    Oostra, R. J.; Tijmes, N. T.; Cobben, J. M.; Bolhuis, P. A.; van Nesselrooij, B. P.; Houtman, W. A.; de Kok-Nazaruk, M. M.; Bleeker-Wagemakers, E. M.

    1997-01-01

    Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder, associated with mutations in the mitochondrial DNA, which is notorious for its aspecific presentations. Two pedigrees are described with cases that are atypical for LHON with respect to sex, age of onset, interval between

  13. On the many faces of Leber hereditary optic neuropathy

    NARCIS (Netherlands)

    Oostra, RJ; Tijmes, NT; Cobben, JM; Bolhuis, PA; vanNesselrooij, BPM; Houtman, WA; deKokNazaruk, MM; BleekerWagemakers, EM

    Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder, associated with mutations in the mitochondrial DNA, which is notorious for its aspecific presentations. Two pedigrees are described with cases that are atypical for LHON with respect to sex, age of onset, interval between

  14. Clinical and Molecular Characterization of BSCL2 Mutations in a Taiwanese Cohort with Hereditary Neuropathy.

    Directory of Open Access Journals (Sweden)

    Cheng-Tsung Hsiao

    Full Text Available A small group of patients with inherited neuropathy that has been shown to be caused by mutations in the BSCL2 gene. However, little information is available about the role of BSCL2 mutations in inherited neuropathies in Taiwan.Utilizing targeted sequencing, 76 patients with molecularly unassigned Charcot-Marie-Tooth disease type 2 (CMT2 and 8 with distal hereditary motor neuropathy (dHMN, who were selected from 348 unrelated patients with inherited neuropathies, were screened for mutations in the coding regions of BSCL2. Two heterozygous BSCL2 mutations, p.S90L and p.R96H, were identified, of which the p.R96H mutation is novel. The p.S90L was identified in a pedigree with CMT2 while the p.R96H was identified in a patient with apparently sporadic dHMN. In vitro studies demonstrated that the p.R96H mutation results in a remarkably low seipin expression and reduced cell viability.BSCL2 mutations account for a small number of patients with inherited neuropathies in Taiwan. The p.R96H mutation is associated with dHMN. This study expands the molecular spectrum of BSCL2 mutations and also emphasizes the pathogenic role of BSCL2 mutations in molecularly unassigned hereditary neuropathies.

  15. Neuromyelitis optica antibody in Leber hereditary optic neuropathy: case report.

    Science.gov (United States)

    Simão, Luciano Mesquita

    2012-01-01

    Neuromyelitis optica antibody (or aquaporin-4 antibody) is a well established serum marker associated to high-risk neuromyelitis optica syndrome that presents as an inflammatory demyelinating disease characterized by the occurrence of bilateral and simultaneous optic neuritis without complete visual recovery or it occurs as an isolated episode of transverse myelitis accompanied by longitudinally extensive spinal cord lesions. On the other hand, Leber hereditary optic neuropathy is a primarily hereditary disorder that affects all tissues of the body and its clinical presentation is tissue-specific for the optic nerve and, eventually, it might reach the spinal cord. Overlapping clinical features of neuromyelitis optica and Leber hereditary optic neuropathy may suggest common target organ diseases. The case report described herein emphasizes the coexistence of serum markers of both diseases, and suggests that further investigation of this challenging clinical presentation is warranted to confirm or rule out this association.

  16. Neuromyelitis optica antibody in Leber hereditary optic neuropathy: case report

    Directory of Open Access Journals (Sweden)

    Luciano Mesquita Simão

    2012-08-01

    Full Text Available Neuromyelitis optica antibody (or aquaporin-4 antibody is a well stablished serum marker associated to high-risk neuromyelitis optica syndrome that presents as an inflammatory demyelinating disease characterized by the occurrence of bilateral and simultaneous optic neuritis without complete visual recovery or it occurs as an isolated episode of transverse myelitis accompanied by longitudinally extensive spinal cord lesions. On the other hand, Leber hereditary optic neuropathy is a primarily hereditary disorder that affects all tissues of the body and its clinical presentation is tissue-specific for the optic nerve and, eventually, it might reach the spinal cord. Overlapping clinical features of neuromyelitis optica and Leber hereditary optic neuropathy may suggest common target organ diseases. The case report described herein emphasizes the coexistence of serum markers of both diseases, and suggests that further investigation of this challenging clinical presentation is warranted to confirm or rule out this association.

  17. Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies.

    Science.gov (United States)

    Tey, S; Ahmad-Annuar, A; Drew, A P; Shahrizaila, N; Nicholson, G A; Kennerson, M L

    2016-08-01

    The cytoplasmic dynein-dynactin genes are attractive candidates for neurodegenerative disorders given their functional role in retrograde transport along neurons. The cytoplasmic dynein heavy chain (DYNC1H1) gene has been implicated in various neurodegenerative disorders, and dynactin 1 (DCTN1) genes have been implicated in a wide spectrum of disorders including motor neuron disease, Parkinson's disease, spinobulbar muscular atrophy and hereditary spastic paraplegia. However, the involvement of other dynactin genes with inherited peripheral neuropathies (IPN) namely, hereditary sensory neuropathy, hereditary motor neuropathy and Charcot-Marie-Tooth disease is under reported. We screened eight genes; DCTN1-6 and ACTR1A and ACTR1B in 136 IPN patients using whole-exome sequencing and high-resolution melt (HRM) analysis. Eight non-synonymous variants (including one novel variant) and three synonymous variants were identified. Four variants have been reported previously in other studies, however segregation analysis within family members excluded them from causing IPN in these families. No variants of disease significance were identified in this study suggesting the dynactin genes are unlikely to be a common cause of IPNs. However, with the ease of querying gene variants from exome data, these genes remain worthwhile candidates to assess unsolved IPN families for variants that may affect the function of the proteins. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Multifocal motor neuropathy and muscle hypertrophy.

    Science.gov (United States)

    Geevasinga, N; Day, B; Ng, K

    2013-11-01

    Multifocal motor neuropathy is frequently an asymmetrical neuropathy predominantly affecting the upper limbs. Patients present with weakness, fasciculations and distal muscle wasting. Hypertrophy of muscles is very infrequently reported. We present two cases of multifocal motor neuropathy with upper limb muscle hypertrophy and discuss possible pathophysiological mechanisms. Botulinum toxin may be useful to alleviate cramp. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

  19. Differentiating Leber Hereditary Optic Neuropathy from Normal-Tension Glaucoma.

    Science.gov (United States)

    Souto, Fernanda Maria Silveira; de Vasconcellos, José Paulo Cabral; de Melo, Mônica Barbosa; Sartorato, Edi Lúcia; Moura, Frederico Castelo

    2017-04-01

    Glaucoma is a neurodegenerative disorder characterized by thinning of neuroretinal rim, enlarged cup-to-disc ratio (CDR) and visual field damage. Although raised intraocular pressure is main risk factor for development of glaucoma, it can occur with consistently normal measurements in the intraocular pressure as normal tension glaucoma (NTG). Enlargement of CDR is a classical sign of glaucoma, but it can also result from non-glaucomatous optic neuropathies such as Leber hereditary optic neuropathy (LHON). We describe a case of LHON with increased CDR, discuss its differential diagnosis with NTG and highlight the reasons for misdiagnoses between these two entities.

  20. Ultrasound pattern sum score, homogeneity score and regional nerve enlargement index for differentiation of demyelinating inflammatory and hereditary neuropathies.

    Science.gov (United States)

    Grimm, Alexander; Vittore, Debora; Schubert, Victoria; Lipski, Christina; Heiling, Bianka; Décard, Bernhard F; Axer, Hubertus

    2016-07-01

    To investigate the use of nerve ultrasound in the differentiation between Charcot-Marie Tooth hereditary neuropathy (CMT1) and chronic inflammatory demyelinating polyradiculoneuropathies (CIDP), multifocal motor neuropathy (MMN) and multifocal acquired demyelinating sensory and motor neuropathies (MADSAM). Ultrasound/electrophysiology of predefined nerves was performed in CMT1a/b, immunoneuropathies, and healthy controls. Ultrasound pattern sum score (UPSS, sum of the amount of 12 predefined measurement points), homogeneity score (HS) and regional nerve enlargement index (RNEI) in ulnar, median, and tibial nerve were used for evaluation of morphology. 13 CMT1, 27 CIDP, 10 MADSAM, 12 MMN, and 23 controls were included. Significant enlargement was shown in all neuropathies compared to the controls, (pdemyelinating neuropathies is operationalized and ameliorated compared to CSA measurements only. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  1. Antiretroviral therapy-induced Leber’s hereditary optic neuropathy

    Directory of Open Access Journals (Sweden)

    Anand Moodley

    2014-05-01

    Full Text Available Optic neuropathy in HIV-infected patients results from the HIV infection itself, post-infectious auto-immune disease, opportunistic infections and drugs. Nucleoside reverse transcriptase inhibitors (NRTIs such as zidovudine and stavudine have known mitochondrial toxicity and can cause mitochondrial myopathies, neuropathies, hyperlactataemia, and can induce mitochondrial genetic disorders. Individuals with the mutation for Leber’s hereditary optic neuropathy (LHON, a mitochondrial disorder, are usually asymptomatic but develop visual loss when exposed to external triggers such as smoking. We report on two HIV-infected patients with LHON mutations (m.14484T>C and m.11778G>A who developed profound visual loss with antiretroviral therapy. We postulate that the phenotypic expression of LHON in these genetically predisposed individuals was triggered by NRTI drugs lamivudine and tenofovir when used in combination, despite their relatively weak mitochondrial toxic effects. 

  2. A MELAS-associated ND1 mutation causing leber hereditary optic neuropathy and spastic dystonia.

    NARCIS (Netherlands)

    Spruijt, L.; Smeets, H.J.M.; Hendrickx, A.; Bettink-Remeijer, M.W.; Maat-Kievit, A.; Schoonderwoerd, K.C.; Sluiter, W.; Coo, I.F.M. de; Hintzen, R.Q.

    2007-01-01

    OBJECTIVE: To report a novel mutation that is associated with Leber hereditary optic neuropathy (LHON) within the same family affected by spastic dystonia. DESIGN: Leber hereditary optic neuropathy is a mitochondrial disorder characterized by isolated central visual loss. Of patients with LHON, 95%

  3. Atypical Leber Hereditary Optic Neuropathy: 18 Year Interval Between Eyes.

    Science.gov (United States)

    Ohden, Kaitlyn L; Tang, Peter H; Lilley, Chrystia C; Lee, Michael S

    2016-09-01

    A 5-year-old boy developed profound loss of vision in his right eye and was found to have a 11778 mitochondrial point mutation consistent with Leber hereditary optic neuropathy (LHON). He maintained 20/20 vision in the left eye for 18 years until age 23, when he experienced loss of vision in that eye. This 18 year interval between eye involvement in LHON is the longest reported to date and reinforces the variability in presentation and progression seen in this disease.

  4. Mitochondrial DNA Mutation Associated with Leber's Hereditary Optic Neuropathy

    Science.gov (United States)

    Wallace, Douglas C.; Singh, Gurparkash; Lott, Marie T.; Hodge, Judy A.; Schurr, Theodore G.; Lezza, Angela M. S.; Elsas, Louis J.; Nikoskelainen, Eeva K.

    1988-12-01

    Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.

  5. Leber Hereditary Optic Neuropathy: Bringing the Lab to the Clinic.

    Science.gov (United States)

    Rasool, Nailyn; Lessell, Simmons; Cestari, Dean M

    2016-01-01

    Leber hereditary optic neuropathy (LHON) was the first clinically characterized mitochondrial disorder. Since its first description in 1871, much has been discovered regarding the genetics and pathophysiology of the disease. This has enabled the development of in vitro cell and animal models that can be used to try to determine not only the effects of the genetic mutation upon the clinical phenotype but to also test potential novel therapies. Treatments for LHON have ranged from vitamins and minerals to immunosuppressants and, more recently, targeted gene therapy. This article reviews the pathophysiology and clinical features of LHON with a focus on translational research.

  6. Leber’s hereditary optic neuropathy - case report

    Directory of Open Access Journals (Sweden)

    Mirjana A. Janicijevic Petrovic

    2012-09-01

    Full Text Available Leber’s hereditary optic neuropathy is a neuro-ophthalmological entity characterized by acute or subacute bilateral, not simultaneous visual loss with centro cekal scotoma and occasional further visual improvement. This rare ophthalmological disease can be accompanied with dyschromatopsia. It is associated with a matrilineal inheritance pattern. Its diagnosis used to be solely clini¬cal, aided by imaging and neuro-physiological studies, until the advent of descriptions of mitochondrial biochemical abnormalities and genetic testing. We describe a case of 24 year old male with progressive painless deterioration of visual acuity and positive family history.

  7. A case of hereditary sensory autonomic neuropathy type IV

    Directory of Open Access Journals (Sweden)

    G P Prashanth

    2012-01-01

    Full Text Available Hereditary sensory autonomic neuropathy type IV (HSAN -IV, also known as congenital insensitivity to pain with anhidrosis, is a very rare condition that presents in infancy with anhidrosis, absence of pain sensation and self -mutilation. Developmental delay and mental retardation are usually present. Ultrastructural study of the peripheral nerves demonstrates loss of the unmyelinated and small myelinated fibers. We here report a 8 year -old boy with HSAN IV with typical clinical features where the diagnosis was supported by nerve biopsy findings. However, our case was unusual since mental development was normal.

  8. Hereditary motor and sensory neuropathy with congenital glaucoma: report on a family Neuropatia hereditária sensitivo-motora com glaucoma congênito: descrição de uma família

    Directory of Open Access Journals (Sweden)

    WALTER O. ARRUDA

    1999-06-01

    Full Text Available We report three siblings of a family with hereditary motor and sensory polyneuropathy (HMSN and buphthalmos. Electrophysiological studies showed a demyelinating neuropathy and pathological findings showed severe loss of myelinated fibers (MF, thin myelin sheaths and myelin infoldings in a few remaining MF. The presumed mode of inheritance is autosomal recessive. This family probably represents an unique form of CMT4 that may be related to one of the congenital glaucoma genic locus, particularly GLC3A and GLC3B, described in Turkish families.Descrevemos três membros afetados de uma família com neuropatia hereditária sensitivo-motora tipo I (desmielinizante e glaucoma congênito (buftalmia. O estudo eletrofisiológico dos membros afetados demonstrou polineuropatia sensitivo-motora desmielinizante, com ausência ou redução acentuada das velocidades de neurocondução sensitiva e motora. A biópsia do nervo sural revelou redução moderada a grave das fibras mielinizadas, bainhas de mielina de espessura diminuída (remielinização com dobramentos delas nas poucas fibras mielinizadas remanescentes. Não foram observadas formações em casca de cebola, nem tampouco alterações hipertróficas. O padrão de herança desta família parece ser autossômico recessivo. Sugerimos tratar-se de uma forma singular de doença de Charcot-Marie-Tooth autossômica recessiva (CMT4, que eventualmente pode possuir locus gênico próximo a um dos locus do glaucoma congênito (GLC3A e GLC3B, localizados nos cromossomos 2p21 e 1p36.

  9. Hereditary neuropathy with liability to pressure palsies: the first publication (1947).

    Science.gov (United States)

    Koehler, Peter J

    2003-04-08

    The first report of hereditary neuropathy with liability to pressure palsies (HNPP) was published in Dutch in 1947. The present paper makes it accessible in the English language. de Jong described two families, but only the cases from the first family may be considered to have had HNPP. Five persons from three generations had recurring peripheral neuropathies. de Jong hypothesized a hereditary disposition for the occurrence of neuropathies, but suggested a relationship with low vitamin B(1) levels.

  10. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies

    NARCIS (Netherlands)

    van Paassen, Barbara W.; van der Kooi, Anneke J.; van Spaendonck-Zwarts, Karin Y.; Verhamme, Camiel; Baas, Frank; de Visser, Marianne

    2014-01-01

    PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes. Overall prevalence of CMT is

  11. Hereditary Neuropathy with Liability to Pressure Palsy: A Recurrent and Bilateral Foot Drop Case Report

    Directory of Open Access Journals (Sweden)

    Filipa Flor-de-Lima

    2013-01-01

    Full Text Available Hereditary neuropathy with liability to pressure palsy is characterized by acute, painless, recurrent mononeuropathies secondary to minor trauma or compression. A 16-year-old boy had the first episode of right foot drop after minor motorcycle accident. Electromyography revealed conduction block and slowing velocity conduction of the right deep peroneal nerve at the fibular head. After motor rehabilitation, he fully recovered. Six months later he had the second episode of foot drop in the opposite site after prolonged squatting position. Electromyography revealed sensorimotor polyneuropathy of left peroneal, sural, posterior tibial, and deep peroneal nerves and also of ulnar, radial, and median nerves of both upper limbs. Histological examination revealed sensory nerve demyelination and focal thickenings of myelin fibers. The diagnosis of hereditary neuropathy with liability to pressure palsy was confirmed by PMP22 deletion of chromosome 17p11.2. He started motor rehabilitation and avoidance of stressing factors with progressive recovery. After one-year followup, he was completely asymptomatic. Recurrent bilateral foot drop history, “sausage-like” swellings of myelin in histological examination, and the results of electromyography led the authors to consider the diagnosis despite negative family history. The authors highlight this rare disease in pediatric population and the importance of high index of clinical suspicion for its diagnosis.

  12. Hereditary motor and sensory neuropathy (HMSN) IA, developmental delay and autism related disorder in a boy with duplication (17)(p11.2p12).

    Science.gov (United States)

    Moog, U; Engelen, J J; Weber, B W; Van Gelderen, M; Steyaert, J; Baas, F; Sijstermans, H M; Fryns, J P

    2004-01-01

    We present a 6-year-old boy with moderate developmental delay, gait disturbance, autism related disorder and mild dysmorphic features. He was seen for evaluation of his retardation since the age of 2.8 years. At first sight, a cytogenetic analysis showed a normal 46,XY karyotype. Neurological examination at the age of 5.5 years revealed a motor and sensory polyneuropathy. A quantitative Southern blot with probes PMP22 and VAW409 specific for Charcot-Marie-Tooth type 1 (CMT1) disclosed a duplication which confirmed the diagnosis HMSN Ia. Subsequently, GTG banded metaphases were re-evaluated and a small duplication 17p was seen on retrospect. Additional FISH with probe LSISMS (Vysis) specific for the Smith-Magenis region at 17p11.2 again showed a duplication. Both parents had a normal karyotype and the duplication test for CMT1 showed normal results for both of them. The boy had a de novo 46,XY,dup(17)(p11.2p12) karyotype. The present observation confirms previous findings of mild psychomotor delay, neurobehavioural features and minor craniofacial anomalies as the major phenotypic features of dup(17)(p11.2) and dup(17)(p11.2p12); in cases of duplications comprising the PMP22 locus HMSN1 is associated. A recognizable facial phenotype emerges characterized by a broad forehead, hypertelorism, downslant of palpebral fissures, smooth philtrum, thin upper lip and ear anomalies.

  13. Nationwide epidemiological survey of Leber hereditary optic neuropathy in Japan.

    Science.gov (United States)

    Ueda, Kaori; Morizane, Yuki; Shiraga, Fumio; Shikishima, Keigo; Ishikawa, Hitoshi; Wakakura, Masato; Nakamura, Makoto

    2017-09-01

    Leber hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy that leads to central loss of vision, predominantly in young males. Most LHON cases have one of three primary point mutations in mitochondrial DNA (mtDNA). The annual incidence and prevalence of LHON in Japan are not known. Thus, we estimated the annual incidence of molecularly confirmed LHON in Japan during 2014. Sequential questionnaires were sent to 1397 facilities, which included all of the university hospitals in Japan, and they were certified by either the Japanese Ophthalmological Society or the Japanese Neuro-Ophthalmological Society. We calculated the incidence number (Ir) as the number of patients who developed LHON in 2014 and its 95% confidence interval. We received 861 responses to the first questionnaire, where 49 facilities reported 72 cases (67 were male and 5 were female) of newly developed LHON during 2014. Ir was calculated as 117, and the 95% confidence interval ranged from 81 to 153. For the second questionnaire, responses were received from 30 facilities, where the median age at onset was 38 years for males and 30 years for females, and 86.5% of cases possessed the mtDNA ND4/G11778A mutation. Approximately 120 cases of newly developed LHON were reported during 2014 in Japan, and 93.2% were males. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  14. Nationwide epidemiological survey of Leber hereditary optic neuropathy in Japan

    Directory of Open Access Journals (Sweden)

    Kaori Ueda

    2017-09-01

    Full Text Available Background: Leber hereditary optic neuropathy (LHON is a maternally inherited optic neuropathy that leads to central loss of vision, predominantly in young males. Most LHON cases have one of three primary point mutations in mitochondrial DNA (mtDNA. The annual incidence and prevalence of LHON in Japan are not known. Thus, we estimated the annual incidence of molecularly confirmed LHON in Japan during 2014. Methods: Sequential questionnaires were sent to 1397 facilities, which included all of the university hospitals in Japan, and they were certified by either the Japanese Ophthalmological Society or the Japanese Neuro-Ophthalmological Society. We calculated the incidence number (Ir as the number of patients who developed LHON in 2014 and its 95% confidence interval. Results: We received 861 responses to the first questionnaire, where 49 facilities reported 72 cases (67 were male and 5 were female of newly developed LHON during 2014. Ir was calculated as 117, and the 95% confidence interval ranged from 81 to 153. For the second questionnaire, responses were received from 30 facilities, where the median age at onset was 38 years for males and 30 years for females, and 86.5% of cases possessed the mtDNA ND4/G11778A mutation. Conclusion: Approximately 120 cases of newly developed LHON were reported during 2014 in Japan, and 93.2% were males.

  15. The aqueous layers within the myelin sheath modulate the membrane properties of simulated hereditary demyelinating neuropathies.

    Science.gov (United States)

    Stephanova, D I; Krustev, S M; Daskalova, M

    2011-03-01

    To expand our studies on the mechanisms underlying the clinical decline of the nerve excitability properties in patients with hereditary demyelinating neuropathies, the contribution of myelin sheath aqueous layers on multiple membrane properties of simulated fiber demyelinations is investigated. Three progressively greater degrees of internodal systematic demyelinations (two mild and one severe termed as ISD1, ISD2 and ISD3, respectively) without/with aqueous layers are simulated using our previous multi-layered model of human motor nerve fiber. The calculated multiple membrane excitability properties are as follows: potentials (intracellular action, electrotonic), strength-duration time constants, rheobasic currents and recovery cycles. They reflect the propagating, accommodative and adaptive processes in the fibers. The results show that all membrane properties, except for the strength-duration time constants and refractoriness, worsen when the myelin lamellae and their corresponding aqueous layers are uniformly reduced along the fiber length. The effect of the aqueous layers is significantly higher on the accommodative and adaptive processes than on the propagating processes in the fibers. Our multi-layered model better approximated some of the functional deficits documented for axons of patients with Charcot-Marie-Tooth disease type 1A. The study provides new and important information on the mechanisms underlying the pathophysiology of hereditary demyelinating neuropathies. © Imperial College Press

  16. Early onset hereditary sensory autonomic neuropathy type I and not leprosy

    Directory of Open Access Journals (Sweden)

    Pande Sushil

    2009-01-01

    Full Text Available Hereditary sensory autonomic neuropathies (HSAN are rare forms of chronic neuropathies in children, which lead to severe complications like foot ulcers, mutilations, fractures and deformities. We report an eight years old female who presented with nonhealing perforating ulcer over anterior sole, resorption of terminal portion of right middle finger and hyperhidrosis over back since two years of age. Deep tendon reflexes were absent in lower legs but were preserved in upper limbs. Nerve conduction studies and nerve biopsy confirmed the diagnosis of HSAN, Type I. Early diagnosis of hereditary sensory neuropathy led to significant reduction in morbidity and hence improvement in the quality of life in our patient.

  17. Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia

    NARCIS (Netherlands)

    DeVries, DD; Went, LN; Bruyn, GW; Scholte, HR; Hofstra, RMW; Bolhuis, PA; vanOost, BA

    A rare form of Leber hereditary optic neuropathy (LHON) that is associated with hereditary spastic dystonia has been studied in a large Dutch family. Neuropathy and ophthalmological lesions were present together in some family members, whereas only one type of abnormality was found in others. mtDNA

  18. Leber hereditary optic neuropathy: bridging the translational gap.

    Science.gov (United States)

    Jurkute, Neringa; Yu-Wai-Man, Patrick

    2017-09-01

    Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) genetic disorder in the population. We address the clinical evolution of the disease, the secondary etiological factors that could contribute to visual loss, and the challenging task of developing effective treatments. LHON is characterized by a preclinical phase that reflects retinal ganglion cell (RGC) dysfunction before rapid visual deterioration ensues. Children can present atypically with slowly progressive visual loss or an insidious/subclinical onset that frequently results in considerable diagnostic delays. The LHON mtDNA mutation is not sufficient on its own to precipitate RGC loss and the current body of evidence supports a role for smoking and estrogen levels influencing disease conversion. Clinical trials are currently investigating the efficacy of adeno-associated viral vectors-based gene therapy approaches for patients carrying the m.11778G>A mutation. Mitochondrial replacement therapy is being developed as a reproductive option to prevent the maternal transmission of pathogenic mtDNA mutations. LHON is phenotypically more heterogeneous than previously considered and a complex interplay of genetic, environmental and hormonal factors modulates the risk of a LHON carrier losing vision. Advances in disease modelling, drug screening and genetic engineering offer promising avenues for therapeutic breakthroughs in LHON.

  19. Mitochondrial genetics and therapeutic overview of Leber's hereditary optic neuropathy

    Science.gov (United States)

    Manickam, Agaath Hedina; Michael, Minu Jenifer; Ramasamy, Sivasamy

    2017-01-01

    Leber's hereditary optic neuropathy (LHON) is a common inherited mitochondrial disorder that is characterized by the degeneration of the optic nerves, leading to vision loss. The major mutations in the mitochondrial genes ND1, ND4, and ND6 of LHON subjects are found to increase the oxidative stress experienced by the optic nerve cell, thereby leading to nerve cell damage. Accurate treatments are not available and drugs that are commercially available like Idebenone, EPI-743, and Bendavia with their antioxidant role help in reducing the oxidative stress experienced by the cell thereby preventing the progression of the disease. Genetic counseling plays an effective role in making the family members aware of the inheritance pattern of the disease. Gene therapy is an alternative for curing the disease but is still under study. This review focuses on the role of mitochondrial genes in causing LHON and therapeutics available for treating the disease. A systematic search has been adopted in various databases using the keywords “LHON,” “mitochondria,” “ND1,” “ND4,” “ND6,” and “therapy” and the following review on mitochondrial genetics and therapeutics of LHON has been developed with obtained articles from 1988 to 2017. PMID:29133631

  20. Leber’s Hereditary Optic Neuropathy: a Case Report

    Directory of Open Access Journals (Sweden)

    R. Daneshvar Kakhki

    2017-02-01

    Full Text Available Aims: One of the most prevalent mitochondrial genetic diseases is Leber disease. Most of the patients are with the bilateral ocular involvement, simultaneously in 25% and one after another in 75% of the patients with an average of 8-week involvement distance between two eyes. The aim of the study was to report a rare case of Leber disease with 11-year engagement distance between two eyes. Patient Profile: A 38 years old male patient, who had been hospitalized in autumn 2012 in Beheshti Hospital in Kashan, Iran, due to his left-eye vision loss, was studied. One day before referring to the hospital, his left-eye vision had gradually blurred, only could perceive light. The patient were with HBs Ag positive (Carrier, and was hypertensive from about one year before hospitalization. Based on the ophthalmoscopy results, the right-eye disc was lost and the left-eye disc was pale. Findings: At first, the patient received methylprednisolone pulse therapy, while no treatment response was observed after a 2-week therapy. Based on the genetic assessments of peripheral blood cells, the homoplastic 14233 mutation was diagnosed, confirming the clinical suspicion of Leber disease (LHON. The patient received 100mg a day Q10 coenzyme and multivitamin. Conclusion: The diagnosis of Leber hereditary optic neuropathy should be noticed in young men with bilateral optic atrophy.

  1. Leber's hereditary optic neuropathy is multiorgan not mono-organ.

    Science.gov (United States)

    Finsterer, Josef; Zarrouk-Mahjoub, Sinda

    2016-01-01

    Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder with bilateral loss of central vision primarily due to mitochondrial DNA (mtDNA) mutations in subunits of complex I in the respiratory chain (primary LHON mutations), while other mtDNA mutations can also be causative. Since the first description, it is known that LHON is not restricted to the eyes but is a multisystem disorder additionally involving the central nervous system, ears, endocrinological organs, heart, bone marrow, arteries, kidneys, or the peripheral nervous system. Multisystem involvement may start before or after the onset of visual impairment. Involvement of organs other than the eyes may be subclinical depending on age, ethnicity, and possibly the heteroplasmy rate of the responsible primary LHON mutation. Primary LHON mutations may rarely manifest without ocular compromise but with arterial hypertension, various neurodegenerative diseases, or Leigh syndrome. Patients with LHON need to be closely followed up to detect at which point organs other than the eyes become affected. Multiorgan disease in LHON often responds more favorably to symptomatic treatment than the ocular compromise.

  2. Gene-environment interactions in Leber hereditary optic neuropathy.

    Science.gov (United States)

    Kirkman, Matthew Anthony; Yu-Wai-Man, Patrick; Korsten, Alex; Leonhardt, Miriam; Dimitriadis, Konstantin; De Coo, Ireneaus F; Klopstock, Thomas; Chinnery, Patrick Francis

    2009-09-01

    Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460G>A, m.11778G>A and m.14484T>C. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake.

  3. Investigation of auditory dysfunction in Leber hereditary optic neuropathy.

    Science.gov (United States)

    Yu-Wai-Man, Patrick; Elliott, Clive; Griffiths, Philip G; Johnson, Ian J; Chinnery, Patrick F

    2008-09-01

    To investigate the possibility of auditory dysfunction in patients with Leber hereditary optic neuropathy (LHON). We prospectively recruited 10 affected patients from the north-east of England harbouring one of the three primary mitochondrial LHON mutations (3460G>A n = 3, 11778G>A n = 5 and 14484T>C n = 2). A detailed auditory history was taken and they were asked to complete a validated hearing questionnaire. Each patient then underwent a comprehensive topographic neuroauditory assessment to evaluate both middle- and inner-ear functions and the integrity of the brainstem auditory pathways. We found no evidence of cochlear nerve dysfunction or abnormalities of the central brainstem auditory pathways in our LHON cohort and five patients had completely normal hearing tests. The remainder had mild conductive hearing loss from childhood ear infections and/or high-frequency sensorineural hearing loss from previous noise injury. Although further studies are required to confirm our findings, auditory dysfunction as a result of a primary LHON mutation is probably uncommon.

  4. Mitochondrial genetics and therapeutic overview of Leber's hereditary optic neuropathy

    Directory of Open Access Journals (Sweden)

    Agaath Hedina Manickam

    2017-01-01

    Full Text Available Leber's hereditary optic neuropathy (LHON is a common inherited mitochondrial disorder that is characterized by the degeneration of the optic nerves, leading to vision loss. The major mutations in the mitochondrial genes ND1, ND4, and ND6 of LHON subjects are found to increase the oxidative stress experienced by the optic nerve cell, thereby leading to nerve cell damage. Accurate treatments are not available and drugs that are commercially available like Idebenone, EPI-743, and Bendavia with their antioxidant role help in reducing the oxidative stress experienced by the cell thereby preventing the progression of the disease. Genetic counseling plays an effective role in making the family members aware of the inheritance pattern of the disease. Gene therapy is an alternative for curing the disease but is still under study. This review focuses on the role of mitochondrial genes in causing LHON and therapeutics available for treating the disease. A systematic search has been adopted in various databases using the keywords “LHON,” “mitochondria,” “ND1,” “ND4,” “ND6,” and “therapy” and the following review on mitochondrial genetics and therapeutics of LHON has been developed with obtained articles from 1988 to 2017.

  5. Cold paresis in multifocal motor neuropathy

    OpenAIRE

    Straver, Dirk C. G.; van Asseldonk, Jan-Thies H.; Notermans, Nicolette C.; Wokke, John H. J.; van den Berg, Leonard H.; Franssen, Hessel

    2010-01-01

    Increased weakness during cold (cold paresis) was reported in single cases of multifocal motor neuropathy (MMN). This was unexpected because demyelination is a feature of MMN and symptoms of demyelination improve, rather than worsen, in cold. It was hypothesized that cold paresis in MMN does not reflect demyelination only, but may indicate the existence of inflammatory nerve lesions with permanently depolarized axons that only just conduct at normal temperature, but fail at lower temperatures...

  6. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort.

    LENUS (Irish Health Repository)

    Davidson, G L

    2012-08-01

    The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1\\/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1\\/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.

  7. [Leber's hereditary optic neuropathy - phenotype, genetics, therapeutic options].

    Science.gov (United States)

    Gallenmüller, C; Klopstock, T

    2014-03-01

    Leber's hereditary optic neuropathy is a rare genetic disorder affecting the retinal ganglion cells leading to a persistent severe bilateral loss of visual acuity within weeks or months. Males are much more likely to be affected than females, disease onset in most cases takes place between age 15 and 35 years. The disease is caused by point mutations in the mitochondrial DNA. The penetrance of the disease is incomplete, i.e., not all mutation carriers develop clinical symptoms. The phenotype is relatively uniform, but age at onset, severity and prognosis may vary even within the same family. Environmental and endocrine factors, optic disc anatomy as well as mitochondrial and nuclear genetic factors are discussed to influence penetrance as well as interindividual and intrafamilial variability. However, only cigarette smoking and excessive alcohol consumption have been shown to trigger disease onset. The disease is characterised by a central visual field defect, impaired colour vision and fundoscopically a peripapillary microangiopathy in the acute phase. Most patients end up after some months with a severe visual loss below 0.1 and in most cases there is no significant improvement of visual acuity in the course. In rare cases patients experience a mostly partial visual recovery which depends on the type of mutation. For confirmation of the diagnosis a detailed ophthalmological examination with fundoscopy, family history and genetic analysis of the mitochondrial DNA is needed. To date, there is no proven causal therapy, but at early disease stages treatment with idebenone can be tried. Georg Thieme Verlag KG Stuttgart · New York.

  8. Secondary post-geniculate involvement in Leber's hereditary optic neuropathy.

    Directory of Open Access Journals (Sweden)

    Giovanni Rizzo

    Full Text Available Leber's hereditary optic neuropathy (LHON is characterized by retinal ganglion cell (RGC degeneration with the preferential involvement of those forming the papillomacular bundle. The optic nerve is considered the main pathological target for LHON. Our aim was to investigate the possible involvement of the post-geniculate visual pathway in LHON patients. We used diffusion-weighted imaging for in vivo evaluation. Mean diffusivity maps from 22 LHON visually impaired, 11 unaffected LHON mutation carriers and 22 healthy subjects were generated and compared at level of optic radiation (OR. Prefrontal and cerebellar white matter were also analyzed as internal controls. Furthermore, we studied the optic nerve and the lateral geniculate nucleus (LGN in post-mortem specimens obtained from a severe case of LHON compared to an age-matched control. Mean diffusivity values of affected patients were higher than unaffected mutation carriers (P<0.05 and healthy subjects (P<0.01 in OR and not in the other brain regions. Increased OR diffusivity was associated with both disease duration (B = 0.002; P<0.05 and lack of recovery of visual acuity (B = 0.060; P<0.01. Post-mortem investigation detected atrophy (41.9% decrease of neuron soma size in the magnocellular layers and 44.7% decrease in the parvocellular layers and, to a lesser extent, degeneration (28.5% decrease of neuron density in the magnocellular layers and 28.7% decrease in the parvocellular layers in the LHON LGN associated with extremely severe axonal loss (99% in the optic nerve. The post-geniculate involvement in LHON patients is a downstream post-synaptic secondary phenomenon, reflecting de-afferentation rather than a primary neurodegeneration due to mitochondrial dysfunction of LGN neurons.

  9. Molecular epidemiology of Leber hereditary optic neuropathy in Xingtai China

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    Shi-Peng Xie

    2016-04-01

    Full Text Available AIM:To estimate the prevalence and molecular epidemiology of Leber hereditary optic neuropathy(LHONin the south of North China.METHODS:Patients suspected with LHON who went to Hebei Ophthalmic Hospital(formerly Xingtai Eye Hospitalfrom December 2001 to December 2014, were conducted mtDNA(mitochondrial DNAscreening. The patients whose origin were Xingtai, the sourth of North China, were screened out. The LHON families were given detailed follow-up, pedigree investigation and examinations of visual acuity, fundus, color vision, visual field and other clinical exam to diagnose the sick ones in the pedigrees. We took the resident population which date was from the sixth national census in 2010 in Xingtai area as the base, then conducted statistically analysis for those pedigrees to roughly estimate the incidence and molecular genetics characteristics of LHON in this area.RESULTS:From December 2001 to December 2014, the 463 people from four generations in 33 LHON families were investigated, and 72 patients were diagnosed as LHON, 65 males and 7 females. One patient was found with mutation at T3866C,60 at G11778A,8 at T14484C,2 at G11696A+G11778A, and 1 at G3460A. In the sixth national census in 2010, the population aged 0~64 in Xingtai area was 6 592 466, and the prevalence of LHON was 1.092/100 000(95%CI:0.964~1.22/100 000, and the incidence of G11778A, which was the most common one, was 0.91/100 000(95%CI:0.79~1.03/100 000.CONCLUSION:The incidence of LHON in Xingtai China is high, the lower limit of prevalence is about 1.092/100 000, and the ND4 is the hot spot region. The mutation at G11778A is the most common one. Male patients were significantly more than female patients.

  10. Cardiac arrest after anesthetic management in a patient with hereditary sensory autonomic neuropathy type IV

    Directory of Open Access Journals (Sweden)

    Ergül Yakup

    2011-01-01

    Full Text Available Hereditary sensory autonomic neuropathy type IV is a rare disorder with an autosomal recessive transmission and characterized by self-mutilation due to a lack in pain and heat sensation. Recurrent hyperpyrexia and anhydrosis are seen in patients as a result of a lack of sweat gland innervation. Self-mutilation and insensitivity to pain result in orthopedic complications and patients undergone recurrent surgical interventions with anesthesia. However, these patients are prone to perioperative complications such as hyperthermia, hypothermia, and cardiac complications like bradycardia and hypotension. We report a 5-year-old boy with hereditary sensory autonomic neuropathy type IV, developing hyperpyrexia and cardiac arrest after anesthesia.

  11. The metabolomic signature of Leber's hereditary optic neuropathy reveals endoplasmic reticulum stress.

    Science.gov (United States)

    Chao de la Barca, Juan Manuel; Simard, Gilles; Amati-Bonneau, Patrizia; Safiedeen, Zainab; Prunier-Mirebeau, Delphine; Chupin, Stéphanie; Gadras, Cédric; Tessier, Lydie; Gueguen, Naïg; Chevrollier, Arnaud; Desquiret-Dumas, Valérie; Ferré, Marc; Bris, Céline; Kouassi Nzoughet, Judith; Bocca, Cinzia; Leruez, Stéphanie; Verny, Christophe; Miléa, Dan; Bonneau, Dominique; Lenaers, Guy; Martinez, M Carmen; Procaccio, Vincent; Reynier, Pascal

    2016-11-01

    Leber's hereditary optic neuropathy (MIM#535000), the commonest mitochondrial DNA-related disease, is caused by mutations affecting mitochondrial complex I. The clinical expression of the disorder, usually occurring in young adults, is typically characterized by subacute, usually sequential, bilateral visual loss, resulting from the degeneration of retinal ganglion cells. As the precise action of mitochondrial DNA mutations on the overall cell metabolism in Leber's hereditary optic neuropathy is unknown, we investigated the metabolomic profile of the disease. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites in fibroblasts from 16 patients with Leber's hereditary optic neuropathy and eight healthy control subjects. Latent variable-based statistical methods were used to identify discriminating metabolites. One hundred and twenty-four of the metabolites were considered to be accurately quantified. A supervised orthogonal partial least squares discriminant analysis model separating patients with Leber's hereditary optic neuropathy from control subjects showed good predictive capability (Q 2cumulated = 0.57). Thirty-eight metabolites appeared to be the most significant variables, defining a Leber's hereditary optic neuropathy metabolic signature that revealed decreased concentrations of all proteinogenic amino acids, spermidine, putrescine, isovaleryl-carnitine, propionyl-carnitine and five sphingomyelin species, together with increased concentrations of 10 phosphatidylcholine species. This signature was not reproduced by the inhibition of complex I with rotenone or piericidin A in control fibroblasts. The importance of sphingomyelins and phosphatidylcholines in the Leber's hereditary optic neuropathy signature, together with the decreased amino acid pool, suggested an involvement of the endoplasmic reticulum. This was confirmed by the significantly increased phosphorylation of PERK and eIF2α, as well as

  12. Progress of the factors influencing the penetrance of Leber's hereditary optic neuropathy

    Directory of Open Access Journals (Sweden)

    Jun-Wei Zhong

    2015-11-01

    Full Text Available Leber's hereditary optic neuropathy(LHONis a maternally inherited blinding disease. The clinical phenotype of LHON is the degeneration of retinal ganglion cells(RGCsand a progressive degeneration of the optic nerve. Three common mutations, G11778A, T14484C and G3460A are responsible for over 90% of cases. Differences in penetrance indicate the additional modifier genes influencing penetrance of the mitochondrial DNA mutation for LHON patients. Different types of mitochondrial haplogroups, environmental factors also have different effects on the penetrance of the mitochondrial DNA mutations. In the present paper, here the progress of the factors influencing the penetrance of Leber's hereditary optic neuropathy will be summarized.

  13. Vision improvement in a Taiwanese (Han Chinese family with Leber's hereditary optic neuropathy

    Directory of Open Access Journals (Sweden)

    Hong-Zin Lin

    2012-12-01

    Full Text Available In this report, we describe a Taiwanese (Han Chinese family with Leber's hereditary optic neuropathy. The family carried a mitochondrial DNA mutation (mtDNA m.14484T>C associated with spontaneous visual improvement. A 15-year-old boy from this family was diagnosed with Leber's hereditary optic neuropathy 6 months after losing his vision. His vision recovered after 8 months of supportive treatment. His mother, older brother, and two sisters also had the same mutation and had previously experienced vision loss. In this family, there was no male predominance.

  14. Multifocal Motor Neuropathy Associated with Infliximab.

    Science.gov (United States)

    Rowan, Catherine R; Tubridy, Niall; Cullen, Garret

    2015-12-01

    The anti-tumour necrosis factor [TNF] monoclonal antibody, infliximab, is commonly prescribed in both ulcerative colitis and Crohn's disease. Neurological side effects such as optic neuritis are well recognised, although not as frequently seen as hypersensitivity and serious infections. We present a case of peripheral neuropathy in a young man on infliximab therapy for ulcerative colitis. This presented as an asymmetrical and slowly progressive weakness in his right upper limb, severely impacting on function. Investigations confirmed a diagnosis of multifocal motor neuropathy [MMN]. This has been previously described in patients receiving infliximab for rheumatological conditions. The exact mechanism is unclear, but the neuropathy responds well to intravenous immunoglobulin. In our case, infliximab was discontinued. The patient was treated with immunoglobin for 5 days and recovered rapidly. Mercaptopurine was instituted as maintanence therapy, with good effect. Gastroenterologists prescribing infliximab should be cognisant of both peripheral and central neurological complications, ensuring prompt withdrawal of the offending agent and appropriate alternative treatment. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  15. Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results.

    Science.gov (United States)

    Feuer, William J; Schiffman, Joyce C; Davis, Janet L; Porciatti, Vittorio; Gonzalez, Phillip; Koilkonda, Rajeshwari D; Yuan, Huijun; Lalwani, Anil; Lam, Byron L; Guy, John

    2016-03-01

    Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADH:ubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome. In this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. The first 3 participants were treated at the low dose of vector (5 × 10(9) vg), and the fourth participant was treated at the medium dose (2.46 × 10(10) vg). The fifth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. Five legally blind patients with G11778A LHON. Loss of visual acuity. Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative

  16. Congenital talipes equinovarus associated with hereditary congenital common peroneal nerve neuropathy: a literature review.

    Science.gov (United States)

    Matar, Hosam E; Garg, Neeraj K

    2016-03-01

    We present a unique case of a congenital hereditary common peroneal nerve neuropathy with congenital idiopathic congenital talipes equinovarus that had been treated with the Ponseti method with satisfactory outcome at 5-year follow-up, along with a literature review.

  17. LEBERS HEREDITARY OPTIC NEUROPATHY - CORRELATIONS BETWEEN MITOCHONDRIAL GENOTYPE AND VISUAL OUTCOME

    NARCIS (Netherlands)

    OOSTRA, RJ; BOLHUIS, PA; WIJBURG, FA; ZORNENDE, G; BLEEKERWAGEMAKERS, EM

    Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease associated with mitochondrial DNA (mtDNA) mutations. We describe the distribution of seven different mtDNA mutations and the clinical findings in 334 LHON patients belonging to 29 families. Mutations described only in LHON

  18. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background.

    NARCIS (Netherlands)

    Hudson, G.; Carelli, V.; Spruijt, L.; Gerards, M.; Mowbray, C.; Achilli, A.; Pyle, A.; Elson, J.; Howell, N.; Morgia, C. La; Valentino, M.L.; Huoponen, K.; Savontaus, M.L.; Nikoskelainen, E.; Sadun, A.A.; Salomao, S.R.; Belfort Jr, R.; Griffiths, P.; Man, P.Y.; Coo, R.F. de; Horvath, R.; Zeviani, M.; Smeets, H.J.M.; Torroni, A.; Chinnery, P.F.

    2007-01-01

    Leber hereditary optic neuropathy (LHON) is due primarily to one of three common point mutations of mitochondrial DNA (mtDNA), but the incomplete penetrance implicates additional genetic or environmental factors in the pathophysiology of the disorder. Both the 11778G-->A and 14484T-->C LHON

  19. Genes for Hereditary Sensory and Autonomic Neuropathies: A Genotype-Phenotype Correlation

    Science.gov (United States)

    Rotthier, Annelies; Baets, Jonathan; De Vriendt, Els; Jacobs, An; Auer-Grumbach, Michaela; Levy, Nicolas; Bonello-Palot, Nathalie; Kilic, Sara Sebnem; Weis, Joachim; Nascimento, Andres; Swinkels, Marielle; Kruyt, Moyo C.; Jordanova, Albena; De Jonghe, Peter; Timmerman, Vincent

    2009-01-01

    Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant ("SPTLC1"…

  20. Rapid shift in genotype of human mitochondrial DNA in a family with Leber's hereditary optic neuropathy

    NARCIS (Netherlands)

    Bolhuis, P. A.; Bleeker-Wagemakers, E. M.; Ponne, N. J.; van Schooneveld, M. J.; Westerveld, A.; van den Bogert, C.; Tabak, H. F.

    1990-01-01

    Mitochondrial DNA isolated from white blood cells was investigated in families suffering from Leber's hereditary optic neuropathy. A recently described mutation at nucleotide position 11778 was present in 5 out of 12 families and heteroplasmic mitochondrial DNA was observed in 2 of these 5 families.

  1. Influence of mutation type on clinical expression of Leber hereditary optic neuropathy

    NARCIS (Netherlands)

    Spruijt, Liesbeth; Kolbach, Dinanda N.; de Coo, Rene F.; Plomp, Astrid S.; Bauer, Noel J.; Smeets, Hubertus J.; de Die-Smulders, Christine E. M.

    2006-01-01

    The aim of this research was to determine the molecular factors of influence on the clinical expression of Leber hereditary optic neuropathy (LHON), which might aid in counseling LHON patients and families. The prevalence of LHON in the Dutch population was determined. Observational, retrospective

  2. Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy

    NARCIS (Netherlands)

    Howell, Neil; Oostra, Roelof-Jan; Bolhuis, Piet A.; Spruijt, Liesbeth; Clarke, Lorne A.; Mackey, David A.; Preston, Gwen; Herrnstadt, Corinna

    2003-01-01

    The complete mitochondrial DNA (mtDNA) sequences for 63 Dutch pedigrees with Leber hereditary optic neuropathy (LHON) were determined, 56 of which carried one of the classic LHON mutations at nucleotide (nt) 3460, 11778, or 14484. Analysis of these sequences indicated that there were several

  3. Mitochondrial DNA analysis as a diagnostic tool in singleton cases of Leber's hereditary optic neuropathy

    NARCIS (Netherlands)

    Oostra, R. J.; Bolhuis, P. A.; Bleeker-Wagemakers, E. M.

    1993-01-01

    Leber's hereditary optic neuropathy (LHON) is characterized by subacute loss of central vision due to bilateral optic nerve atrophy accompanied by several nonspecific clinical findings. The only pathognomonic feature is its strictly maternal inheritance. It was therefore impossible to establish the

  4. Leber's hereditary optic neuropathy: no significant evidence for primary or secondary pathogenicity of the 15257 mutation

    NARCIS (Netherlands)

    Oostra, R. J.; Bolhuis, P. A.; Zorn-Ende, I.; de Kok-Nazaruk, M. M.; Bleeker-Wagemakers, E. M.

    1994-01-01

    Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease of the optic nerves associated with various mitochondrial DNA (mtDNA) mutations. Four of these mutations, at nucleotide positions (np) 3460, 11778, 14484 and 15257, have been postulated to be of primary pathogenetical

  5. Is there alteration in aortic stiffness in Leber hereditary optic neuropathy?

    NARCIS (Netherlands)

    Nemes, A.; Coo, I.F.M. de; Spruijt, L.; Smeets, H.J.; Chinnery, P.F.; Soliman, O.I.; Geleijnse, M.L.; Cate, FJ Ten

    2008-01-01

    PURPOSE: Leber hereditary optic neuropathy (LHON) is recognized as the most common cause of isolated blindness in young men. The current study was designed to test whether LHON as a mitochondrial disease is associated with vascular functional alterations characterized by aortic elastic properties

  6. Patients with Leber hereditary optic neuropathy fail to compensate impaired oxidative phosphorylation.

    NARCIS (Netherlands)

    Korsten, A.; Coo, I.F.M. de; Spruijt, L.; Wit, L.E. de; Smeets, H.J.M.; Sluiter, W.

    2010-01-01

    Ninety-five percent of Leber hereditary optic neuropathy (LHON) patients carry a mutation in one out of three mtDNA-encoded ND subunits of complex I. Penetrance is reduced and more male than female carriers are affected. To assess if a consistent biochemical phenotype is associated with LHON

  7. Influence of mutation type on clinical expression of Leber hereditary optic neuropathy.

    NARCIS (Netherlands)

    Spruijt, L.; Kolbach, D.; Coo, R.F. de; Plomp, A.S.; Bauer, N.J.; Smeets, H.J.M.; Die-Smulders, C.E.M. de

    2006-01-01

    PURPOSE: The aim of this research was to determine the molecular factors of influence on the clinical expression of Leber hereditary optic neuropathy (LHON), which might aid in counseling LHON patients and families. The prevalence of LHON in the Dutch population was determined. DESIGN:

  8. Clinical and neurophysiological features of the hereditary neuropathy with liability to pressure palsy due to the 17p11.2 deletion

    Directory of Open Access Journals (Sweden)

    Aline Pinheiro Martins de Oliveira

    2016-02-01

    Full Text Available ABSTRACT The hereditary neuropathy with liability to pressure palsies (HNPP is an autossomal dominant disorder manifesting recurrent mononeuropathies. Objective Evaluate its clinical and nerve conduction studies (NCS characteristics, searching for diagnostic particularities. Method We reviewed the neurological manifestations of 39 and the NCS of 33 patients. Results Family history was absent in 16/39 (41%. The onset complaints were weakness in 24, pain in 6, sensory deficit in 5 and paresthesias in 4. Pain was seen in 3 other patients. The following neuropathy patterns were found: multiple mononeuropathy (26, mononeuropathy (7, chronic sensorimotor polyneuropathy (4, chronic sensory polyneuropathy (1 and unilateral brachial plexopathy (1. NCS showed a sensorimotor neuropathy with focal conduction slowing in 31, two had mononeuropathy and another brachial plexopathy. Conclusion HNPP presentation is variable and may include pain. The most frequent pattern is of an asymmetrical sensory and motor neuropathy with focal slowing at specific topographies on NCS.

  9. Abnormal interaction of motor neuropathy-associated mutant HspB8 (Hsp22) forms with the RNA helicase Ddx20 (gemin3)

    NARCIS (Netherlands)

    Sun, Xiankui; Fontaine, Jean-Marc; Hoppe, Adam D.; Carra, Serena; DeGuzman, Cheryl; Martin, Jody L.; Simon, Stephanie; Vicart, Patrick; Welsh, Michael J.; Landry, Jacques; Benndorf, Rainer

    A number of missense mutations in the two related small heat shock proteins HspB8 (Hsp22) and HspB1 (Hsp27) have been associated with the inherited motor neuron diseases (MND) distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. HspB8 and HspB1 interact with each other, suggesting

  10. Multifocal motor neuropathy and progressive atrophy : Pathophysiological similarities and differences

    NARCIS (Netherlands)

    Vlam, L.

    2015-01-01

    Progressive muscular atrophy (PMA) and multifocal motor neuropathy (MMN) share many clinical similarities. They are both characterized by progressive asymmetric muscle weakness with atrophy and fasciculations. Tendon reflexes are normally low or absent, although in some patients with MMN normal

  11. Mutations in HINT1 are one of the most frequent causes of hereditary neuropathy among Czech patients and neuromyotonia is rather an underdiagnosed symptom.

    Science.gov (United States)

    Laššuthová, P; Brožková, D Šafka; Krůtová, M; Neupauerová, J; Haberlová, J; Mazanec, R; Dvořáčková, N; Goldenberg, Z; Seeman, P

    2015-01-01

    Mutations in the HINT1 gene were recently discovered as being the major cause of autosomal recessive axonal neuropathy with neuromyotonia. This combination was clinically recognized and described previously in a few reports but is generally unknown. We aimed to establish the importance of HINT1 mutations as the cause of hereditary neuropathy and particularly hereditary motor neuropathy/axonal Charcot-Marie-Tooth (HMN/CMT2) among Czech patients. Overall, mutations in the HINT1 gene seem to be a surprisingly frequent cause of inherited neuropathy in our group of patients. Biallelic pathogenic mutations were found in 21 patients from 19 families. The prevalent mutation in the Czech population is the p.R37P (95% of pathogenic alleles). Clinically, all patients with biallelic mutations presented with early onset of symptoms at the end of the first decade. Foot/toe extension weakness to plegia was present in almost all patients. Neuromyotonia was present in all but two patients. However, it had been properly recognized in only three patients prior to molecular genetic diagnosis. HINT1 mutations seem to be one of the most frequent causes of inherited neuropathy and are probably the most frequent cause of HMN in Czech patients. We suggest all HMN/CMT2 patients be tested for the presence of the prevalent mutation, the p.R37P.

  12. Mitochondrial DNA mutation in an Italian family with Leber hereditary optic neuropathy.

    Science.gov (United States)

    Carducci, C; Leuzzi, V; Scuderi, M; De Negri, A M; Gabrieli, C B; Antonozzi, I; Pontecorvi, A

    1991-10-01

    Mitochondrial (mt) DNA from a Southern Italian family with Leber hereditary optic neuropathy was analyzed for the presence of the reported mutation at position 11778 of the ND4 subunit gene. The point mutation was found in mt DNA extracted from peripheral blood in all members of the family with the exclusion of the father, and was present in a homoplasmic fashion, despite the phenotypic heterogeneity of disease presentation among family members.

  13. Hereditary and inflammatory neuropathies: a review of reported associations, mimics and misdiagnoses.

    Science.gov (United States)

    Rajabally, Yusuf A; Adams, David; Latour, Philippe; Attarian, Shahram

    2016-10-01

    Distinguishing between hereditary and inflammatory neuropathy is usually straightforward on clinical grounds with the help of a family history. There are nevertheless cases where the distinction is less clear. The advent of molecular genetics has in the past several years aided confirmatory diagnosis for an increasing proportion of patients with genetic neuropathy. Various reports have described associations of Charcot-Marie-Tooth disease with a suspected or confirmed inflammatory neuropathy occasionally responding to immunotherapy. Possible predisposition to an inflammatory component was suggested in a subset of patients. Such reports have, however, been relatively few in number, suggesting the rarity of such associations and of such a predisposition if it exists. There have been a number of publications detailing clinical presentations suggestive of inflammatory neuropathy in patients with a known or later proven genetic aetiology, and subsequently felt to be part of the phenotype rather than representing an association. A number of genetically mediated multisystemic diseases with neuropathy have otherwise been reported as mimicking chronic inflammatory demyelinating polyneuropathy (CIDP). The most common example is that of familial amyloid polyneuropathy, of particular concern for the clinician when misdiagnosed as CIDP, in view of the therapeutic implications. We review the literature on reported associations, mimics and misdiagnoses of hereditary and inflammatory neuropathy and attempt to determine a practical approach to the problem in clinical practice using clinical features, electrophysiology, histopathology and targeted early genetic testing. The issue of attempting immunomodulatory therapy is discussed in view of the published literature. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  14. ORAL MANIFESTATIONS AND PROSTHETIC REHABILITATION IN HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY (HSANTYPE IV:A CASE REPORT*

    Directory of Open Access Journals (Sweden)

    Duygu OFLUOĞLU

    2016-04-01

    Full Text Available Hereditary sensory and autonomic neuropathies (HSAN are rare genetic syndromes of unknown etiology. They are seen in early childhood and are categorized into six different types by their symptoms. HSAN type 4 demonstrates autosomal recessive transmission pattern, with such major characteristics as loss of sense of pain, self-mutilation, anhydrosis and mental retardation. Sympathetic innervations are deficient despite the existence of sweat glands. Sufferers are hypotonic without any tendon reflexes, and neuro-motor development is retarded. In some cases tactile sensation and vibration may be intact. Biting injuries due to lack of pain sensation cause laceration, ulceration and scarring of the tongue, lips and other parts of oral mucosa. Tooth luxation and severe dental attrition have been observed. This case report presents oral and dental findings, surgical treatments and prosthetic rehabilitation of an 11- year-old boy with HSAN type 4.

  15. Identification of two novel KIF5A mutations in hereditary spastic paraplegia associated with mild peripheral neuropathy.

    Science.gov (United States)

    López, Eva; Casasnovas, Carlos; Giménez, Javier; Santamaría, Raúl; Terrazas, Jesús M; Volpini, Víctor

    2015-11-15

    Spastic paraplegia type 10 (SPG10) is a rare form of autosomal dominant hereditary spastic paraplegia (AD-HSP) due to mutations in KIF5A, a gene encoding the neuronal kinesin heavy-chain involved in axonal transport. KIF5A mutations have been associated with a wide clinical spectrum, ranging from pure HSP to isolated peripheral nerve involvement or complicated HSP phenotypes. Most KIF5A mutations are clustered in the motor domain of the protein that is necessary for microtubule interaction. Here we describe two Spanish families with an adult onset complicated AD-HSP in which neurological studies revealed a mild sensory neuropathy. Intention tremor was also present in both families. Molecular genetic analysis identified two novel mutations c.773 C>T and c.833 C>T in the KIF5A gene resulting in the P258L and P278L substitutions respectively. Both were located in the highly conserved kinesin motor domain of the protein which has previously been identified as a hot spot for KIF5A mutations. This study adds to the evidence associating the known occurrence of mild peripheral neuropathy in the adult onset SPG10 type of AD-HSP. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients

    Science.gov (United States)

    2017-06-09

    Charcot Marie Tooth Disease (CMT); Hereditary Sensory and Motor Neuropathy; Nerve Compression Syndromes; Tooth Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System

  17. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy.

    Science.gov (United States)

    Irobi, Joy; Van Impe, Katrien; Seeman, Pavel; Jordanova, Albena; Dierick, Ines; Verpoorten, Nathalie; Michalik, Andrej; De Vriendt, Els; Jacobs, An; Van Gerwen, Veerle; Vennekens, Krist'l; Mazanec, Radim; Tournev, Ivailo; Hilton-Jones, David; Talbot, Kevin; Kremensky, Ivo; Van Den Bosch, Ludo; Robberecht, Wim; Van Vandekerckhove, Joël; Van Broeckhoven, Christine; Gettemans, Jan; De Jonghe, Peter; Timmerman, Vincent

    2004-06-01

    Distal hereditary motor neuropathies are pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles. In two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22). We found a second mutation (K141E) in two smaller families. Both mutations target the same amino acid, which is essential to the structural and functional integrity of the small heat-shock protein alphaA-crystallin. This positively charged residue, when mutated in other small heat-shock proteins, results in various human disorders. Coimmunoprecipitation experiments showed greater binding of both HSPB8 mutants to the interacting partner HSPB1. Expression of mutant HSPB8 in cultured cells promoted formation of intracellular aggregates. Our findings provide further evidence that mutations in heat-shock proteins have an important role in neurodegenerative disorders.

  18. New MT-ND1 pathologic mutation for Leber hereditary optic neuropathy.

    Science.gov (United States)

    Martínez-Romero, Íñigo; Herrero-Martín, M Dolores; Llobet, Laura; Emperador, Sonia; Martín-Navarro, Antonio; Narberhaus, Bernat; Ascaso, Francisco J; López-Gallardo, Ester; Montoya, Julio; Ruiz-Pesini, Eduardo

    2014-12-01

    Mutations causing Leber hereditary optic neuropathy are usually homoplasmic, show incomplete penetrance, and many of the affected positions are not well conserved through evolution. A large percentage of patients harbouring these mutations have no family history of disease. Moreover, the transfer of the mutation in the cybrid model is frequently not accompanied by the transfer of the cellular, biochemical and molecular phenotype. All these features make difficult their classification as the etiologic factors for this disease. We report a patient who exhibits typical clinical features of Leber hereditary optic neuropathy but lacks all three of the most common mitochondrial DNA mutations. The diagnosis was made based on clinical studies. The mitochondrial DNA was completely sequenced, and the candidate mutation was analysed in more than 18 000 individuals around the world, its conservation index was estimated in more than 3100 species from protists to mammals, its position was modelled in the crystal structure of a bacteria ortholog subunit, and its functional consequences were studied in a cybrid model. Genetic analysis revealed an m.3472T>C transition in the MT-ND1 gene that changes a phenylalanine to leucine at position 56. Bioinformatics, molecular-genetic analysis and functional studies suggest that this transition is the etiological factor for the disorder. This mutation expands the spectrum of deleterious changes in mitochondrial DNA-encoded complex I polypeptides associated with this pathology and highlights the difficulties in assigning pathogenicity to new homoplasmic mutations that show incomplete penetrance in sporadic Leber hereditary optic neuropathy patients. © 2014 Royal Australian and New Zealand College of Ophthalmologists.

  19. Leber hereditary optic neuropathy - historical report in comparison with the current knowledge.

    Science.gov (United States)

    Piotrowska, Agnieszka; Korwin, Magdalena; Bartnik, Ewa; Tońska, Katarzyna

    2015-01-15

    Leber hereditary optic neuropathy (LHON) is a genetic, maternally inherited disease caused by point mutations in the mitochondrial genome. LHON patients present with sudden, painless and usually bilateral loss of vision caused by optic nerve atrophy. The first clinical description of the disease was made by Theodor Leber, a German ophthalmologist, in 1871. Here we present his thorough notes about members of four families and their pedigrees. We also provide insights into the current knowledge about LHON pathology, genetics and treatment in comparison with Leber's findings. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Mitochondria in neuroinflammation - Multiple sclerosis (MS), leber hereditary optic neuropathy (LHON) and LHON-MS.

    Science.gov (United States)

    Bargiela, David; Chinnery, Patrick F

    2017-06-28

    Mitochondrial dysfunction is associated with neuroinflammation and neurodegenerative disease, but its role as a driver in these processes is uncertain. Understanding the pathogenesis of inherited mitochondrial disorders may help us to uncover mechanisms involved during acquired mitochondrial dysfunction. We review the mechanisms of mitochondrial dysfunction in Leber's hereditary optic neuropathy and multiple sclerosis and discuss shared clinical and molecular features in both conditions. Targeting mitochondrial pathways involved in inflammation or apoptosis may be a possible therapeutic approach in multiple sclerosis. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  1. SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I.

    Science.gov (United States)

    Verhoeven, K; Coen, K; De Vriendt, E; Jacobs, A; Van Gerwen, V; Smouts, I; Pou-Serradell, A; Martin, J J; Timmerman, V; De Jonghe, P

    2004-03-23

    Hereditary sensory neuropathy type I (HSN I) is an autosomal dominant ulceromutilating disorder of the peripheral nervous system characterized by progressive sensory loss. HSN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long-chain base subunit 1 (SPTLC1). A novel missense mutation in exon 13 of the SPTLC1 gene (c.1160G-->C; p.G387A) in twin sisters with a severe HSN I phenotype is reported.

  2. Leber hereditary optic neuropathy due to a new ND1 mutation

    DEFF Research Database (Denmark)

    Soldath, Patrick; Wegener, Marianne; Sander, Birgit

    2017-01-01

    We report a proband with Leber hereditary optic neuropathy (LHON), in whom we have identified a novel homoplasmic m.3,395A>G mutation in the ND1 gene. The mutation alters a highly conserved amino acid in codon 30 which previously has been associated with LHON and leads to a severe selective complex...... I deficiency. By providing further evidence for pathogenicity we conclude that m.3,395A>G is pathogenic. High definition optical coherence tomography of the retina and peripapillary retinal nerve fiber layer (pRNFL) confirms recent reports that retinal ganglion cell loss precedes axonal loss in LHON...

  3. Clinical and neurophysiologic characterization of an European family with hereditary sensory neuropathy, paroxysmal cough and gastroesophageal reflux

    Directory of Open Access Journals (Sweden)

    Pedro Barros

    2014-04-01

    Full Text Available In 2002, Spring et al reported a family with an autosomal dominant form of hereditary sensory neuropathy; patients also presented adult onset of gastroesophageal reflux and cough. Since then, no further families have been described. Objective: To study a new Portuguese family with these characteristics. Method: To describe the clinical and neurophysiologic characteristics of one family with features of sensory neuropathy associated with cough and gastroesophageal erflux. Results: Three of five siblings presented a similar history of paroxysmal cough (5th decade. About a decade later they experienced numbness and paraesthesia in the feets and in all cases there was evidence of an axonal sensory neuropathy. A history of gastroesophageal reflux of variable severity and age of onset was also present. Discussion: Molecular genetic studies have demonstrated genetic heterogeneity between the hereditary sensory neuropathy type 1 subtypes. The identification of these families is of major importance because further work is required to identify the underlying genetic defect.

  4. The Decrease in Mitochondrial DNA Mutation Load Parallels Visual Recovery in a Leber Hereditary Optic Neuropathy Patient

    Directory of Open Access Journals (Sweden)

    Sonia Emperador

    2018-02-01

    Full Text Available The onset of Leber hereditary optic neuropathy is relatively rare in childhood and, interestingly, the rate of spontaneous visual recovery is very high in this group of patients. Here, we report a child harboring a rare pathological mitochondrial DNA mutation, present in heteroplasmy, associated with the disease. A patient follow-up showed a rapid recovery of the vision accompanied by a decrease of the percentage of mutated mtDNA. A retrospective study on the age of recovery of all childhood-onset Leber hereditary optic neuropathy patients reported in the literature suggested that this process was probably related with pubertal changes.

  5. HSMNR belongs to the most frequent types of hereditary neuropathy in the Czech Republic and is twice more frequent than HMSNL.

    Science.gov (United States)

    Šafka Brožková, D; Haberlová, J; Mazanec, R; Laštůvková, J; Seeman, P

    2016-08-01

    Hereditary motor and sensory neuropathy type Russe (HMSNR), also called CMT4G, is an autosomal recessive inherited peripheral neuropathy (IPN) caused by a founder mutation in the HK1 gene. HMSNR affects only patients with Roma origin, similar to the better known HMSN type Lom clarified earlier. By testing IPN patients with Roma origin, we realized that HMSNR affects surprisingly many patients in the Czech Republic. HMSNR is one of the most frequent types of IPN in this country and appears to be twice more frequent than HMSNL. Pronounced lower limb atrophies and severe deformities often lead to walking inability in even young patients, but hands are usually only mildly affected even after many years of disease duration. The group of 20 patients with HMSNR presented here is the first report about the prevalence of HMSNR from central Europe. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Increased Mortality and Comorbidity Associated With Leber's Hereditary Optic Neuropathy: A Nationwide Cohort Study.

    Science.gov (United States)

    Vestergaard, Nanna; Rosenberg, Thomas; Torp-Pedersen, Christian; Vorum, Henrik; Andersen, Carl U; Aasbjerg, Kristian

    2017-09-01

    Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease in which optic neuropathy is considered a key feature. Several other manifestations of LHON have been reported; however, only little is known of their incidence and the life expectancy in LHON patients. This study, based on Danish nationwide health registries, included 141 patients diagnosed with LHON and 297 unaffected family members in the maternal line. The incidence of comorbidities and mortality for patients with LHON and unaffected family members was compared with that in the general population. Having LHON was associated with an almost 2-fold risk of mortality with a rate ratio (RR) of 1.95 (95% confidence interval [CI]: 1.47-2.59; P LHON patients, but not for family members. The incidence of stroke was 5.73 per 1000 patient-years for LHON patients compared to 2.33 for the general population, and the RR was 2.38 (95% CI: 1.58-3.58; P LHON patients (RR: 4.26, 95% CI: 1.91-9.48; P LHON and 0.37 for the general population. Moreover, LHON patients had an increased risk of epilepsy, atherosclerosis, nerve symptoms, neuropathy, and alcohol-related disorders. The manifestation of LHON was associated with increased mortality and increased incidence of several disorders including stroke, demyelinating disorder, dementia, and epilepsy.

  7. Leber's hereditary optic neuropathy: implications of the sex ratio for linkage studies in families with the 3460 ND1 mutation

    NARCIS (Netherlands)

    Black, G. C.; Craig, I. W.; Oostra, R. J.; Norby, S.; Rosenberg, T.; Morten, K.; Laborde, A.; Poulton, J.

    1995-01-01

    Leber's hereditary optic neuropathy (LHON), which is associated with mutations in mitochondrial DNA (mtDNA), is commoner in males than females. A study of over 30 LHON families with a mutation at position 3460 of mtDNA demonstrates a significantly decreased male excess from that generally quoted,

  8. No evidence for 'skewed' inactivation of the X-chromosome as cause of Leber's hereditary optic neuropathy in female carriers

    NARCIS (Netherlands)

    Oostra, R. J.; Kemp, S.; Bolhuis, P. A.; Bleeker-Wagemakers, E. M.

    1996-01-01

    Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder of the optic nerves. It has been proposed that the specific mutations in the mitochondrial DNA (mtDNA) that are associated with LHON require and X-chromosomally encoded permissive factor in order to become expressed. This

  9. Genetic and Clinical Analyses of DOA and LHON in 304 Chinese Patients with Suspected Childhood-Onset Hereditary Optic Neuropathy.

    Science.gov (United States)

    Li, Yadi; Li, Jie; Jia, Xiaoyun; Xiao, Xueshan; Li, Shiqiang; Guo, Xiangming

    2017-01-01

    Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA), the most common forms of hereditary optic neuropathy, are easily confused, and it is difficult to distinguish one from the other in the clinic, especially in young children. The present study was designed to survey the mutation spectrum of common pathogenic genes (OPA1, OPA3 and mtDNA genes) and to analyze the genotype-phenotype characteristics of Chinese patients with suspected childhood-onset hereditary optic neuropathy. Genomic DNA and clinical data were collected from 304 unrelated Chinese probands with suspected hereditary optic neuropathy with an age of onset below 14 years. Sanger sequencing was used to screen variants in the coding and adjacent regions of OPA1, OPA3 and the three primary LHON-related mutation sites in mitochondrial DNA (mtDNA) (m.3460G>A, m.11778G>A and m.14484T>C). All patients underwent a complete ophthalmic examination and were compared with age-matched controls. We identified 89/304 (29.3%) primary mtDNA mutations related to LHON in 304 probands, including 76 mutations at m.11778 (76/89, 85.4% of all mtDNA mutations), four at m.3460 (4/89, 4.5%) and nine at m.14484 (9/89, 10.1%). This result was similar to the mutation frequency among Chinese patients with LHON of any age. Screening of OPA1 revealed 23 pathogenic variants, including 11 novel and 12 known pathogenic mutations. This study expanded the OPA1 mutation spectrum, and our results showed that OPA1 mutation is another common cause of childhood-onset hereditary optic neuropathy in Chinese pediatric patients, especially those with disease onset during preschool age.

  10. Genetic and Clinical Analyses of DOA and LHON in 304 Chinese Patients with Suspected Childhood-Onset Hereditary Optic Neuropathy.

    Directory of Open Access Journals (Sweden)

    Yadi Li

    Full Text Available Leber hereditary optic neuropathy (LHON and dominant optic atrophy (DOA, the most common forms of hereditary optic neuropathy, are easily confused, and it is difficult to distinguish one from the other in the clinic, especially in young children. The present study was designed to survey the mutation spectrum of common pathogenic genes (OPA1, OPA3 and mtDNA genes and to analyze the genotype-phenotype characteristics of Chinese patients with suspected childhood-onset hereditary optic neuropathy. Genomic DNA and clinical data were collected from 304 unrelated Chinese probands with suspected hereditary optic neuropathy with an age of onset below 14 years. Sanger sequencing was used to screen variants in the coding and adjacent regions of OPA1, OPA3 and the three primary LHON-related mutation sites in mitochondrial DNA (mtDNA (m.3460G>A, m.11778G>A and m.14484T>C. All patients underwent a complete ophthalmic examination and were compared with age-matched controls. We identified 89/304 (29.3% primary mtDNA mutations related to LHON in 304 probands, including 76 mutations at m.11778 (76/89, 85.4% of all mtDNA mutations, four at m.3460 (4/89, 4.5% and nine at m.14484 (9/89, 10.1%. This result was similar to the mutation frequency among Chinese patients with LHON of any age. Screening of OPA1 revealed 23 pathogenic variants, including 11 novel and 12 known pathogenic mutations. This study expanded the OPA1 mutation spectrum, and our results showed that OPA1 mutation is another common cause of childhood-onset hereditary optic neuropathy in Chinese pediatric patients, especially those with disease onset during preschool age.

  11. Motor activation in SPG4-linked hereditary spastic paraplegia

    DEFF Research Database (Denmark)

    Scheuer, KH; Nielsen, JE; Krabbe, Katja

    2006-01-01

    OBJECTIVE: The aim of this study was to investigate the extent of motor cortical functional reorganisation in patients with SPG4-linked hereditary spastic paraplegia by exploring cortical motor activation related to movements of clinically affected (lower) and unaffected (upper) limbs. METHODS......) and between-group comparisons of movement vs. rest (group x behavioural state interaction) were performed using a random effects approach and statistical parametric mapping (SPM99). RESULTS: Patterns of motor activation were generally comparable between groups during both tasks, although patients had...... a tendency towards more widespread activation in sensorimotor cortical and cerebellar regions. Statistically significant differences were restricted to the ankle movement response, however, where patients showed significantly increased regional cerebral blood flow in the right and left primary motor cortices...

  12. Multifocal Motor Neuropathy, Multifocal Acquired Demyelinating Sensory and Motor Neuropathy and Other Chronic Acquired Demyelinating Polyneuropathy Variants

    Science.gov (United States)

    Barohn, Richard J.; Katz, Jonathan

    2014-01-01

    Chronic acquired demyelinating neuropathies (CADP) are an important group of immune neuromuscular disorders affecting myelin. These are distinct from chronic inflammatory demyelinating polyneuropathy (CIDP). Classically, CIDP is characterized by proximal and distal weakness, large fiber sensory loss, elevated cerebrospinal fluid (CSF) protein content, demyelinating changes nerve conduction studies or nerve biopsy, and response to immunomodulating treatment. In this chapter we discuss CADP with emphasis on multifocal motor neuropathy (MMN), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), distal acquired demyelinating symmetric (DADS) neuropathy and conclude with less common variants. While each of these entities has distinctive laboratory and electrodiagnostic features that aid in their diagnosis, clinical characteristics are of paramount importance in diagnosing specific conditions and determining the most appropriate therapies. Unlike CIDP, MMN is typically asymmetric and affects only the motor nerve fibers. MMN is a rare disease that presents chronically, over several years of progression affecting the arms are more commonly than the legs. Men are more likely than women to develop MMN. MADSAM should be suspected in patients who have weakness and loss of sensation in primarily one arm or leg which progresses slowly over several months to years. It is important in patient with multifocal demyelinating clinical presentation to distinguish MMN from MADSAM since corticosteroids are not effective in MMN where the mainstay of therapy is intravenous gammaglobulin (IVIg). DADS can be subdivided into DADS-M (associated woth M-protein) and DADS-I which is idioapthic. While DADS-I patients respond somewhat to immunotherapy, DADS-M patients present with distal predominant sensorimotor demyelinating neuropathy phenotype and are notoriously refractory to immunotherapies regardless of antibodies to myelin-associated glycoprotein (MAG). Our knowledge

  13. Gene-Based Therapies for Leber Hereditary Optic Neuropathy. Hype or Hope?

    Science.gov (United States)

    Mackey, David A; Kearns, Lisa S; Hewitt, Alex W

    2016-01-01

    Leber hereditary optic neuropathy has now joined Leber congenital amaurosis in the list of genetic eye diseases undergoing gene therapy clinical trials. Although a dramatic response to treatment would be welcome, a minor improvement in vision is a major challenge in efficacy assessment, given this may occur spontaneously as part of the natural history of minor recovery in some patients. Thus, we must await the outcome of adequately powered clinical trials to know if the treatment is effective, particularly given the likely high cost of such therapeutic interventions in the future. We need global cooperation to ensure that the most suitable patients are enrolled in these trials and that support is provided for participants who need to travel from the Asia-Pacific region to Europe or North America if there are no local arms of these trials.

  14. Evaluating the therapeutic potential of idebenone and related quinone analogues in Leber hereditary optic neuropathy.

    Science.gov (United States)

    Yu-Wai-Man, Patrick; Soiferman, Devorah; Moore, David G; Burté, Florence; Saada, Ann

    2017-09-01

    Leber hereditary optic neuropathy (LHON) is an important cause of mitochondrial blindness among young adults. In this study, we investigated the potential of four quinone analogues (CoQ1, CoQ10, decylubiquinone and idebenone) in compensating for the deleterious effect of the m.11778G>A mitochondrial DNA mutation. The LHON fibroblast cell lines tested exhibited reduced cell growth, impaired mitochondrial bioenergetics and elevated levels of reactive oxygen species (ROS). Idebenone increased ATP production and reduced ROS levels, but the effect was partial and cell-specific. The remaining quinone analogues had variable effects and a negative impact on certain mitochondrial parameters was observed in some cell lines. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  15. Leber Hereditary Optic Neuropathy with Interval of Visual Loss Greater Than 12 Months.

    Science.gov (United States)

    Prado, Renata Cristina Ferreira; Moura, Frederico Castelo

    2016-10-01

    A 28-year-old man presented with severe left visual loss and normal right visual acuity. The left fundus examination showed temporal pallor and complete absence of the nerve fibre layer (NFL) of papillomacular bundle. Right fundus examination showed focal loss of inferotemporal NFL. Magnetic resonance and serum aquaporin-4 antibody were negative. After 14 months of the initial visual involvement, the patient suffered subacute visual loss in contralateral eye. Genetic study revealed the 11778 point mitochondrial DNA (mtDNA) mutation associated with Leber hereditary optic neuropathy (LHON). Although very rare, interval of involvement of second eye greater than 12 months can occurs in LHON. Detailed optic nerve examination and careful interpretation of optical coherence tomography (OCT) printout support the diagnosis.

  16. Leber hereditary optic neuropathy due to a new ND1 mutation.

    Science.gov (United States)

    Soldath, Patrick; Wegener, Marianne; Sander, Birgit; Rosenberg, Thomas; Duno, Morten; Wibrand, Flemming; Vissing, John

    2017-01-01

    We report a proband with Leber hereditary optic neuropathy (LHON), in whom we have identified a novel homoplasmic m.3,395A>G mutation in the ND1 gene. The mutation alters a highly conserved amino acid in codon 30 which previously has been associated with LHON and leads to a severe selective complex I deficiency. By providing further evidence for pathogenicity we conclude that m.3,395A>G is pathogenic. High definition optical coherence tomography of the retina and peripapillary retinal nerve fiber layer (pRNFL) confirms recent reports that retinal ganglion cell loss precedes axonal loss in LHON and is present in the early stage of the disease. Furthermore, evaluation of two unaffected mutation carriers disclosed asymptomatic borderline ganglion cell loss and thin pRNFL in one.

  17. Hereditary Sensory Autonomic Neuropathy II, a rare disease in a large Pakistani family.

    Science.gov (United States)

    Arain, Fazal Manzoor; Chand, Prem

    2015-10-01

    Hereditary Sensory Autonomic Neuropathy II (HSAN II) is a rare genetic disorder, characterized by severe loss of pain, temperature and touch sensation. Injuries in these patients can progress to necrosis and shedding of digits and limbs. Here we report two cases of HSAN II belonging to a Pakistani family. Individual 1, a forty five year old man, had complete loss of pain sensation since birth. Self-mutilation and complication of injuries resulted in the shedding of all the digits and right foot and surgical amputation of left leg. Individual 2, a five year old girl,had delay in healing of wounds and self-mutilation. Examination showed a complete lack of pain sensation throughout her body and hyporeflexia. As the genetic cause of HSAN II is unknown, identification of more patients will allow further research on this disease and possibly develop a cure.

  18. Evidence against an X-linked visual loss susceptibility locus in Leber hereditary optic neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Chalmers, R.M.; Davis, M.B.; Sweeney, M.G.; Wood, N.W.; Harding, A.E. [Inst. of Neurology, London (United Kingdom)

    1996-07-01

    Pedigree analysis of British families with Leber hereditary optic neuropathy (LHON) closely fits a model in which a pathogenic mtDNA mutation interacts with an X-linked visual loss susceptibility locus (VLSL). This model predicts that 60% of affected females will show marked skewing of X inactivation. Linkage analysis in British and Italian families with genetically proven LHON has excluded the presence of such a VLSL over 169 cM of the X chromosome both when all families were analyzed together and when only families with the bp 11778 mutation were studied. Further, there was no excess skewing of X inactivation in affected females. There was no evidence for close linkage to three markers in the pseudoautosomal region of the sex chromosomes. The mechanism of incomplete penetrance and male predominance in LHON remains unclear. 27 refs., 1 fig., 3 tabs.

  19. Single-cell analysis of intercellular heteroplasmy of mtDNA in Leber hereditary optic neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, Y.; Sharpe, H.; Brown, N.

    1994-07-01

    The authors have investigated the distribution of mutant mtDNA molecules in single cells from a patient with Leber hereditary optic neuropathy (LHON). LHON is a maternally inherited disease that is characterized by a sudden-onset bilateral loss of central vision, which typically occurs in early adulthood. More than 50% of all LHON patients carry an mtDNA mutation at nucleotide position 11778. This nucleotide change converts a highly conserved arginine residue to histidine at codon 340 in the NADH-ubiquinone oxidoreductase subunit 4 (ND4) gene of mtDNA. In the present study, the authors used PCR amplification of mtDNA from lymphocytes to investigate mtDNA heteroplasmy at the single-cell level in a LHON patient. They found that most cells were either homoplasmic normal or homoplasmic mutant at nucleotide position 11778. Some (16%) cells contained both mutant and normal mtDNA.

  20. Differential cerebro spinal fluid proteome investigation of Leber hereditary optic neuropathy (LHON) and multiple sclerosis.

    Science.gov (United States)

    D'Aguanno, Simona; Barassi, Alessandra; Lupisella, Santina; d'eril, Gianlodovico Melzi; Del Boccio, Piero; Pieragostino, Damiana; Pallotti, Francesco; Carelli, Valerio; Valentino, Maria Lucia; Liguori, Rocco; Avoni, Patrizia; Bernardini, Sergio; Gambi, Domenico; Urbani, Andrea; Federici, Giorgio

    2008-01-01

    Leber's hereditary optic neuropathy (LHON) is a genetic disease leading to the loss of central vision and optic nerve atrophy. The existence of occasional cases of LHON patients developing a Multiple Sclerosis (MS)-like illness and the hypothesis that mtDNA variants may be involved in MS suggest the possibility of some common molecular mechanisms linking the two diseases. We have pursued a comparative proteomics approach on cerebrospinal fluid (CSF) samples from LHON and MS patients, as well as healthy donors by employing 2-DE gel separations coupled to MALDI-TOF-MS and nLC-MS/MS investigations. 7 protein spots showed significant differential distribution among the three groups. Both CSF of LHON or MS patients are characterized by lower level of transthyretin dimer adduct while a specific up regulation of Apo A-IV was detected in LHON CSF.

  1. Prevalence and Genetics of Leber Hereditary Optic Neuropathy in the Danish Population

    DEFF Research Database (Denmark)

    Rosenberg, Niels Thomas; Nørby, Søren; Schwartz, Marianne

    2016-01-01

    in the files of NEC. Genealogic follow-up on the maternal ancestry of all affected individuals was performed to identify a possible relation to an already known maternal line. A full genotypic characterization of the nation-based LHON cohort is provided. RESULTS: Forty different lines were identified......PURPOSE: In Denmark, the occurrence of Leber hereditary optic neuropathy (LHON) has continuously been monitored since 1944. We provide here a summary of 70 years of data collection including registered lines and subjects by the end of 2012. METHODS: Affected individuals were identified from....... The number of live affected individuals with a verified mitochondrial DNA mutation was 104 on January 1, 2013, which translates to a prevalence rate of 1:54,000 in the Danish population. CONCLUSIONS: Haplogroup distribution as well as mutational spectrum of the Danish LHON cohort do not deviate from those...

  2. Raised intraocular pressure as a potential risk factor for visual loss in Leber Hereditary Optic Neuropathy.

    Directory of Open Access Journals (Sweden)

    Anais Thouin

    Full Text Available Leber Hereditary Optic Neuropathy (LHON is an important cause of inherited mitochondrial blindness among young adults. The majority of patients carry one of three mitochondrial DNA (mtDNA point mutations: m.3460G>A, m.11778G>A and m.14484T>C, all of which affect critical complex I subunits of the mitochondrial respiratory chain. LHON is characterised by marked incomplete penetrance, clearly implying that the mtDNA mutation is insufficient on its own to trigger retinal ganglion cell dysfunction and visual loss. In this case series of three affected patients harbouring the m.11778G>A mutation, we provide evidence suggesting that raised intraocular pressure could be a risk factor triggering visual loss in at-risk LHON carriers.

  3. Leber Hereditary Optic Neuropathy Plus: A Case Report and Review of Literatures

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    Maryam Sharifian Dorche

    2017-08-01

    Full Text Available Background: Leber hereditary optic neuropathy (LHON is an inherited visual loss and optic atrophy due to mitochondrial mutation. Most of these patients had not any other neurological signs and symptoms more than a visual loss. In a small group of the patients, other neurological manifestations may be occurs. This rare presentation of the disease was named " LHON plus syndromes ." Case presentation: A 15-year-old boy who was completely healthy until age 9, when he gradually developed painless visual loss in his right eye. After 3 months, similar symptoms occurred in his left eye. Within next 2 years, psychomotor regression happened, and at age 11, very intractable seizures were started. According to physical examination and past medical history, LHON plus syndrome was diagnosed for him.  Management of seizure and other symptomatic treatments were started, and there was a weak response to drugs. Conclusion: Early diagnosis and ruling out treatable conditions are critical points in these patients.

  4. Hereditary sensory and autonomic neuropathy type V: Report of a rare case

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    Ritesh Kalaskar

    2015-01-01

    Full Text Available Hereditary sensory and autonomic neuropathy (HSAN type V is a rare inherited disease caused by a mutation in the neurotrophic tyrosine kinase receptor, type 1 gene located on chromosome 1 (1q21-q22. It is characterized by pain insensitivity, partial anhydrosis without mental retardation and unimpaired touch and pressure sensitivity. Self-mutilation injury involving the teeth, lips, tongue, ears, eyes, nose, and fingers are invariable feature of this disorder. The purpose of this paper was to discuss the diagnosis and oral management of 18-month-old girl with HSAN type V, having typical oral manifestation of bitten tongue and auto-extraction of primary teeth. Modified bite guard was given to the patient to prevent further self-mutilating injuries to the tongue.

  5. Clinical and electrophysiology findings in Slovene patients with Leber hereditary optic neuropathy.

    Science.gov (United States)

    Jarc-Vidmar, Martina; Tajnik, Mojca; Brecelj, Jelka; Fakin, Ana; Sustar, Maja; Naji, Mateja; Stirn-Kranjc, Branka; Glavač, Damjan; Hawlina, Marko

    2015-06-01

    To report clinical and electrophysiology findings in Slovene patients with Leber hereditary optic neuropathy (LHON). Eight patients with LHON (11-26 years; one female and seven males) were examined in acute stages and at follow-up visits by means of Snellen visual acuity, Ishihara color vision, Goldmann or Octopus G2TOP perimetry, fluorescein angiography (FAG), pattern electroretinogram (PERG), visual evoked potentials (VEP) and genetic testing. Patients presented with typical LHON phenotype with bilateral visual acuity loss, abnormal color vision, central scotoma and hyperemic discs with no leakage on FAG. In the acute stage, electrophysiology was performed in 7/8 patients. The PERG P50 component was normal in 14/14 eyes, while the N95 component was reduced in 7/14 eyes. VEP wave P100 was reduced and delayed in 14/14 eyes. In this stage, temporal pallor of the optic disc was visible in 4/7 eyes with reduced PERG N95. At follow-up (1-11 months after), a reduced PERG N95 component was seen in 13/14 eyes and severely affected VEP in all eyes. In the only eye with a normal PERG N95, hyperemic optic disc was seen 5 months after visual acuity loss, while it was atrophic in all the others. Known mutations (14484T>C, 3460G>A) were found in 2/8 patients, while in others high-throughput sequencing identified new potentially pathogenic mutations. In Leber hereditary optic neuropathy, a reduced N95 component of PERG and severely reduced VEP P100 may be present already in the acute stage of disease, before optic disc pallor appears, suggesting primary dysfunction of retinal ganglion cells.

  6. Peripheral arthropathy in hereditary sensory and autonomic neuropathy types III and IV.

    Science.gov (United States)

    Feldman, David S; Ruchelsman, David E; Spencer, Daniel B; Straight, Joseph J; Schweitzer, Mark E; Axelrod, Felicia B

    2009-01-01

    To determine the features of the underlying destructive arthropathy in the peripheral joints of children with hereditary sensory and autonomic neuropathy (HSAN) type III and to compare and contrast this to the arthropathy noted in HSAN type IV, as both groups experience decreased pain perception. From a database of 547 patients with HSAN type III and 32 patients with HSAN type IV, we performed a retrospective chart review and radiographic analysis of all patients who presented with joint swelling and deformity. Underlying joint pathology was classified as either osteonecrosis or Charcot arthropathy. In the HSAN type III population, 44 (8%; 22 males and 22 females) of the 547 patients had clinical evidence of arthropathy. In 42 patients, 48 joints demonstrated radiographic evidence of osteonecrosis; 45 (94%) of the 48 joints with osteonecrosis occurred in the lower extremity. In each case of osteonecrosis of the knee (n = 19), isolated involvement of the lateral distal femoral condyle was seen consisting of varying sizes of posterolateral osteochondral fragmentation. In the 32 patients comprising the HSAN type IV population, 18 (56%) were found to have radiographic findings consistent with Charcot arthropathy in a total of 30 affected joints. One patient demonstrated Charcot arthropathy of the spine and subsequent progressive spondylolisthesis. Nine patients (12 joints) also demonstrated osteomyelitis. In patients with HSAN type III, osteonecrosis is the initial lesion preceding destructive arthropathy. Osteonecrosis and osteochondral fragmentation were always isolated at the lateral distal femoral condyle in the knee. This pathology may be amenable to surgical reconstruction and fixation to stabilize the knee and prevent further degeneration. Hereditary sensory and autonomic neuropathy type IV was most commonly associated with Charcot arthropathy or joint subluxation and dislocation. Late secondary changes at the articular surface may make radiographic distinction

  7. Unilateral pure trigeminal motor nerve neuropathy: A rare case report

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    Nishant K Srivastava

    2014-01-01

    Full Text Available Unilateral pure trigeminal motor nerve neuropathy is an extremely rare and unique condition, characterized by atrophy of the muscles, innervated by the motor branch of the trigeminal nerve. We report such a case in a 25-year-old male patient. The diagnosis was made on the basis of clinical and radiological examinations. Magnetic Resonance Imaging (MRI proved to be the key for establishing the diagnosis, which showed atrophy and fatty infiltration over the affected side of the muscles of mastication. We were unable to establish the cause of the condition even after performing a brain MRI.

  8. A Case of Apoplexy Attack-Like Neuropathy due to Hereditary Neuropathy with Liability to Pressure Palsies in a Patient Diagnosed with Chronic Cerebral Infarction.

    Science.gov (United States)

    Hachisuka, Akiko; Matsushima, Yasuyuki; Hachisuka, Kenji; Saeki, Satoru

    2016-06-01

    Hereditary neuropathy with liability to pressure palsies is an inherited disease associated with the loss of a copy of the PMP22 gene. The condition leads to mononeuropathy due to compression and easy strangulation during daily life activities, resulting in sudden muscle weakness and sensory disturbance, and displaying symptoms similar to cerebrovascular diseases. We report the case of an 80-year-old man with left paralysis due to chronic cerebral infarction. His medical history indicated remarkable recovery from about 4 months after the onset of left hemiplegia with predominant involvement of the fingers. Despite subsequent recurrent monoplegia of the upper or lower limbs, brain magnetic resonance imaging consistently revealed only previous cerebral infarction in the right corona radiata without new lesions. Medical examination showed reduced deep tendon reflexes in his extremities on both the healthy and hemiplegic sides. Nerve conduction studies showed delayed conduction at the bilateral carpal and cubital tunnels and near the right caput fibulae. Genetic analysis revealed loss of a copy of the PMP22 gene. Thus, he was diagnosed with a cerebral infarction complicated by hereditary neuropathy with liability to pressure palsies. Stroke patients develop sudden muscle weakness and sensory disturbance. However, if such patients have no hyperactive deep tendon reflexes and show atypical recovery of paralysis that does not correspond to findings of imaging modalities, nerve conduction studies and genetic analysis may be necessary, considering the complication of hereditary neuropathy with liability to pressure palsies. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Vision Recovery Despite Retinal Ganglion Cell Loss in Leber's Hereditary Optic Neuropathy.

    Science.gov (United States)

    Webber, Ann L

    2016-12-01

    To report vision recovery in a single case of Leber's hereditary optic neuropathy (LHON) (mtDNA14484/ND6 mutation) with longitudinal documentation of retinal ganglion cell layer by ocular coherence tomography (OCT) that includes the pre-onset, acute, and chronic stages of vision loss. We report LHON in a 16-year-old male patient with Type 1 diabetes and known and documented family history of LHON. The patient presented with best-corrected visual acuities of right eye 20/150 and left eye 20/25-. His retinal nerve fiber layer had thickened compared with baseline measures obtained 19 months before the onset of vision loss. Vision rapidly reduced to "hand movements" vision in each eye over the following 2 months. Despite OCT-documented significant recalcitrant loss of ganglion cell layer, visual acuity remarkably recovered to right eye 20/40+ left eye 20/50+ 16 months after onset of neuropathy. A selective loss of ganglion cells and nerve fiber layer can be documented in LHON. Significant recovery of visual acuity can occur without apparent structural recovery.

  10. X-inactivation pattern in multiple tissues from two Leber's hereditary optic neuropathy (LHON) patients.

    Science.gov (United States)

    Pegoraro, Elena; Vettori, Andrea; Valentino, Maria L; Molon, Annamaria; Mostacciuolo, Maria L; Howell, Neil; Carelli, Valerio

    2003-05-15

    The more frequent manifestation of ophthalmological abnormalities in males, relative to females, is an unexplained feature of Leber's hereditary optic neuropathy (LHON) that suggests an X-linked modifying gene acting in concert with the pathogenic LHON mitochondrial DNA (mtDNA) mutation. In addition, segregation analysis of the optic neuropathy in LHON pedigrees was compatible with the presence of a recessive-modifying gene on chromosome X. According to this two-locus model, females would be affected only if homozygous or if they were susceptible to skewed X-inactivation. Attempts both to localize the putative LHON-modifying gene by linkage analysis and to find an excess of skewed X-inactivation in affected females were unsuccessful, although the inactivation pattern was only studied in DNA isolated from blood cells. We had the opportunity to analyze a wide range of tissues at autopsy, including the optic nerves and the retina, from two LHON female patients. We found no evidence of skewed X-inactivation in the affected tissues, thus weakening further the hypothesized involvement of a specific X chromosome locus in the pathophysiological expression of LHON. Copyright 2003 Wiley-Liss, Inc.

  11. Frequency of primary mutations of Leber's hereditary optic neuropathy patients in North Indian population

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    Anushree Mishra

    2017-01-01

    Full Text Available Purpose: Leber's hereditary optic neuropathy (LHON is an inherited optic neuropathy characterized by subacute painless vision loss. The majority of LHON is caused due to one of the three primary mutations in the mitochondrial DNA (m.G3460A, m.G11778A, and m.T14484C. The frequency of these mutations differs in different populations. The purpose of this study is to observe the frequency of three common primary mutations in the North Indian population. Methods: Forty LHON patients within the age group of 10–50 years underwent molecular testing for primary mutations. For two patients, testing for mother and other siblings was also carried out, using bidirectional sequencing. Results: A total of 11 out of 40 (27.5% patients were found to be carrying m.G11778A mutation. Siblings of two probands were also positive for the same mutation. In one family, two primary mutations (m.G11778A and m.T14484C were found in the proband and in the mother as well. Conclusion: In this study, 27.5% mutation was detected in North Indian LHON families. These results suggest that m.G11778A mutation is more frequent in this population. The results of the present study are compatible with studies of an Asian population and Northern European population.

  12. Prevalence and Genetics of Leber Hereditary Optic Neuropathy in the Danish Population.

    Science.gov (United States)

    Rosenberg, Thomas; Nørby, Søren; Schwartz, Marianne; Saillard, Juliette; Magalhães, Paulo J; Leroy, David; Kann, Erik C; Duno, Morten

    2016-03-01

    In Denmark, the occurrence of Leber hereditary optic neuropathy (LHON) has continuously been monitored since 1944. We provide here a summary of 70 years of data collection including registered lines and subjects by the end of 2012. Affected individuals were identified from a national register of hereditary eye diseases at the National Eye Clinic (NEC), a tertiary low vision rehabilitation center for the entire Danish population. The assembling of LHON pedigrees was based on the reconstruction of published families and newly diagnosed cases from 1980 to 2012 identified in the files of NEC. Genealogic follow-up on the maternal ancestry of all affected individuals was performed to identify a possible relation to an already known maternal line. A full genotypic characterization of the nation-based LHON cohort is provided. Forty different lines were identified. The number of live affected individuals with a verified mitochondrial DNA mutation was 104 on January 1, 2013, which translates to a prevalence rate of 1:54,000 in the Danish population. Haplogroup distribution as well as mutational spectrum of the Danish LHON cohort do not deviate from those of other European populations. The genealogic follow-up reveals a relatively high turnover among families with approximately 15 newly affected families per century and the dying out of earlier maternal lines.

  13. Exome sequencing establishes a gelsolin mutation as the cause of inherited bulbar-onset neuropathy.

    Science.gov (United States)

    Caress, James B; Johnson, Janel O; Abramzon, Yevgeniya A; Hawkins, Gregory A; Gibbs, J Raphael; Sullivan, Elizabeth A; Chahal, Chamanpreet S; Traynor, Bryan J

    2017-11-01

    Progressive bulbar motor neuropathy is primarily caused by bulbar-onset ALS. Hereditary amyloidosis type IV also presents with a bulbar neuropathy that mimics motor neuron disease. The disease is prevalent in Finland only and is not commonly included in the differential diagnosis of ALS. We studied 18 members of a family in which some had bulbar motor neuropathy, and we performed exome sequencing. Five affected family members were found to have a D187Y substitution in the GSN gene known to cause hereditary amyloidosis type IV. This American family presented with progressive bulbar neuropathy due to a gelsolin mutation not found in Finland. Hereditary amyloidosis type IV presents with bulbar motor neuropathy and not with peripheral neuropathy as occurs with common forms of amyloidosis. This report demonstrates the power of exome sequencing to determine the cause of rare hereditary diseases with incomplete or atypical phenotypes. Muscle Nerve 56: 1001-1005, 2017. © 2016 Wiley Periodicals, Inc.

  14. Multifocal motor neuropathy: a review of pathogenesis, diagnosis, and treatment

    Directory of Open Access Journals (Sweden)

    Lawson VH

    2014-04-01

    Full Text Available Victoria H Lawson,1 W David Arnold1,2 1Division of Neuromuscular Disorders, Department of Neurology, 2Department of Physical Medicine and Rehabilitation, Wexner Medical Center at The Ohio State University, Columbus, Ohio, USA Abstract: Multifocal motor neuropathy (MMN is an uncommon, purely motor neuropathy associated with asymmetric deficits with predilection for upper limb involvement. Even in the early descriptions of MMN, the associations of anti-GM1 antibodies and robust response to immunomodulatory treatment were recognized. These features highlight the likelihood of an underlying autoimmune etiology of MMN. The clinical presentation of MMN can closely mimic several neurological conditions including those with more malignant prognoses such as motor neuron disease. Therefore early and rapid recognition of MMN is critical. Serological evidence of anti GM-1 antibodies and electrodiagnostic findings of conduction block are helpful diagnostic clues for MMN. Importantly, these diagnostic features are not universally present, and patients lacking these characteristic findings can demonstrate similar robust response to immunodulatory treatment. In the current review, recent research in the areas of diagnosis, pathogenesis, and treatment of MMN and needs for the future are discussed. The characteristic findings of MMN and treatment implications are reviewed and contrasted with other mimicking disorders. Keywords: autoimmune, conduction block, electrodiagnosis, motor neuron, nerve, inflammatory

  15. Antiretroviral Therapy-Associated Acute Motor and Sensory Axonal Neuropathy

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    Kimberly N. Capers

    2011-01-01

    Full Text Available Guillain-Barré syndrome (GBS has been reported in HIV-infected patients in association with the immune reconstitution syndrome whose symptoms can be mimicked by highly active antiretroviral therapy (HAART-mediated mitochondrial toxicity. We report a case of a 17-year-old, HIV-infected patient on HAART with a normal CD4 count and undetectable viral load, presenting with acute lower extremity weakness associated with lactatemia. Electromyography/nerve conduction studies revealed absent sensory potentials and decreased compound muscle action potentials, consistent with a diagnosis of acute motor and sensory axonal neuropathy. Lactatemia resolved following cessation of HAART; however, neurological deficits minimally improved over several months in spite of immune modulatory therapy. This case highlights the potential association between HAART, mitochondrial toxicity and acute axonal neuropathies in HIV-infected patients, distinct from the immune reconstitution syndrome.

  16. Hereditary spastic paraplegias: membrane traffic and the motor pathway.

    Science.gov (United States)

    Blackstone, Craig; O'Kane, Cahir J; Reid, Evan

    2011-01-01

    Voluntary movement is a fundamental way in which animals respond to, and interact with, their environment. In mammals, the main CNS pathway controlling voluntary movement is the corticospinal tract, which encompasses connections between the cerebral motor cortex and the spinal cord. Hereditary spastic paraplegias (HSPs) are a group of genetic disorders that lead to a length-dependent, distal axonopathy of fibres of the corticospinal tract, causing lower limb spasticity and weakness. Recent work aimed at elucidating the molecular cell biology underlying the HSPs has revealed the importance of basic cellular processes — especially membrane trafficking and organelle morphogenesis and distribution— in axonal maintenance and degeneration.

  17. Progressive arm weakness and tonic hand spasm from multifocal motor neuropathy in the brachial plexus.

    Science.gov (United States)

    Veltkamp, R; Krause, M; Schranz, C; Meinck, H-M

    2003-08-01

    A 50-year-old waitress presented with a 10-year history of progressive weakness in her right arm without atrophy and with tonic hand spasms suggesting a central motor disorder. Electromyography, however, disclosed chronic neurogenic changes including fasciculations and atypical cramps. Isolated motor conduction block in the right brachial plexus suggested a variant of multifocal motor neuropathy. Strength recovered and cramps disappeared after intravenous immunoglobulins. Motor neuropathies may thus manifest with features of central motor disorders.

  18. Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novel OPA1 mutations

    DEFF Research Database (Denmark)

    Ferré, Marc; Bonneau, Dominique; Milea, Dan

    2009-01-01

    We report the results of molecular screening in 980 patients carried out as part of their work-up for suspected hereditary optic neuropathies. All the patients were investigated for Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA), by searching for the ten...... primary LHON-causing mtDNA mutations and examining the entire coding sequences of the OPA1 and OPA3 genes, the two genes currently identified in ADOA. Molecular defects were identified in 440 patients (45% of screened patients). Among these, 295 patients (67%) had an OPA1 mutation, 131 patients (30%) had...... an mtDNA mutation, and 14 patients (3%), belonging to three unrelated families, had an OPA3 mutation. Interestingly, OPA1 mutations were found in 157 (40%) of the 392 apparently sporadic cases of optic atrophy. The eOPA1 locus-specific database now contains a total of 204 OPA1 mutations, including 77...

  19. Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia

    Energy Technology Data Exchange (ETDEWEB)

    De Vries, D.D.; Oost, B.A. van [Univ. Hospital Nijmegen (Netherlands); Went, L.N.; Bruyn, G.W. [Univ. of Leiden (Netherlands)] [and others

    1996-04-01

    A rare form of Leber hereditary optic neuropathy (LHON) that is associated with hereditary spastic dystonia has been studied in a large Dutch family. Neuropathy and ophthalmological lesions were present together in some family members, whereas only one type of abnormality was found in others. mtDNA mutations previously reported in LHON were not present. Sequence analysis of the protein-coding mitochondrial genes revealed two previously unreported mtDNA mutations. A heteroplasmic A{yields}G transition at nucleotide position 11696 in the ND4 gene resulted in the substitution of an isoleucine for valine at amino acid position 312. A second mutation, a homoplasmic T{yields}A transition at nucleotide position 14596 in the ND6 gene, resulted in the substitution of a methionine for the isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy revealed a severe complex I deficiency, providing a link between these unique mtDNA mutations and this rare, complex phenotype including Leber optic neuropathy. 80 refs., 2 figs., 3 tabs.

  20. Use of Idebenone for the Treatment of Leber’s Hereditary Optic Neuropathy

    Directory of Open Access Journals (Sweden)

    Claudia B. Catarino MD, PhD

    2017-09-01

    Full Text Available Leber’s hereditary optic neuropathy (LHON is one of the most frequent mitochondrial disorders. It is caused by mutations in genes of the mitochondrial DNA coding for subunits of the respiratory chain and leads to severe bilateral vision loss, from which spontaneous recovery is infrequent. Retinal ganglion cells show a selective vulnerability to mitochondrial dysfunction in LHON. Idebenone is the first medication approved for LHON. It is a short-chain benzoquinone, which is an analogue of coenzyme Q10, but with distinct properties and mechanisms of action. Idebenone is a potent antioxidant and inhibitor of lipid peroxidation. Importantly, it facilitates electron flux directly to complex III, bypassing the dysfunctional complex I of the mitochondrial respiratory chain, thereby increasing adenosine triphosphate (ATP production. In the Rescue of Hereditary Optic Disease Outpatient Study (RHODOS randomized placebo-controlled clinical trial, 85 patients with LHON were enrolled, in the first 5 years after symptom onset, and randomized to either idebenone 900 mg/d for 6 months or placebo. Idebenone was well tolerated, and although the prespecified primary end point (best recovery in visual acuity [VA] did not reach statistical significance, all secondary end points (change in best VA, change of VA of best eye at baseline, and change of VA in all eyes showed a trend toward visual recovery in favor of idebenone. An increasing body of evidence shows that idebenone is effective and safe for the treatment of patients with LHON, including a large retrospective open-label study, several case reports and case series, an expanded access program, and ongoing post-authorization clinical studies. Here, we review the literature on idebenone for the treatment of patients with LHON.

  1. Multiplex MALDI-TOF MS detection of mitochondrial variants in Brazilian patients with hereditary optic neuropathy

    Science.gov (United States)

    Matilde da Silva-Costa, Sueli; Balieiro, Juliane Cristina; Fernandes, Marcela Scabello Amaral; Alves, Rogério Marins; Guerra, Andrea Trevas Maciel; Marcondes, Ana Maria; Sartorato, Edi Lúcia

    2016-01-01

    Purpose Leber hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by bilateral vision loss. More than 95% of LHON cases are associated with one of the three main mtDNA mutations: G11778A, T14484C, and G3460A. The other 5% of cases are due to other rare mutations related to the disease. The aim of this study was to identify the prevalence and spectrum of LHON mtDNA mutations, including the haplogroup, in a cohort of Brazilian patients with optic neuropathy and to evaluate the usefulness of iPLEX Gold/matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) technology in detecting LHON mutations. Methods We analyzed a total of 101 patients; 67 had a clinical diagnosis of LHON and 34 had optic neuropathy of unknown etiology. Direct sequencing and iPLEX Gold/MALDI-TOF MS were used to screen for the most common pathogenic point mutations in LHON, together with the rare mutations G3733A, C4171A, T10663C, G14459A, C14482G, A14495G, C14568T, and C14482A. Results We identified mutations in 36 patients, of whom 83.3% carried the G11778A mutation and 16.7% carried the T14484C mutation. In individuals with mutations, the haplogroups found were L1/L2, L3, C, R, U, D, and H. Rare mutations were not detected in any of the patients analyzed. Conclusions The frequencies of the main LHON mutations were similar to those previously reported for Latin America. A different frequency was found only for the A3460G mutation. The most frequent haplogroups identified were of African origin. The iPLEX Gold/MALDI-TOF MS technology proved to be highly accurate and efficient for screening mutations and identifying the haplogroups related to LHON. The MassArray platform, combined with other techniques, enabled definitive diagnosis of LHON in 36% (36/101) of the cases studied. PMID:27582625

  2. Multiplex MALDI-TOF MS detection of mitochondrial variants in Brazilian patients with hereditary optic neuropathy.

    Science.gov (United States)

    Miranda, Paulo Maurício do Amôr Divino; Matilde da Silva-Costa, Sueli; Balieiro, Juliane Cristina; Fernandes, Marcela Scabello Amaral; Alves, Rogério Marins; Guerra, Andrea Trevas Maciel; Marcondes, Ana Maria; Sartorato, Edi Lúcia

    2016-01-01

    Leber hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by bilateral vision loss. More than 95% of LHON cases are associated with one of the three main mtDNA mutations: G11778A, T14484C, and G3460A. The other 5% of cases are due to other rare mutations related to the disease. The aim of this study was to identify the prevalence and spectrum of LHON mtDNA mutations, including the haplogroup, in a cohort of Brazilian patients with optic neuropathy and to evaluate the usefulness of iPLEX Gold/matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) technology in detecting LHON mutations. We analyzed a total of 101 patients; 67 had a clinical diagnosis of LHON and 34 had optic neuropathy of unknown etiology. Direct sequencing and iPLEX Gold/MALDI-TOF MS were used to screen for the most common pathogenic point mutations in LHON, together with the rare mutations G3733A, C4171A, T10663C, G14459A, C14482G, A14495G, C14568T, and C14482A. We identified mutations in 36 patients, of whom 83.3% carried the G11778A mutation and 16.7% carried the T14484C mutation. In individuals with mutations, the haplogroups found were L1/L2, L3, C, R, U, D, and H. Rare mutations were not detected in any of the patients analyzed. The frequencies of the main LHON mutations were similar to those previously reported for Latin America. A different frequency was found only for the A3460G mutation. The most frequent haplogroups identified were of African origin. The iPLEX Gold/MALDI-TOF MS technology proved to be highly accurate and efficient for screening mutations and identifying the haplogroups related to LHON. The MassArray platform, combined with other techniques, enabled definitive diagnosis of LHON in 36% (36/101) of the cases studied.

  3. [Leber hereditary optic neuropathy: Usefulness of next generation sequencing to study mitochondrial mutations on apparent homoplasmy].

    Science.gov (United States)

    Carrasco Salas, Pilar; Palma Milla, Carmen; López Montiel, Javier; Benito, Carmen; Franco Freire, Sara; López Siles, Juan

    2016-02-19

    Leber hereditary optic neuropathy is characterized by acute and subacute visual loss, produced by mitochondrial DNA mutations. The molecular study of a family with only one affected member is presented. In the index case and in her mother, the mitochondrial mutation m.11778G>A in the MT-ND4 was detected in the heteroplasmic state. The index case's sister, without ocular manifestations, asked for genetic counseling. The study of the mentioned mutation by Sanger sequencing identified it in an apparent homoplasmic state. However, by means of next-generation sequencing (NGS), the mutation was actually in a heteroplasmic state. Regarding genetic counseling, verifying a mutation in homoplasmic state is really important. We have observed that NGS allows us to discriminate between high levels of heteroplasmy and homoplasmy, meaning that it is a useful technique for the analysis of apparent homoplasmic results obtained with less sensitive technique, as Sanger sequencing. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  4. Cells bearing mutations causing Leber's hereditary optic neuropathy are sensitized to Fas-Induced apoptosis.

    Science.gov (United States)

    Danielson, Steven R; Wong, Alice; Carelli, Valerio; Martinuzzi, Andrea; Schapira, Anthony H V; Cortopassi, Gino A

    2002-02-22

    Three prevalent mitochondrial DNA pathogenic mutations at positions 11778, 3460, and 14484, which affect different subunits of Complex I, cause retinal ganglion cell death and optic nerve atrophy in Leber's hereditary optic neuropathy (LHON). The cell death is painless and without inflammation, consistent with an apoptotic mechanism. We have investigated the possibility that the LHON mutation confers a pro-apoptotic stimulus and have tested the sensitivity of osteosarcoma-derived cybrid cells carrying the most common and severe mutations (11778 and 3460) to cell death induced by Fas. We observed that LHON cybrids were sensitized to Fas-dependent death. Control cells that bear the same mitochondrial genetic background (the J haplogroup) without the pathogenic 11778 mutation are no more sensitive than other controls, indicating that increased Fas-dependent death in LHON cybrids was induced by the LHON pathogenic mutations. The type of death was apoptotic by several criteria, including induction by Fas, inhibition by the caspase inhibitor zVAD-fmk (zVal-Ala-Asp-fluoro-methyl ketone), activation of DEVDase activity (Asp-Glu-Val-Asp protease), specific cleavage of caspase-3, DNA fragmentation, and increased Annexin-V labeling. These data indicate that the most common and severe LHON pathogenic mutations 11778 and 3460 predispose cells to apoptosis, which may be relevant for the pathophysiology of cell death in LHON, and potential therapy.

  5. Leber Hereditary Optic Neuropathy: A Mitochondrial Disease Unique in Many Ways.

    Science.gov (United States)

    Bi, Rui; Logan, Ian; Yao, Yong-Gang

    2017-01-01

    Leber hereditary optic neuropathy (LHON) was the first mitochondrial disease to be identified as being caused by mutations in the mitochondrial DNA (mtDNA). This disease has been studied extensively in the past two decades, particularly in Brazilian, Chinese and European populations; and many primary mutations have been reported. However, the disease is enigmatic with many unique features, and there still are several important questions to be resolved. The incomplete penetrance, the male-biased disease expression and the prevalence in young adults all defy a proper explanation. It has been reported that the development of LHON is affected by the interaction between mtDNA mutations, mtDNA haplogroup background, nuclear genes, environmental factors and epigenetics. Furthermore, with the help of new animal models for LHON that have been created in recent years, we are continuing to learn more about the mechanism of this disease. The stage has now been reached at which there is a good understanding of both the genetic basis of the disease and its epidemiology, but just how the blindness that follows from the death of cells in the optic nerve can be prevented remains to be a pharmacological challenge. In this chapter, we summarize the progress that has been made in various recent studies on LHON, focusing on the molecular pathogenic mechanisms, clinical features, biochemical effects, the pharmacology and its treatment.

  6. Human extraocular muscles in mitochondrial diseases: comparing chronic progressive external ophthalmoplegia with Leber's hereditary optic neuropathy.

    Science.gov (United States)

    Carta, A; Carelli, V; D'Adda, T; Ross-Cisneros, F N; Sadun, A A

    2005-07-01

    To compare the ultrastructural aspects of human extraocular muscles in two types of mitochondrial disease: chronic progressive external ophthalmoplegia (CPEO) and Leber's hereditary optic neuropathy (LHON). Muscle samples of the medial rectus obtained from surgery in a sporadic case of CPEO associated with deleted mitochondrial DNA, and post mortem in a case of 3460/ND1 LHON were processed for electron microscopy (EM). The medial rectus from an autoptic time to fixation matched control was used to exclude postmortem artefacts. The CPEO specimen revealed focal areas of disruption and abnormalities of mitochondria in some muscle fibres, creating a "mosaic-like" pattern. In the LHON specimen a diffuse increase in both number and size of mitochondria (mean diameter 0.85 mum v 0.65 mum of control, pCPEO and LHON reveals marked differences. A "mosaic-like" pattern caused by a selective damage of muscle fibres was evident in CPEO, whereas a diffuse increase in mitochondria with preservation of myofibrils characterised the LHON case. These ultrastructural changes may relate to the different expression of the two diseases, resulting in ophthalmoplegia in CPEO and normal eye movements in LHON.

  7. International Consensus Statement on the Clinical and Therapeutic Management of Leber Hereditary Optic Neuropathy.

    Science.gov (United States)

    Carelli, Valerio; Carbonelli, Michele; de Coo, Irenaeus F; Kawasaki, Aki; Klopstock, Thomas; Lagrèze, Wolf A; La Morgia, Chiara; Newman, Nancy J; Orssaud, Christophe; Pott, Jan Willem R; Sadun, Alfredo A; van Everdingen, Judith; Vignal-Clermont, Catherine; Votruba, Marcela; Yu-Wai-Man, Patrick; Barboni, Piero

    2017-12-01

    Leber hereditary optic neuropathy (LHON) is currently estimated as the most frequent mitochondrial disease (1 in 27,000-45,000). Its molecular pathogenesis and natural history is now fairly well understood. LHON also is the first mitochondrial disease for which a treatment has been approved (idebenone-Raxone, Santhera Pharmaceuticals) by the European Medicine Agency, under exceptional circumstances because of the rarity and severity of the disease. However, what remains unclear includes the optimal target population, timing, dose, and frequency of administration of idebenone in LHON due to lack of accepted definitions, criteria, and general guidelines for the clinical management of LHON. To address these issues, a consensus conference with a panel of experts from Europe and North America was held in Milan, Italy, in 2016. The intent was to provide expert consensus statements for the clinical and therapeutic management of LHON based on the currently available evidence. We report the conclusions of this conference, providing the guidelines for clinical and therapeutic management of LHON.

  8. Pitfalls in the molecular genetic diagnosis of Leber hereditary optic neuropathy (LHON)

    Energy Technology Data Exchange (ETDEWEB)

    Johns, D.R. (Beth Israel Hospital, Boston, MA (United States)); Neufeld, M.J. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States))

    1993-10-01

    Pathogenetic mutations in mtDNA are found in the majority of patients with Leber hereditary optic neuropathy (LHON), and molecular genetic techniques to detect them are important for diagnosis. A false-positive molecular genetic error has adverse consequences for the diagnosis of this maternally inherited disease. The authors found a number of mtDNA polymorphisms that occur adjacent to known LHON-associated mutations and that confound their molecular genetic detection. These transition mutations occur at mtDNA nt 11779 (SfaNI site loss, 11778 mutation), nt 3459 (BsaHI site loss, 3460 mutation), nt 15258 (AccI site loss, 15257 mutation), nt 14485 (mismatch primer Sau3AI site loss, 14484 mutation), and nt 13707 (BstNI site loss, 13708 mutation). Molecular genetic detection of the most common pathogenetic mtDNA mutations in LHON, using a single restriction enzyme, may be confounded by adjacent polymorphisms that occur with a false-positive rate of 2%-7%. 19 refs.

  9. Hereditary Neuropathy with Liability to Pressure Palsies Masked by Previous Gunshots and Tuberculosis

    Directory of Open Access Journals (Sweden)

    Martin Gencik

    2015-01-01

    Full Text Available Objectives. Although hereditary neuropathy with liability to pressure palsies (HNPP presents with a distinct phenotype on history, clinical exam, and nerve conduction studies, it may be masked if diagnostic work-up suggests other causes. Case Report. In a 37-year-old male with pseudoradicular lumbar pain, neurological exam revealed sore neck muscles, peripheral facial nerve palsy, right anacusis and left hypoacusis, hemihypesthesia of the right face, mild distal quadriparesis, diffuse wasting, and generally reduced tendon reflexes. He had a history of skull fracture due to a gunshot behind the right ear and tuberculosis for which he had received adequate treatment for 3 years; MRI revealed a disc prolapse at C6/7 and Th11/12. Nerve conduction studies were indicative of demyelinating polyneuropathy with conduction blocks. Despite elevated antinuclear antibodies and elevated CSF-protein, HNPP was diagnosed genetically after having excluded vasculitis, CIDP, radiculopathy, and the side effects of antituberculous treatment. Conclusions. HNPP may manifest with mild, painless, distal quadriparesis. The diagnosis of HNPP may be blurred by a history of tuberculosis, tuberculostatic treatment, hepatitis, and the presence of elevated CSF-protein.

  10. Mathematically Modeling the Involvement of Axons in Leber's Hereditary Optic Neuropathy

    Science.gov (United States)

    Pan, Billy X.; Ross-Cisneros, Fred N.; Carelli, Valerio; Rue, Kelly S.; Salomao, Solange R.; Moraes-Filho, Milton N.; Moraes, Milton N.; Berezovsky, Adriana; Belfort, Rubens; Sadun, Alfredo A.

    2012-01-01

    Purpose. Leber's hereditary optic neuropathy (LHON), a mitochondrial disease, has clinical manifestations that reflect the initial preferential involvement of the papillomacular bundle (PMB). The present study seeks to predict the order of axonal loss in LHON optic nerves using the Nerve Fiber Layer Stress Index (NFL-SI), which is a novel mathematical model. Methods. Optic nerves were obtained postmortem from four molecularly characterized LHON patients with varying degrees of neurodegenerative changes and three age-matched controls. Tissues were cut in cross-section and stained with p-phenylenediamine to visualize myelin. Light microscopic images were captured in 32 regions of each optic nerve. Control and LHON tissues were evaluated by measuring axonal dimensions to generate an axonal diameter distribution map. LHON tissues were further evaluated by determining regions of total axonal depletion. Results. A size gradient was evident in the control optic nerves, with average axonal diameter increasing progressively from the temporal to nasal borders. LHON optic nerves showed an orderly loss of axons, starting inferotemporally, progressing centrally, and sparing the superonasal region until the end. Values generated from the NFL-SI equation fit a linear regression curve (R2 = 0.97; P LHON, supporting clinical findings seen early in the course of disease onset. The present study also showed that the subsequent progression of axonal loss within the optic nerve can be predicted precisely with the NFL-SI equation. The results presented provided further insight into the pathophysiology of LHON. PMID:23060142

  11. Changes in Choroidal Thickness follow the RNFL Changes in Leber’s Hereditary Optic Neuropathy

    Science.gov (United States)

    Borrelli, Enrico; Triolo, Giacinto; Cascavilla, Maria Lucia; La Morgia, Chiara; Rizzo, Giovanni; Savini, Giacomo; Balducci, Nicole; Nucci, Paolo; Giglio, Rosa; Darvizeh, Fatemeh; Parisi, Vincenzo; Bandello, Francesco; Sadun, Alfredo A.; Carelli, Valerio; Barboni, Piero

    2016-01-01

    Leber’s hereditary optic neuropathy (LHON) is typically characterized by vascular alterations in the acute phase. The aim of this study was to evaluate choroidal changes occurring in asymptomatic, acute and chronic stages of LHON. We enrolled 49 patients with LHON, 19 with Dominant Optic Atrophy (DOA) and 22 healthy controls. Spectral Domain-Optical Coherence Tomography (SD-OCT) scans of macular and peripapillary regions were performed in all subjects, to evaluate macular and peripapillary choroidal thickness, and retinal nerve fiber layer (RNFL) thicknes. Macular and peripapillary choroidal thicknesses were significantly increased in the acute LHON stage. On the contrary, macular choroidal thickness was significantly reduced in the chronic stage. Furthermore, peripapillary choroidal thickness was decreased in chronic LHON and in DOA. Both RNFL and choroid had the same trend (increased thickness, followed by thinning), but RNFL changes preceded those affecting the choroid. In conclusion, our study quantitatively demonstrated the involvement of the choroid in LHON pathology. The increase in choroidal thickness is a feature of the LHON acute stage, which follows the thickening of RNFL. Conversely, thinning of the choroid is the common outcome in chronic LHON and in DOA. PMID:27853297

  12. Changes in Choroidal Thickness follow the RNFL Changes in Leber's Hereditary Optic Neuropathy.

    Science.gov (United States)

    Borrelli, Enrico; Triolo, Giacinto; Cascavilla, Maria Lucia; La Morgia, Chiara; Rizzo, Giovanni; Savini, Giacomo; Balducci, Nicole; Nucci, Paolo; Giglio, Rosa; Darvizeh, Fatemeh; Parisi, Vincenzo; Bandello, Francesco; Sadun, Alfredo A; Carelli, Valerio; Barboni, Piero

    2016-11-17

    Leber's hereditary optic neuropathy (LHON) is typically characterized by vascular alterations in the acute phase. The aim of this study was to evaluate choroidal changes occurring in asymptomatic, acute and chronic stages of LHON. We enrolled 49 patients with LHON, 19 with Dominant Optic Atrophy (DOA) and 22 healthy controls. Spectral Domain-Optical Coherence Tomography (SD-OCT) scans of macular and peripapillary regions were performed in all subjects, to evaluate macular and peripapillary choroidal thickness, and retinal nerve fiber layer (RNFL) thicknes. Macular and peripapillary choroidal thicknesses were significantly increased in the acute LHON stage. On the contrary, macular choroidal thickness was significantly reduced in the chronic stage. Furthermore, peripapillary choroidal thickness was decreased in chronic LHON and in DOA. Both RNFL and choroid had the same trend (increased thickness, followed by thinning), but RNFL changes preceded those affecting the choroid. In conclusion, our study quantitatively demonstrated the involvement of the choroid in LHON pathology. The increase in choroidal thickness is a feature of the LHON acute stage, which follows the thickening of RNFL. Conversely, thinning of the choroid is the common outcome in chronic LHON and in DOA.

  13. Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside

    Science.gov (United States)

    Koilkonda, Rajeshwari D.; Guy, John

    2011-01-01

    Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disorder caused by point mutations in mitochondrial DNA (mtDNA). Most cases are due to mutations in genes encoding subunits of the NADH-ubiquinone oxidoreductase that is Complex I of the electron transport chain (ETC). These mutations are located at nucleotide positions 3460, 11778, or 14484 in the mitochondrial genome. The disease is characterized by apoplectic, bilateral, and severe visual loss. While the mutated mtDNA impairs generation of ATP by all mitochondria, there is only a selective loss of retinal ganglion cells and degeneration of optic nerve axons. Thus, blindness is typically permanent. Half of the men and 10% of females who harbor the pathogenic mtDNA mutation actually develop the phenotype. This incomplete penetrance and gender bias is not fully understood. Additional mitochondrial and/or nuclear genetic factors may modulate the phenotypic expression of LHON. In a population-based study, the mtDNA background of haplogroup J was associated with an inverse relationship of low-ATP generation and increased production of reactive oxygen species (ROS). Effective therapy for LHON has been elusive. In this paper, we describe the findings of pertinent published studies and discuss the controversies of potential strategies to ameliorate the disease. PMID:21253496

  14. Secondary Post-Geniculate Involvement in Leber’s Hereditary Optic Neuropathy

    Science.gov (United States)

    Rizzo, Giovanni; Tozer, Kevin R.; Tonon, Caterina; Manners, David; Testa, Claudia; Malucelli, Emil; Valentino, Maria Lucia; La Morgia, Chiara; Barboni, Piero; Randhawa, Ruvdeep S.; Ross-Cisneros, Fred N.; Sadun, Alfredo A.; Carelli, Valerio; Lodi, Raffaele

    2012-01-01

    Leber’s hereditary optic neuropathy (LHON) is characterized by retinal ganglion cell (RGC) degeneration with the preferential involvement of those forming the papillomacular bundle. The optic nerve is considered the main pathological target for LHON. Our aim was to investigate the possible involvement of the post-geniculate visual pathway in LHON patients. We used diffusion-weighted imaging for in vivo evaluation. Mean diffusivity maps from 22 LHON visually impaired, 11 unaffected LHON mutation carriers and 22 healthy subjects were generated and compared at level of optic radiation (OR). Prefrontal and cerebellar white matter were also analyzed as internal controls. Furthermore, we studied the optic nerve and the lateral geniculate nucleus (LGN) in post-mortem specimens obtained from a severe case of LHON compared to an age-matched control. Mean diffusivity values of affected patients were higher than unaffected mutation carriers (PLHON LGN associated with extremely severe axonal loss (99%) in the optic nerve. The post-geniculate involvement in LHON patients is a downstream post-synaptic secondary phenomenon, reflecting de-afferentation rather than a primary neurodegeneration due to mitochondrial dysfunction of LGN neurons. PMID:23209682

  15. Progression of visual field defects in leber hereditary optic neuropathy: experience of the LHON treatment trial.

    Science.gov (United States)

    Newman, Nancy J; Biousse, Valérie; Newman, Steven A; Bhatti, M Tariq; Hamilton, Steven R; Farris, Bradley K; Lesser, Robert L; Turbin, Roger E

    2006-06-01

    To describe the visual fields of patients with Leber hereditary optic neuropathy (LHON), a maternally inherited disorder characterized by bilateral, often sequential vision loss, before and during progressive visual deterioration. Prospective longitudinal follow-up of serial visual fields in patients enrolled onto an open-label, nonrandomized pilot study of topical brimonidine purite as prophylactic treatment after first eye involvement in LHON. Nine molecularly confirmed primary mutation patients with LHON with monocular vision loss for less than six months and normal visual function in the other eye were followed prospectively for up to two years. Visual fields were performed on automated perimetry at baseline and on many follow-up visits. Despite normal visual acuity at baseline in all patients, seven patients had some minimal changes in the central visual field of the second eye. All patients had subsequent deterioration of visual acuity, mean deviation, and foveal sensitivity in their second eye. The earliest pattern of abnormality was typically a cecocentral defect enlarging to become a central defect, often with a superior or inferior predilection. The visual field defects in the two eyes of any given patient were remarkably similar. LHON may be a bilateral condition at onset more frequently than appreciated. Automated static perimetry of the "normal" eye may reveal subclinical findings that typically worsen rapidly over weeks to months to similar central scotomatous damage. Quantitative automated static perimetry is helpful in elucidating the natural history of LHON and in understanding the underlying pathology and pathophysiology of this disease.

  16. Effects of Idebenone on Color Vision in Patients With Leber Hereditary Optic Neuropathy

    Science.gov (United States)

    Rudolph, Guenther; Dimitriadis, Konstantinos; Büchner, Boriana; Heck, Suzette; Al-Tamami, Jasmina; Seidensticker, Florian; Rummey, Christian; Leinonen, Mika; Meier, Thomas

    2013-01-01

    Background: The authors investigated the correlation of protan and tritan color vision with disease characteristics in Leber hereditary optic neuropathy (LHON). The authors also characterized the therapeutic potential of idebenone in protecting patients from developing dyschromatopsia in LHON. Methods: Color contrast data of 39 LHON patients participating in a randomized, double-blind placebo-controlled intervention study were evaluated. Patients reported disease onset A mutation, and mean duration since onset was 2 years. Assessing protan and tritan color vision at baseline revealed a high degree of color confusion even in young patients (0.2). In this subgroup, the treatment effect at week 24 was 20.4% (P = 0.005) in favor of idebenone for the tritan color domain and 13.5% (P = 0.067) for the protan domain. Conclusion: This study confirms that protan and tritan color confusion is an early symptom in LHON. Treatment with idebenone can protect from loss of color vision, particularly in patients who are at imminent risk of further vision loss. PMID:23263355

  17. Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside

    Directory of Open Access Journals (Sweden)

    Rajeshwari D. Koilkonda

    2011-01-01

    Full Text Available Leber's hereditary optic neuropathy (LHON is a maternally transmitted disorder caused by point mutations in mitochondrial DNA (mtDNA. Most cases are due to mutations in genes encoding subunits of the NADH-ubiquinone oxidoreductase that is Complex I of the electron transport chain (ETC. These mutations are located at nucleotide positions 3460, 11778, or 14484 in the mitochondrial genome. The disease is characterized by apoplectic, bilateral, and severe visual loss. While the mutated mtDNA impairs generation of ATP by all mitochondria, there is only a selective loss of retinal ganglion cells and degeneration of optic nerve axons. Thus, blindness is typically permanent. Half of the men and 10% of females who harbor the pathogenic mtDNA mutation actually develop the phenotype. This incomplete penetrance and gender bias is not fully understood. Additional mitochondrial and/or nuclear genetic factors may modulate the phenotypic expression of LHON. In a population-based study, the mtDNA background of haplogroup J was associated with an inverse relationship of low-ATP generation and increased production of reactive oxygen species (ROS. Effective therapy for LHON has been elusive. In this paper, we describe the findings of pertinent published studies and discuss the controversies of potential strategies to ameliorate the disease.

  18. A Female Patient with Down Syndrome and Low-Penetrance Leber's Hereditary Optic Neuropathy

    Directory of Open Access Journals (Sweden)

    Starleen E. Frousiakis

    2014-11-01

    Full Text Available We present the case of a 19-year-old female with a history of Down syndrome (DS who was referred to our neuro-ophthalmology clinic for evaluation of Leber's hereditary optic neuropathy (LHON. The patient's family history was significant for a known G11778A mutation in a maternal relative, consistent with LHON. The patient was also positive for the G11778A mutation; however, the genotype demonstrated low penetrance in the pedigree, with only 1 out of 10 adult male offspring showing signs or symptoms of the disease. Mitochondrial mutations implicated in LHON have been shown to impair complex I of the electron transport chain and thereby reducing the effective generation of adenosine triphosphate and increasing the production of toxic reactive oxygen species. Although the partial or complete triplicate of chromosome 21 constitutes the etiology of DS, some of the pleiotropic phenotypes of the syndrome have been attributed to oxidative stress and mitochondrial dysfunction. Given the low penetrance of the mutation and the patient's sex, this case illustrates the possibility that the mitochondrial mutation demonstrated increased penetrance due to pre-existing mitochondrial dysfunction related to DS.

  19. Leber’s hereditary optic neuropathy is multiorgan not mono-organ

    Directory of Open Access Journals (Sweden)

    Finsterer J

    2016-11-01

    Full Text Available Josef Finsterer,1 Sinda Zarrouk-Mahjoub2 1Krankenanstalt Rudolfstiftung, Vienna, Austria; 2Genomics Platform, Pasteur Institute of Tunis, Tunisia Abstract: Leber’s hereditary optic neuropathy (LHON is a maternally inherited mitochondrial disorder with bilateral loss of central vision primarily due to mitochondrial DNA (mtDNA mutations in subunits of complex I in the respiratory chain (primary LHON mutations, while other mtDNA mutations can also be causative. Since the first description, it is known that LHON is not restricted to the eyes but is a multisystem disorder additionally involving the central nervous system, ears, endocrinological organs, heart, bone marrow, arteries, kidneys, or the peripheral nervous system. Multisystem involvement may start before or after the onset of visual impairment. Involvement of organs other than the eyes may be subclinical depending on age, ethnicity, and possibly the heteroplasmy rate of the responsible primary LHON mutation. Primary LHON mutations may rarely manifest without ocular compromise but with arterial hypertension, various neurodegenerative diseases, or Leigh syndrome. Patients with LHON need to be closely followed up to detect at which point organs other than the eyes become affected. Multiorgan disease in LHON often responds more favorably to symptomatic treatment than the ocular compromise. Keywords: mitochondrial DNA, heteroplasmy, respiratory chain, LHON, genotype–phenotype correlation

  20. Leber′s hereditary optic neuropathy with molecular characterization in two Indian families

    Directory of Open Access Journals (Sweden)

    Verma I

    2005-01-01

    Full Text Available PURPOSE: Leber′s hereditary optic neuropathy (LHON presents in early adulthood with painless progressive blindness of one or both eyes. Usually there is a positive family history of similar disease on the maternal side. Definitive diagnosis can be established by finding the change in the mitochondrial gene. No molecular studies have been reported from India. MATERIAL AND METHODS: Clinical, ophthalmologic and molecular studies were carried out in two patients from different families and available first degree relatives. The subjects were tested for the three common mutations seen in LHON by molecular techniques of polymerase chain reaction using mutation specific primers. RESULTS: The mutations G3460A and G11778A in the mitochondrial genes MTND1 and MTND4, known to be causative for LHON, were found in one family each. CONCLUSION: Diagnosis of LHON should be considered in familial cases and in young adults with optic atrophy. Confirmation of diagnosis should be sought by molecular gene analysis. Genetic counselling should be offered to all ′at risk′ relatives of a patient harbouring the mutation.

  1. Male prevalence of acquired color vision defects in asymptomatic carriers of Leber's hereditary optic neuropathy.

    Science.gov (United States)

    Ventura, Dora Fix; Gualtieri, Mirella; Oliveira, André G F; Costa, Marcelo F; Quiros, Peter; Sadun, Federico; de Negri, Anna Maria; Salomão, Solange R; Berezovsky, Adriana; Sherman, Jerome; Sadun, Alfredo A; Carelli, Valerio

    2007-05-01

    Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease resulting in loss of central vision and dyschromatopsia, caused by mitochondrial DNA point mutations. However, only a subset of the mutation carriers becomes affected, with a higher penetrance in males. This study was conducted to investigate chromatic losses in asymptomatic carriers of the LHON mutation. Monocular chromatic discrimination was studied with the Cambridge Colour Test (CCT; Cambridge Research Systems, Ltd., Rochester, UK) along the protan, deutan, and tritan cone isolation axes in 46 LHON carriers (15 men) belonging to the same LHON maternal lineage and 74 age-matched control subjects (39 men). Inclusion criteria were absence of ophthalmic complaints and clear ocular media. A detailed neuro-ophthalmic examination was performed in all the LHON carriers. The differences in threshold between carriers and control subjects were significant for the three cone isolation axes at P women for the protan and deutan axes (ANOVA; P women had instances of diffuse defect whereas all the men displayed a red-green defect. Male LHON asymptomatic carriers had color vision losses with the red-green pattern of dyschromatopsia typical of patients affected with LHON, which includes elevation of tritan thresholds as well. This predominantly parvocellular (red-green) impairment is compatible with the histopathology of LHON, which affects mostly the papillomacular bundle. In contrast with male losses, female losses were less frequent and severe. These gender differences are relevant to understanding LHON pathophysiology, suggesting that hormonal factors may be of great importance.

  2. Hereditary spastic paraplegia: More than an upper motor neuron disease.

    Science.gov (United States)

    Parodi, L; Fenu, S; Stevanin, G; Durr, A

    2017-05-01

    Hereditary spastic paraplegias (HSPs) are a group of rare inherited neurological diseases characterized by extreme heterogeneity in both their clinical manifestations and genetic backgrounds. Based on symptoms, HSPs can be divided into pure forms, presenting with pyramidal signs leading to lower-limb spasticity, and complex forms, when additional neurological or extraneurological symptoms are detected. The clinical diversity of HSPs partially reflects their underlying genetic backgrounds. To date, 76 loci and 58 corresponding genes [spastic paraplegia genes (SPGs)] have been linked to HSPs. The genetic diagnosis is further complicated by the fact that causative mutations of HSP can be inherited through all possible modes of transmission (autosomal-dominant and -recessive, X-linked, maternal), with some genes showing multiple inheritance patterns. The pathogenic mutations of SPGs primarily lead to progressive degeneration of the upper motor neurons (UMNs) comprising corticospinal tracts. However, it is possible to observe lower-limb muscle atrophy and fasciculations on clinical examination that are clear signs of lower motor neuron (LMN) involvement. The purpose of this review is to classify HSPs based on their degree of motor neuron involvement, distinguishing forms in which only UMNs are affected from those involving both UMN and LMN degeneration, and to describe their differential diagnosis from diseases such as amyotrophic lateral sclerosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial.

    Science.gov (United States)

    Koilkonda, Rajeshwari D; Yu, Hong; Chou, Tsung-Han; Feuer, William J; Ruggeri, Marco; Porciatti, Vittorio; Tse, David; Hauswirth, William W; Chiodo, Vince; Boye, Sanford L; Lewin, Alfred S; Neuringer, Martha; Renner, Lauren; Guy, John

    2014-04-01

    IMPORTANCE We developed a novel strategy for treatment of Leber hereditary optic neuropathy (LHON) caused by a mutation in the nicotinamide adenine dinucleotide dehydrogenase subunit IV (ND4) mitochondrial gene. OBJECTIVE To demonstrate the safety and effects of the gene therapy vector to be used in a proposed gene therapy clinical trial. DESIGN AND SETTING In a series of laboratory experiments, we modified the mitochondrial ND4 subunit of complex I in the nuclear genetic code for import into mitochondria. The protein was targeted into the organelle by agency of a targeting sequence (allotopic expression). The gene was packaged into adeno-associated viral vectors and then vitreally injected into rodent, nonhuman primate, and ex vivo human eyes that underwent testing for expression and integration by immunohistochemical analysis and blue native polyacrylamide gel electrophoresis. During serial follow-up, the animal eyes underwent fundus photography, optical coherence tomography, and multifocal or pattern electroretinography. We tested for rescue of visual loss in rodent eyes also injected with a mutant G11778A ND4 homologue responsible for most cases of LHON. EXPOSURE Ocular infection with recombinant adeno-associated viral vectors containing a wild-type allotopic human ND4 gene. MAIN OUTCOMES AND MEASURES Expression of human ND4 and rescue of optic neuropathy induced by mutant human ND4. RESULTS We found human ND4 expressed in almost all mouse retinal ganglion cells by 1 week after injection and ND4 integrated into the mouse complex I. In rodent eyes also injected with a mutant allotopic ND4, wild-type allotopic ND4 prevented defective adenosine triphosphate synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells, and prevented demise of axons in the optic nerve. Injection of ND4 in the ex vivo human eye resulted in expression in most retinal ganglion cells. Primates undergoing vitreal injection with the ND4 test article and followed up for 3

  4. Subcutaneous versus intravenous immunoglobulin in multifocal motor neuropathy

    DEFF Research Database (Denmark)

    Harbo, T; Andersen, Henning; Hess, A

    2009-01-01

    strength of affected muscles and (ii) the SF-36 quality of life questionnaire. Results: The two treatments were equally effective, the mean change in muscle strength after SCIG being 3.6% (95% CI -3.6% to 10.9%) vs. 4.3% (-1.3% to 10.0%) after IVIG (P = 0.86). One patient had sustained erythema and oedema......Background and purpose: For treatment of multifocal motor neuropathy (MMN), we hypothesized that (i) infusion of equivalent dosages of subcutaneous immunoglobulin (SCIG) is as effective as intravenous immunoglobulin (IVIG) and that (ii) subcutaneous infusion at home is associated with a better...... quality of life. Methods: In a randomized single-blinded cross-over study, nine IVIG responsive patients were allocated to receive either SCIG or IVIG for a period equivalent to three IVIG treatment intervals and, subsequently, crossed over to the other treatment. Primary end-points were (i) dynamometric...

  5. Epidemiology of hereditary sensory and autonomic neuropathy type IV and V in Japan.

    Science.gov (United States)

    Haga, Nobuhiko; Kubota, Masaya; Miwa, Zenzo

    2013-04-01

    Hereditary sensory and autonomic neuropathy (HASN) refers to a group of rare congenital disorders characterized by loss of pain sensation and other sensory or autonomic abnormalities. Among them, a relatively large proportion of patients with HSAN type IV, which is accompanied by anhidrosis and intellectual disability, are reported from Israel and Japan. HSAN type V, with normal sweating and mental development, is rarely reported in Japan. In 2009, we founded a research group for congenital insensitivity to pain and performed the first epidemiological survey of HSAN types IV and V in Japan. Questionnaires were sent to a total of 3,488 certified training institutions of five nationwide medical societies comprising pediatricians, neurologists, orthopedic surgeons, and dentists. Answers were obtained from 1,610 institutions, and 192 HSAN patients (152 with type IV and 28 with type V) were reported from 105 institutions. After excluding duplicated patients, we identified a total of 62 current, 36 past, and five deceased patients for HSAN-IV, and a total of 14 current, 13 past, and 0 deceased patients for HSAN-V. Using these figures, we estimated that the number of Japanese patients with HSAN types IV and V as 130-210 and 30-60 patients, respectively. We identified no gender differences, and patients with a family history of the disorder were limited to affected siblings in both conditions. Most patients with HSAN-IV were 5-40 years of age, whereas half of the patients with HSAN-V were 40 years or older. Copyright © 2013 Wiley Periodicals, Inc.

  6. Point mutations associated with Leber hereditary optic neuropathy in a Latvian population.

    Science.gov (United States)

    Aitullina, Aleksandra; Baumane, Kristine; Zalite, Solveiga; Ranka, Renate; Zole, Egija; Pole, Ilva; Sepetiene, Svetlana; Laganovska, Guna; Baumanis, Viesturs; Pliss, Liana

    2013-01-01

    To study mutations associated with Leber hereditary optic neuropathy (LHON) in patients suspected of having this mitochondrial disorder in a Latvian population. Additional aims were to determine the heteroplasmy status of all non-synonymous polymorphisms identified in the current study and to identify the mitochondrial haplogroups of the studied participants because these factors may contribute to the manifestation of LHON. Twelve patients, including patients in two families, were enrolled in the current study. LHON was suspected based on the findings of ophthalmologic examinations. In clinically affected individuals, the presence of all previously reported LHON-associated mutations was assessed with sequencing analysis. Additionally, the SURVEYOR endonuclease assay was used to detect heteroplasmy. The mitochondrial haplogroups were identified with restriction analysis and the sequencing of hypervariable segment 1. In one family (mother and son), there was one primary LHON-associated mutation, G11778A. In addition, one rare previously reported LHON-associated polymorphism, A13637G, was detected in two unrelated patients. A non-synonymous polymorphism at T6253C was found in one individual. This mutation was reported in the background of the 3460 mutation among LHON patients in a Chinese population. No non-synonymous point mutations in mitochondrial DNA were found in five of the study participants. Molecular analysis of 12 patients with suspected LHON confirmed the diagnosis in four patients and allowed the use of appropriate prophylactic measures and treatment. Further investigations and additional studies of different populations are necessary to confirm the role of the non-synonymous polymorphisms A13637G and T6253C in the manifestation of LHON and the associations of these polymorphisms with mitochondrial haplogroups and heteroplasmy.

  7. Retinal ganglion cell dysfunction in asymptomatic G11778A: Leber hereditary optic neuropathy.

    Science.gov (United States)

    Guy, John; Feuer, William J; Porciatti, Vittorio; Schiffman, Joyce; Abukhalil, Fawzi; Vandenbroucke, Ruth; Rosa, Potyra R; Lam, Byron L

    2014-02-10

    To report the serial evaluation of asymptomatic eyes of subjects with mutated G11778A mitochondrial DNA. Forty-five asymptomatic G11778A Leber hereditary optic neuropathy (LHON) carriers and two patients with the mutation who developed unilateral visual loss underwent testing that included visual acuity, automated visual field, pattern electroretinogram (PERG), and spectral-domain optical coherence tomography every 6 months between September 2008 and March 2012. Visual acuity, visual fields, and retinal nerve fiber layer thickness remained stable within the normal range. Mean PERG amplitudes of carriers dropped progressively by ∼ 40% from baseline to 36 months. In addition, comparisons with the fellow eyes of patients with unilateral optic neuritis revealed a 3.4 ETDRS (Early Treatment Diabetic Retinopathy Study) letter loss in the LHON carriers. A single carrier developed visual loss, with PERG amplitudes dropping by half. In one of two LHON cases who presented with unilateral visual loss, visual acuity in the asymptomatic eye was ∼ 20/40 at baseline. The PERG amplitude of this eye was reduced to ∼ 30% of normal. Six months later, his visual acuity had dropped to ∼ 20/500. A second patient who was ∼ 20/20 and had a visual field defect in the asymptomatic eye at baseline remained at this level for the 18 months of follow-up. His PERG amplitudes were similar to those of asymptomatic carriers, with 0.78 μV at baseline that did not decline with follow-up. Declines of the PERG amplitude suggest subclinical retinal ganglion cell dysfunction in asymptomatic G11778A subjects, which is progressive.

  8. Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations.

    Science.gov (United States)

    Pfeffer, Gerald; Burke, Ailbhe; Yu-Wai-Man, Patrick; Compston, D Alastair S; Chinnery, Patrick F

    2013-12-10

    To determine whether the association between multiple sclerosis (MS) and Leber hereditary optic neuropathy (LHON) (known as "Harding disease") is a chance finding, or the 2 disorders are mechanistically linked. We performed a United Kingdom-wide prospective cohort study of prevalent cases of MS with LHON mitochondrial DNA (mtDNA) mutations. The new cases were compared with published cases, enabling a comprehensive clinical description. We also performed a meta-analysis of studies screening patients with MS for LHON mtDNA mutations to find evidence of a genetic association. Twelve new patients were identified from 11 pedigrees, and 44 cases were identified in the literature. The combined cohort had the following characteristics: multiple episodes of visual loss, predominance for women, and lengthy time interval before the fellow eye is affected (average 1.66 years), which is very atypical of LHON; conversely, most patients presented without eye pain and had a poor visual prognosis, which is unusual for optic neuritis associated with MS. The number of UK cases of LHON-MS fell well within the range predicted by the chance occurrence of MS and the mtDNA mutations known to cause LHON. There was no association between LHON mtDNA mutations and MS in a meta-analysis of the published data. Although the co-occurrence of MS and LHON mtDNA mutations is likely to be due to chance, the resulting disorder has a distinct phenotype, implicating a mechanistic interaction. Patients with LHON-MS have a more aggressive course, and prognostication and treatment should be guarded.

  9. Leber Hereditary Optic Neuropathy: Exemplar of an mtDNA Disease.

    Science.gov (United States)

    Wallace, Douglas C; Lott, Marie T

    2017-01-01

    The report in 1988 that Leber Hereditary Optic Neuropathy (LHON) was the product of mitochondrial DNA (mtDNA) mutations provided the first demonstration of the clinical relevance of inherited mtDNA variation. From LHON studies, the medical importance was demonstrated for the mtDNA showing its coding for the most important energy genes, its maternal inheritance, its high mutation rate, its presence in hundreds to thousands of copies per cell, its quantitatively segregation of biallelic genotypes during both mitosis and meiosis, its preferential effect on the most energetic tissues including the eye and brain, its wide range of functional polymorphisms that predispose to common diseases, and its accumulation of mutations within somatic tissues providing the aging clock. These features of mtDNA genetics, in combination with the genetics of the 1-2000 nuclear DNA (nDNA) coded mitochondrial genes, is not only explaining the genetics of LHON but also providing a model for understanding the complexity of many common diseases. With the maturation of LHON biology and genetics, novel animal models for complex disease have been developed and new therapeutic targets and strategies envisioned, both pharmacological and genetic. Multiple somatic gene therapy approaches are being developed for LHON which are applicable to other mtDNA diseases. Moreover, the unique cytoplasmic genetics of the mtDNA has permitted the first successful human germline gene therapy via spindle nDNA transfer from mtDNA mutant oocytes to enucleated normal mtDNA oocytes. Such LHON lessons are actively being applied to common ophthalmological diseases like glaucoma and neurological diseases like Parkinsonism.

  10. Pathogenic mitochondrial DNA mutations and associated clinical features in Korean patients with Leber's hereditary optic neuropathy.

    Science.gov (United States)

    Yum, Hae Ri; Chae, Hyojin; Shin, Sun Young; Kim, Yonggoo; Kim, Myungshin; Park, Shin Hae

    2014-10-23

    To identify the spectrum of pathogenic mitochondrial DNA (mtDNA) mutations and clinical features in Korean patients with genetically confirmed Leber's hereditary optic neuropathy (LHON). The medical records of 34 unrelated, genetically confirmed LHON patients were reviewed. Total genomic DNA was isolated from the peripheral blood leukocytes of the patients with suspected LHON, and primary or secondary mtDNA mutations were identified by direct sequencing. We analyzed the visual acuity (VA), color vision, RNFL thickness, and visual field (VF) at the final visit from 20 patients who were followed-up for more than 6 months after the onset of LHON. Among 34 patients, 21 (61.8%) had the homoplasmic primary mutation, 11 (32.4%) had the homoplasmic secondary mutation, and 2 (5.9%) had the heteroplasmic primary mutation along with the homoplasmic secondary mutation. Analysis of mtDNA sequences revealed six different types of LHON-associated mutations: two primary LHON-associated primary mutations, m.11778G>A (20 patients, 58.8%) and m.14484T>C (3 patients, 8.8%), and four secondary LHON-associated mutations, which were m.3394T>C (3 patients, 8.8%), m.3497C>T (4 patients, 11.8%), m.11696G>A (4 patients, 11.8%), and m.14502T>C (2 patients, 5.9%). Secondary mutation-carrying patients demonstrated a decreased in RNFL thickness, similar to those in primary mutation-carrying LHON patients. These patients had a higher female ratio (P = 0.019), better VA (P = 0.043) and color vision (P = 0.005), as well as better VF. In addition to common primary LHON-associated mutations, our study identified secondary mtDNA mutations, which should be considered when evaluating patients with optic atrophy. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  11. Extra-Visual Functional and Structural Connection Abnormalities in Leber's Hereditary Optic Neuropathy

    Science.gov (United States)

    Rocca, Maria A.; Valsasina, Paola; Pagani, Elisabetta; Bianchi-Marzoli, Stefania; Milesi, Jacopo; Falini, Andrea; Comi, Giancarlo; Filippi, Massimo

    2011-01-01

    We assessed abnormalities within the principal brain resting state networks (RSNs) in patients with Leber's hereditary optic neuropathy (LHON) to define whether functional abnormalities in this disease are limited to the visual system or, conversely, tend to be more diffuse. We also defined the structural substrates of fMRI changes using a connectivity-based analysis of diffusion tensor (DT) MRI data. Neuro-ophthalmologic assessment, DT MRI and RS fMRI data were acquired from 13 LHON patients and 13 healthy controls. RS fMRI data were analyzed using independent component analysis and SPM5. A DT MRI connectivity-based parcellation analysis was performed using the primary visual and auditory cortices, bilaterally, as seed regions. Compared to controls, LHON patients had a significant increase of RS fluctuations in the primary visual and auditory cortices, bilaterally. They also showed decreased RS fluctuations in the right lateral occipital cortex and right temporal occipital fusiform cortex. Abnormalities of RS fluctuations were correlated significantly with retinal damage and disease duration. The DT MRI connectivity-based parcellation identified a higher number of clusters in the right auditory cortex in LHON vs. controls. Differences of cluster-centroid profiles were found between the two groups for all the four seeds analyzed. For three of these areas, a correspondence was found between abnormalities of functional and structural connectivities. These results suggest that functional and structural abnormalities extend beyond the visual network in LHON patients. Such abnormalities also involve the auditory network, thus corroborating the notion of a cross-modal plasticity between these sensory modalities in patients with severe visual deficits. PMID:21347331

  12. MRI in Leber's hereditary optic neuropathy: the relationship to multiple sclerosis.

    Science.gov (United States)

    Matthews, Lucy; Enzinger, Christian; Fazekas, Franz; Rovira, Alex; Ciccarelli, Olga; Dotti, Maria Teresa; Filippi, Massimo; Frederiksen, Jette L; Giorgio, Antonio; Küker, Wilhelm; Lukas, Carsten; Rocca, Maria A; De Stefano, Nicola; Toosy, Ahmed; Yousry, Tarek; Palace, Jacqueline

    2015-05-01

    Leber's hereditary optic neuropathy (LHON) and a multiple sclerosis (MS)-like illness appear to coexist 50 times more frequently than would be expected by chance. This association of LHON and MS (LMS) raises an important question about whether there could be a common pathophysiological mechanism involving mitochondrial dysfunction. The primary aim was to define MRI features of LMS and LHON, and to assess the proportions of individuals displaying features typical of MS. Secondarily, we investigated the effect of gender on the risk of developing white matter lesions in the context of LHON. A blinded standardised review of conventional brain MRIs of 30 patients with MS, 31 patients with LHON and 11 patients with LMS was conducted by three independent experts in the field. MS-like MRI features were assessed. All patients with LMS and 26% of patients with LHON had white matter lesions. Of these, all patients with LMS and 25% with LHON were found to have an MRI appearance typical of MS. Female patients with LHON had a significantly greater risk of having white matter lesions consistent with MS compared with male patients (relative risk 8.3). A blinded review of conventional brain MRIs shows that patients with LMS have a scan appearance indistinguishable from MS. Mitochondrial dysfunction could be a common pathophysiological pathway in the formation of white matter lesions. There appears to be a strong female influence on the radiological appearance as well as clinical development of MS in patients with LHON. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  13. Targeting estrogen receptor β as preventive therapeutic strategy for Leber's hereditary optic neuropathy.

    Science.gov (United States)

    Pisano, Annalinda; Preziuso, Carmela; Iommarini, Luisa; Perli, Elena; Grazioli, Paola; Campese, Antonio F; Maresca, Alessandra; Montopoli, Monica; Masuelli, Laura; Sadun, Alfredo A; d'Amati, Giulia; Carelli, Valerio; Ghelli, Anna; Giordano, Carla

    2015-12-15

    Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease characterized by degeneration of retinal ganglion cells (RGCs) and consequent optic nerve atrophy. Peculiar features of LHON are incomplete penetrance and gender bias, with a marked male prevalence. Based on the different hormonal metabolism between genders, we proposed that estrogens play a protective role in females and showed that these hormones ameliorate mitochondrial dysfunction in LHON through the estrogen receptors (ERs). We also showed that ERβ localize to the mitochondria of RGCs. Thus, targeting ERβ may become a therapeutic strategy for LHON specifically aimed at avoiding or delaying the onset of disease in mutation carriers. Here, we tested the effects of ERβ targeting on LHON mitochondrial defective metabolism by treating LHON cybrid cells carrying the m.11778G>A mutation with a combination of natural estrogen-like compounds that bind ERβ with high selectivity. We demonstrated that these molecules improve cell viability by reducing apoptosis, inducing mitochondrial biogenesis and strongly reducing the levels of reactive oxygen species in LHON cells. These effects were abolished in cells with ERβ knockdown by silencing receptor expression or by using specific receptor antagonists. Our observations support the hypothesis that estrogen-like molecules may be useful in LHON prophylactic therapy. This is particularly important for lifelong disease prevention in unaffected LHON mutation carriers. Current strategies attempting to combat degeneration of RGCs during the acute phase of LHON have not been very effective. Implementing a different and preemptive approach with a low risk profile may be very helpful. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Point mutations associated with Leber hereditary optic neuropathy in a Latvian population

    Science.gov (United States)

    Baumane, Kristine; Zalite, Solveiga; Ranka, Renate; Zole, Egija; Pole, Ilva; Sepetiene, Svetlana; Laganovska, Guna; Baumanis, Viesturs; Pliss, Liana

    2013-01-01

    Purpose To study mutations associated with Leber hereditary optic neuropathy (LHON) in patients suspected of having this mitochondrial disorder in a Latvian population. Additional aims were to determine the heteroplasmy status of all non-synonymous polymorphisms identified in the current study and to identify the mitochondrial haplogroups of the studied participants because these factors may contribute to the manifestation of LHON. Methods Twelve patients, including patients in two families, were enrolled in the current study. LHON was suspected based on the findings of ophthalmologic examinations. In clinically affected individuals, the presence of all previously reported LHON-associated mutations was assessed with sequencing analysis. Additionally, the SURVEYOR endonuclease assay was used to detect heteroplasmy. The mitochondrial haplogroups were identified with restriction analysis and the sequencing of hypervariable segment 1. Results In one family (mother and son), there was one primary LHON-associated mutation, G11778A. In addition, one rare previously reported LHON-associated polymorphism, A13637G, was detected in two unrelated patients. A non-synonymous polymorphism at T6253C was found in one individual. This mutation was reported in the background of the 3460 mutation among LHON patients in a Chinese population. No non-synonymous point mutations in mitochondrial DNA were found in five of the study participants. Conclusions Molecular analysis of 12 patients with suspected LHON confirmed the diagnosis in four patients and allowed the use of appropriate prophylactic measures and treatment. Further investigations and additional studies of different populations are necessary to confirm the role of the non-synonymous polymorphisms A13637G and T6253C in the manifestation of LHON and the associations of these polymorphisms with mitochondrial haplogroups and heteroplasmy. PMID:24319328

  15. Extra-visual functional and structural connection abnormalities in Leber's hereditary optic neuropathy.

    Directory of Open Access Journals (Sweden)

    Maria A Rocca

    Full Text Available We assessed abnormalities within the principal brain resting state networks (RSNs in patients with Leber's hereditary optic neuropathy (LHON to define whether functional abnormalities in this disease are limited to the visual system or, conversely, tend to be more diffuse. We also defined the structural substrates of fMRI changes using a connectivity-based analysis of diffusion tensor (DT MRI data. Neuro-ophthalmologic assessment, DT MRI and RS fMRI data were acquired from 13 LHON patients and 13 healthy controls. RS fMRI data were analyzed using independent component analysis and SPM5. A DT MRI connectivity-based parcellation analysis was performed using the primary visual and auditory cortices, bilaterally, as seed regions. Compared to controls, LHON patients had a significant increase of RS fluctuations in the primary visual and auditory cortices, bilaterally. They also showed decreased RS fluctuations in the right lateral occipital cortex and right temporal occipital fusiform cortex. Abnormalities of RS fluctuations were correlated significantly with retinal damage and disease duration. The DT MRI connectivity-based parcellation identified a higher number of clusters in the right auditory cortex in LHON vs. controls. Differences of cluster-centroid profiles were found between the two groups for all the four seeds analyzed. For three of these areas, a correspondence was found between abnormalities of functional and structural connectivities. These results suggest that functional and structural abnormalities extend beyond the visual network in LHON patients. Such abnormalities also involve the auditory network, thus corroborating the notion of a cross-modal plasticity between these sensory modalities in patients with severe visual deficits.

  16. Acute Motor Axonal Neuropathy (Aman) With Motor Conduction Blocks In Childhood; Case Report

    OpenAIRE

    Yildirim, Serhan; Adviye, Rah?an; G?l, Hakan Levent; T?rk B?r?, ?lk?

    2016-01-01

    Objective Acute motor axonal neuropathy (AMAN), characterized with decreased compound muscle action potentials (CMAP) and absence of demyelinating findings in electrophysiological studies, is a subtype of Guillain-Barre Syndrome (GBS). A 4 yr-old male patient presented with ascending weakness, dysarthria and dysphagia to ?stanbul Dr. L?tfi K?rdar Kartal Training and Research Hospital Neurology outpatient for three days to in 2012. Dysphonia, restricted eye movements, flaccid tetraplegia and a...

  17. Leber Hereditary Optic Neuropathy: Visual Recovery in a Patient With the Rare m.3890G>A Point Mutation.

    Science.gov (United States)

    Murray, Jared J; Nolan, Kaitlyn W; McClelland, Collin; Lee, Michael S

    2017-06-01

    A 15-year-old boy experienced painless vision loss in the left eye of unknown duration. Leber hereditary optic neuropathy (LHON) was suspected, despite negative testing for the 3 most common pathogenic gene mutations and idebenone 300 mg 3 times daily was prescribed. Nine months later, the patient developed right eye involvement. Complete mitochondrial genome analysis revealed 2 rare variants-m.3890G>A of the MT-ND1 gene and m.8417C>A of the MT-ATP8 gene. The former has been described in severe infantile Leigh syndrome and LHON; the latter is of unknown significance. The patient experienced progressive visual deterioration through 12 months, but improved to 20/20, right eye and 20/25, left eye, at 21 months. Visual recovery can occur in a patient with bilateral optic neuropathy secondary to the rare m.3890G>A point mutation.

  18. The therapeutic potential of a calorie-restricted ketogenic diet for the management of Leber hereditary optic neuropathy.

    Science.gov (United States)

    Storoni, Mithu; Robert, Matthieu P; Plant, Gordon T

    2017-10-10

    Leber hereditary optic neuropathy (LHON) is a maternally inherited, bilateral, sequential optic neuropathy that usually affects young males. LHON arises from a defect in complex I of the oxidative phosphorylation chain that generates increased reactive oxygen species and causes a decline in cellular ATP production. There exists no cure at present for LHON. Asymptomatic LHON mutation carriers show signs of increased mitochondrial biogenesis that may compensate for the compromise in complex I activity. Partial recovery in LHON is associated with a wider optic disc diameter and a younger age at disease onset, which may allow for greater mitochondrial bioenergetic capacity. Rescuing a mitochondrial bioenergetic deficit soon after disease onset may improve the chances of recovery and reduce visual loss in the second eye. We here propose that a calorie-restricted ketogenic diet has the potential to enhance mitochondrial bioenergetic capacity and should be explored as a potential therapeutic option for treating LHON.

  19. Posterior reversible encephalopathy syndrome in a leber hereditary optic neuropathy patient with mitochondrial DNA 11778G>A point mutation.

    Science.gov (United States)

    Da, Yuwei; Zhang, Xuxiang; Li, Fang; Yang, Xiaoping; Zhang, Xinqing; Jia, Jianping

    2013-09-01

    Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder that primarily affects the optic nerve. We report a case of reduced visual acuity secondary to optic atrophy in a 13-year-old boy. Transient seizures developed subsequently. Serial magnetic resonance imaging of the brain showed posterior reversible encephalopathy syndrome. Ragged red fibers were not detected on skeletal muscle biopsy. A 11778G>A mitochondrial DNA point mutation was identified in the lymphocytes isolated from peripheral blood. His younger brother was a carrier with the same mutation. The presentation of this case is unusual documenting LHON in association with PRES.

  20. Identification of small molecules that improve ATP synthesis defects conferred by Leber’s hereditary optic neuropathy mutations

    Science.gov (United States)

    Datta, Sandipan; Tomilov, Alexey; Cortopassi, Gino

    2016-01-01

    Inherited mitochondrial complex I mutations cause blinding Leber's hereditary Optic Neuropathy (LHON), for which no curative therapy exists. A specific biochemical consequence of LHON mutations in the presence of trace rotenone was observed: deficient complex I-dependent ATP synthesis (CIDAS) and mitochondrial O2 consumption, proportional to the clinical severity of the three primary LHON mutations. We optimized a high-throughput assay of CIDAS to screen 1600 drugs to 2, papaverine and zolpidem, which protected CIDAS in LHON cells concentration-dependently. TSPO and cAMP were investigated as protective mechanisms, but a conclusive mechanism remains to be elucidated; next steps include testing in animal models. PMID:27497748

  1. Acute motor axonal neuropathy and transverse myelitis overlap: the importance of history taking.

    Science.gov (United States)

    Degan, Diana; Tiseo, Cindy; Ornello, Raffaele; Notturno, Francesca

    2017-11-15

    In young adults, acute motor axonal neuropathy and transverse myelitis rarely occur as associated conditions. Clinical reasoning, symptoms, laboratory and ancillary investigations (electroneurographic and radiological findings), should properly address the physician to the correct diagnosis.

  2. [A case of hereditary sensory and autonomic neuropathy type 1E with frontal lobe dysfunction as an initial symptom].

    Science.gov (United States)

    Watanabe, Masashi; Matsumoto, Yushi; Okamoto, Kensho; Okuda, Bungo; Mizuta, Ikuko; Mizuno, Toshiki

    2017-12-27

    A 49-year-old man had developed gradually personality change, gait disturbance, and hearing loss for five years. On admission, he presented with frontal release signs, stuttering, vertical gaze palsy, sensorineural deafness, muscle rigidity, ataxia, and sensory disturbance with areflexia in the lower extremities. Brain MRI demonstrated atrophy in the cerebellum and midbrain tegmentum as well as cerebral atrophy, predominantly in the frontal lobe. He was tentatively diagnosed as progressive supranuclear palsy on the basis of clinical features and imagings. On nerve conduction study, no sensory nerve action potentials were elicited in the upper and lower extremities. Details of family history revealed a hereditary sensory neuropathy with autosomal dominant inheritance in his relatives. Because genetic analysis showed a rare missense mutation (c.1483T>C, p.Y495H) in DNA methyltransferase 1 gene, we diagnosed him as having hereditary sensory and autonomic neuropathy type 1E (HSAN1E). In addition, p.M232R mutation in prion protein gene was detected. It should be kept in mind that there are some patients with HSAN1E presenting with frontal lobe dysfunction as an initial symptom and with clinical features mimicking progressive supranuclear palsy.

  3. Macular Retinal Sublayer Thicknesses in G11778A Leber Hereditary Optic Neuropathy.

    Science.gov (United States)

    Lam, Byron L; Burke, Samuel P; Wang, Mindy X; Nadayil, Gloria A; Rosa, Potyra R; Gregori, Giovanni; Feuer, William J; Cuprill-Nilson, Sophia; Vandenbroucke, Ruth; Zhang, Xiaojun; Guy, John

    2016-09-01

    To determine macular retinal sublayer thickness changes in G11778A Leber hereditary optic neuropathy (LHON). The authors performed a cross-sectional study by segmenting spectral-domain Cirrus OCT (Carl Zeiss Meditec, Dublin, CA) 512 × 128 macular cube scans from a prospective, observational study of G11778A LHON. The thickness of the retinal sublayers of LHON affected subjects and asymptomatic carriers were compared to those of a normal group. The study included 20 LHON-affected subjects (13 males; age: 31 years ± 14 years, range: 10 years to 61 years; time since onset of visual loss: 5.9 years ± 8.7 years; 0.4-29.8), 31 asymptomatic LHON carriers (five males; age: 38 years ± 18 years, range: 9 years to 65 years), and 14 normal subjects (five males; age: 39 years ± 13 years, range: 23 years to 61 years). The retinal sublayer thickness parameters were not significantly correlated with age in any of the groups. There were no differences between carriers and normal subjects for thickness of total retina or any sublayer. Affected LHON retinal nerve fiber layer (RNFL) and ganglion cell layer plus inner plexiform layer (GCL+IPL) were thinner, whereas the photoreceptor outer segment (OS) layer was thicker than carriers and normal subjects (P values ranged from .042 to < .001), except for the OS layer in the inferior inner ring and temporal outer ring. Differences between groups were not significant in the inner nuclear layer plus outer plexiform layer (INL+OPL). The affected LHON outer nuclear layer plus inner segment layer was thicker in some quadrants, and the affected LHON choroid layer was generally thinner than carriers and normal subjects; however, these differences were not significant after accounting for age. LHON-affected patients have thickened photoreceptor OS layers in spite of having thinner RNFL and GCL+IPL layers. The findings indicate LHON also has an effect on the morphology of the photoreceptors. [Ophthalmic Surg Lasers Imaging Retina. 2016

  4. Clinical characterization and mitochondrial DNA sequence variations in Leber hereditary optic neuropathy

    Science.gov (United States)

    Kumar, Manoj; Kaur, Punit; Kumar, Manoj; Saxena, Rohit; Sharma, Pradeep

    2012-01-01

    Purpose Leber hereditary optic neuropathy (LHON), a maternally inherited disorder, results from point mutations in mitochondrial DNA (mtDNA). MtDNA is highly polymorphic in nature with very high mutation rate, 10–17 fold higher as compared to nuclear genome. Identification of new mtDNA sequence variations is necessary to establish a clean link with human disease. Thus this study was aimed to assess or evaluate LHON patients for novel mtDNA sequence variations. Materials and Methods Twenty LHON patients were selected from the neuro-ophthalmology clinic of the All India Institute of Medical Sciences, New Delhi, India. DNA was isolated from whole blood samples. The entire coding region of the mitochondrial genome was amplified by PCR in 20 patients and 20 controls. For structural analysis (molecular modeling and simulation) the MODELER 9.2 program in Discovery Studio (DS 2.0) was used. Results MtDNA sequencing revealed a total of 47 nucleotide variations in the 20 LHON patients and 29 variations in 20 controls. Of 47 changes in patients 21.2% (10/47) were nonsynonymous and the remaining 78.72% (37/47) were synonymous. Five nonsynonymous changes, including primary LHON mutations (NADH dehydrogenase subunit 1 [ND1]:p.A52T, NADH dehydrogenase subunit 6 [ND6]:p.M64V, adenosine triphosphate [ATP] synthase subunit a (F-ATPase protein 6) [ATPase6]:p.M181T, NADH dehydrogenase subunit 4 [ND4]:p.R340H, and cytochrome B [CYB]:p.F181L), were found to be pathogenic. A greater number of changes were present in complex I (53.19%; 25/47), followed by complex III (19.14%; 9/47), then complex IV (19.14%; 9/47), then complex V (8.5%; 4/47). Nonsynonymous variations may impair respiratory chain and oxidative phosphorylation (OXPHOS) pathways, which results in low ATP production and elevated reactive oxygen species (ROS) levels. Oxidative stress is the underlying etiology in various diseases and also plays a crucial role in LHON. Conclusions This study describes the role of mt

  5. Phosphorylated neurofilament heavy chain is a marker of neurodegeneration in Leber hereditary optic neuropathy (LHON).

    Science.gov (United States)

    Guy, John; Shaw, Gerry; Ross-Cisneros, Fred N; Quiros, Peter; Salomao, Solange R; Berezovsky, Adriana; Carelli, Valerio; Feuer, William J; Sadun, Alfredo A

    2008-01-01

    To determine the profile of neurodegeneration in Leber hereditary optic neuropathy (LHON). We quantitated serum levels of phosphorylated neurofilament heavy chain (pNF-H) in a Brazilian pedigree of 16 affected patients and 59 carriers with LHON, both molecularly characterized as harboring the G to A mutation at nucleotide 11,778 of the mitochondrial genome. The association of subject characteristics to pNF-H levels was studied with multiple regression; pNF-H data were square-root transformed to effect normality of distribution of residuals. Relationships between the square-root of pNF-H and age and sex were investigated within groups with Pearson correlation and the two-sample t-test. Linear regression was used to assess the difference between groups and to determine if the relationship of age was different between affected individuals and carriers. Results of plotting pNF-H levels by age suggested a nonlinear, quadratic association so age squared was used in the statistical analysis. ANCOVA was used to assess the influence of age and group on pNF-H levels. In the carrier group, there was a significant correlation of square-root pNF-H (mean=0.24 ng/ml(2)) with age (r=0.30, p=0.022) and a stronger correlation with quadratic age (r=0.37, p=0.003). With a higher mean pNF-H (0.33 ng/ml(2)) for the affected group, correlations were of similar magnitude, although they were not statistically significant: age (r=0.22, p=0.42), quadratic age (r=0.22, p=0.45). There was no correlation between age and pNF-H levels (mean=0.34 ng/ml(2)) in the off-pedigree group: age (r=0.03, p=0.87), quadratic age (r=0.04, p=0.84). There was no difference between sexes and pNF-H levels in any of the groups (affected, p=0.65; carriers, p=0.19; off-pedigree, p=0.93). Elevated pNF-H released into the serum of some affected LHON patients may suggest that axonal degeneration occurs at some point after loss of visual function. Increases in pNF-H levels of carriers with increasing age, not seen in

  6. Rare Primary Mitochondrial DNA Mutations and Probable Synergistic Variants in Leber’s Hereditary Optic Neuropathy

    Science.gov (United States)

    Olivieri, Anna; Pala, Maria; Hooshiar Kashani, Baharak; Reynier, Pascal; La Morgia, Chiara; Valentino, Maria Lucia; Liguori, Rocco; Pizza, Fabio; Barboni, Piero; Sadun, Federico; De Negri, Anna Maria; Zeviani, Massimo; Dollfus, Helene; Moulignier, Antoine; Ducos, Ghislaine; Orssaud, Christophe; Bonneau, Dominique; Procaccio, Vincent; Leo-Kottler, Beate; Fauser, Sascha; Wissinger, Bernd; Amati-Bonneau, Patrizia; Torroni, Antonio; Carelli, Valerio

    2012-01-01

    Background Leber’s hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA) point mutations (m.11778G>A, m.3460G>A and m.14484T>C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes). However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined. Methodology/Principal Findings In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G>A/p.A132T, m.3733G>A-C/p.E143K-Q, m.4171C>A/p.L289M), MT-ND4L (m.10663T>C/p.V65A) and MT-ND6 (m.14459G>A/p.A72V, m.14495A>G/p.M64I, m.14482C>A/p.L60S, and m.14568C>T/p.G36S). Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I. Conclusions/Significance Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe) and other putative synergistic mtDNA variants in LHON expression. PMID:22879922

  7. Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy

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    Shuo Yang

    2016-08-01

    Full Text Available Leber's hereditary optic neuropathy (LHON is a disease that leads to blindness. Gene therapy has been investigated with some success, and could lead to important advancements in treating LHON. This was a prospective, open-label trial involving 9 LHON patients at Tongji Hospital, Wuhan, China, from August 2011 to December 2015. The purpose of this study was to evaluate the long-term outcomes of gene therapy for LHON. Nine LHON patients voluntarily received an intravitreal injection of rAAV2-ND4. Systemic examinations and visual function tests were performed during the 36-month follow-up period to determine the safety and efficacy of this gene therapy. Based on successful experiments in an animal model of LHON, 1 subject also received an rAAV2-ND4 injection in the second eye 12 months after gene therapy was administered in the first eye. Recovery of visual acuity was defined as the primary outcome of this study. Changes in the visual field, visual evoked potential (VEP, optical coherence tomography findings, liver and kidney function, and antibodies against AAV2 were defined as secondary endpoints. Eight patients (Patients 2–9 received unilateral gene therapy and visual function improvement was observed in both treated eyes (Patients 4, 6, 7, and 8 and untreated eyes (Patients 2, 3, 4, 6 and 8. Visual regression fluctuations, defined as changes in visual acuity greater than or equal to 0.3 logMAR, were observed in Patients 2 and 9. Age at disease onset, disease duration, and the amount of remaining optic nerve fibers did not have a significant effect on the visual function improvement. The visual field and pattern reversal VEP also improved. The patient (Patient 1 who received gene therapy in both eyes had improved visual acuity in the injected eye after the first treatment. Unfortunately, visual acuity in this eye decreased 3 months after he received gene therapy in the second eye. Animal experiments suggested that ND4 expression remains

  8. Leber's hereditary optic neuropathy differentially affects smaller axons in the optic nerve.

    Science.gov (United States)

    Sadun, A A; Win, P H; Ross-Cisneros, F N; Walker, S O; Carelli, V

    2000-01-01

    PURPOSE: Leber's hereditary optic neuropathy (LHON), though known to be due to 1 of 3 pathogenic mtDNA point mutations (nucleotide positions 11,778, 3460, and 14,484), usually manifests itself acutely in young adulthood with a stereotypical presentation of dyschromatopsia, loss of central vision, and loss of the papillomacular bundle nerve fiber layer. Histopathologic investigations have demonstrated devastating losses of axons with relative sparing of the most peripherally placed fibers in the optic nerves. This study was designed to morphometrically investigate the nerve fiber spectrum from ultrastructural studies of optic nerves obtained from 2 patients with LHON. METHODS: Two cases of LHON were molecularly characterized and the optic nerves from these cases studied by light microscopy and electron microscopy. Montages were made of electron micrographs cut orthogonal to fibers obtained from the periphery of each optic nerve, and these were then used for the measurement of each axon (short and long axis) and its myelin sheath. From this, a spectrum of nerve fiber layer was generated, yielding axon caliber profiles that could be compared between optic nerves. RESULTS: The total depletion of optic nerve fiber population in the 2 cases of LHON varied from 95% to 99%. Those fibers that were spared were limited to the peripheral optic nerve. The nerve fiber layer spectra of these remaining fibers showed a marked diminution of the first peak of axons of less than 1 micron in diameter, with relative emphasis of a second peak of axons of about 2 microns in diameter. In comparison to normal controls, this reflected a preferential loss of the smallest axons corresponding to the P-cell population. CONCLUSIONS: The clinical features of dyschromatopsia and central scotoma (with preservation of pupils) in LHON suggests the selective loss of the P-cell population known to subserve these (and not pupil) functions. This also correlates well with the fundus findings of early

  9. Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy.

    Directory of Open Access Journals (Sweden)

    Alessandro Achilli

    Full Text Available Leber's hereditary optic neuropathy (LHON is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA point mutations (m.11778G>A, m.3460G>A and m.14484T>C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes. However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined.In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G>A/p.A132T, m.3733G>A-C/p.E143K-Q, m.4171C>A/p.L289M, MT-ND4L (m.10663T>C/p.V65A and MT-ND6 (m.14459G>A/p.A72V, m.14495A>G/p.M64I, m.14482C>A/p.L60S, and m.14568C>T/p.G36S. Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I.Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe and other putative synergistic mtDNA variants in LHON expression.

  10. Enteritis caused by Campylobacter jejuni followed by acute motor axonal neuropathy: a case report

    Directory of Open Access Journals (Sweden)

    Babić Tatjana

    2010-03-01

    Full Text Available Abstract Introduction Campylobacter species represent the main cause of bacterial diarrhea in developed countries and one of the most frequent causes of enterocolitis in developing ones. In some patients, Campylobacter jejuni infection of the gastrointestinal tract has been observed as an antecedent illness of acute motor axonal neuropathy, a variant of Guillain-Barré syndrome. Case presentation We present a case of acute motor axonal neuropathy following infection with Campylobacter jejuni subspecies jejuni, biotype II, heat stable serotype O:19. A 46-year-old Caucasian man developed acute motor neuropathy 10 days after mild intestinal infection. The proximal and distal muscle weakness of his upper and lower extremities was associated with serum antibodies to Campylobacter jejuni and antibodies to ganglioside GM1. The electromyographic signs of neuropathic muscle action potentials with almost normal nerve conduction velocities indicated axonal neuropathy. Our patient's clinical and electrophysiological features fulfilled criteria for the diagnosis of an acute motor axonal neuropathy, a subtype of Guillain-Barré syndrome. Conclusion As this is the first case of acute motor axonal neuropathy following infection with Campylobacter jejuni subspecies jejuni reported from the Balkan area, the present findings indicate the need for systematic studies and further clinical, epidemiological and microbiological investigations on the prevalence of Campylobacter jejuni and its heat stable serotypes in the etiology of Guillain-Barré syndrome and other post-infectious sequelae.

  11. Enteritis caused by Campylobacter jejuni followed by acute motor axonal neuropathy: a case report.

    Science.gov (United States)

    Miljković-Selimović, Biljana; Lavrnić, Dragana; Morić, Olga; Ng, Lai-King; Price, Lawrence; Suturkova, Ljubica; Kocic, Branislava; Babić, Tatjana; Ristić, Ljiljana; Apostolski, Slobodan

    2010-03-31

    Campylobacter species represent the main cause of bacterial diarrhea in developed countries and one of the most frequent causes of enterocolitis in developing ones. In some patients, Campylobacter jejuni infection of the gastrointestinal tract has been observed as an antecedent illness of acute motor axonal neuropathy, a variant of Guillain-Barré syndrome. We present a case of acute motor axonal neuropathy following infection with Campylobacter jejuni subspecies jejuni, biotype II, heat stable serotype O:19. A 46-year-old Caucasian man developed acute motor neuropathy 10 days after mild intestinal infection. The proximal and distal muscle weakness of his upper and lower extremities was associated with serum antibodies to Campylobacter jejuni and antibodies to ganglioside GM1. The electromyographic signs of neuropathic muscle action potentials with almost normal nerve conduction velocities indicated axonal neuropathy. Our patient's clinical and electrophysiological features fulfilled criteria for the diagnosis of an acute motor axonal neuropathy, a subtype of Guillain-Barré syndrome. As this is the first case of acute motor axonal neuropathy following infection with Campylobacter jejuni subspecies jejuni reported from the Balkan area, the present findings indicate the need for systematic studies and further clinical, epidemiological and microbiological investigations on the prevalence of Campylobacter jejuni and its heat stable serotypes in the etiology of Guillain-Barré syndrome and other post-infectious sequelae.

  12. The mitochondrial DNA mutation ND6*14,484C associated with leber hereditary optic neuropathy, leads to deficiency of complex I of the respiratory chain

    NARCIS (Netherlands)

    Oostra, R. J.; van Galen, M. J.; Bolhuis, P. A.; Bleeker-Wagemakers, E. M.; van den Bogert, C.

    1995-01-01

    The electron transfer activity of Complex I of the respiratory chain and Complex I-linked ATP synthesis were investigated in leukocytes of four males affected by Leber hereditary optic neuropathy and a mutation in the ND6 gene at nucleotide position 14,484 of mtDNA. The electron transfer activity in

  13. Gene Therapy for Leber Hereditary Optic Neuropathy: Low- and Medium-Dose Visual Results.

    Science.gov (United States)

    Guy, John; Feuer, William J; Davis, Janet L; Porciatti, Vittorio; Gonzalez, Phillip J; Koilkonda, Rajeshwari D; Yuan, Huijun; Hauswirth, William W; Lam, Byron L

    2017-11-01

    To determine the effects of AAV2(Y444,500,730F)-P1ND4v2 in patients with Leber hereditary optic neuropathy (LHON). Prospective open-label, unilateral single-dose, intravitreal injection of AAV2(Y444,500,730F)-P1ND4v2 per participant. Fourteen patients with visual loss and mutated G11778A mitochondrial DNA. Intravitreal injection with the gene therapy vector AAV2(Y444,500,730F)-P1ND4v2 into 1 eye. Six participants with chronic bilateral visual loss lasting more than 12 months (group 1), 6 participants with bilateral visual loss lasting less than 12 months (group 2), and 2 participants with unilateral visual loss (group 3) were treated. Nine patients had at least 12 months of follow-up. Clinical testing included visual acuity, visual fields, optical coherence tomography, pattern electroretinography, and neuro-ophthalmic examinations. Generalized estimating equation methods were used for longitudinal analyses. Loss of visual acuity. For groups 1 and 2, month 12 average acuity improvements with treatment relative to baseline were 0.24 logarithm of the minimum angle of resolution (logMAR). Fellow eyes had a 0.09-logMAR improvement. A post hoc comparison found that at month 12, the difference between study eye minus fellow eye improvement in group 2 patients of 0.53 logMAR was greater than that observed in our prior acute natural history patients of 0.21 logMAR (P = 0.053). At month 18, the difference between study eye minus fellow eye improvement in our acute group 2 gene therapy patients of 0.96 was more than that observed in our prior acute natural history patients (0.17 logMAR; P < 0.001). Two patients demonstrated asymptomatic uveitis that resolved without treatment. Optical coherence tomography of treated eyes showed an average temporal retinal nerve fiber layer thickness of 54 μm before injection and 55 μm at month 12. For fellow eyes before injection, it was 56 μm, decreasing to 50 μm at month 12 (P = 0.013). Generalized estimating equations suggested

  14. Autoantibody pathogenicity in a multifocal motor neuropathy induced pluripotent stem cell-derived model

    NARCIS (Netherlands)

    Härschnitz, Oliver|info:eu-repo/dai/nl/413650197; van den Berg, Leonard H.|info:eu-repo/dai/nl/288255216; Johansen, Lill Eva|info:eu-repo/dai/nl/413663833; Jansen, Marc D.|info:eu-repo/dai/nl/311460577; Kling, Sandra; Vieira de Sá, Renata|info:eu-repo/dai/nl/413634906; Vlam, Lotte; van Rheenen, Wouter|info:eu-repo/dai/nl/413970736; Karst, Henk|info:eu-repo/dai/nl/07955279X; Wierenga, Corette J.; Pasterkamp, R. Jeroen|info:eu-repo/dai/nl/197768814; van der Pol, W. Ludo|info:eu-repo/dai/nl/203721721

    OBJECTIVE: We investigated the pathogenicity of immunoglobulin M (IgM) anti-GM1 antibodies in serum from patients with multifocal motor neuropathy (MMN) using human induced pluripotent stem cell (iPSC)-derived motor neurons (MNs). METHODS: iPSCs were generated from fibroblasts and differentiated

  15. Features of mtDNA mutation patterns in European pedigrees and sporadic cases with leber hereditary optic neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Obermaier-Kusser, B.; Schubring, S.; Paprotta, A.; Meitinger, T.; Jaksch, M.; Gerbitz, K.D. [Univ. of Munich (Germany); Lorenz, B. [Univ. of Rogensburgh (Germany); Zerres, K. [Univ. of Bonn (Germany); Meire, F. [Univ. of Ghent (Belgium); Cochaux, P. [Univ. of Brussels (Belgium)] [and others

    1994-11-01

    Leber hereditary optic neuropathy (LHON) is maternally transmitted and is characterized by bilateral loss of central vision in young adults as a result of optic nerve degeneration. Fifteen transition mutations located in different genes for the mitochondrially encoded subunits of respiratory chain complexes have been associated thus far with the disease. Genetic studies have led to the classification of the pathogenic significance of these different mutations. However, more research is required to determine the causality of the mutations and the penetrance of the disease. The present study compares studies of populations of different ethnic origins, namely European LHON pedigrees and sporadic cases, in order to elucidate the pathogenic mechanisms involved. 21 refs., 2 figs., 1 tab.

  16. Evidence for Detrimental Cross Interactions between Reactive Oxygen and Nitrogen Species in Leber's Hereditary Optic Neuropathy Cells

    Science.gov (United States)

    Santini, Paolo

    2016-01-01

    Here we have collected evidence suggesting that chronic changes in the NO homeostasis and the rise of reactive oxygen species bioavailability can contribute to cell dysfunction in Leber's hereditary optic neuropathy (LHON) patients. We report that peripheral blood mononuclear cells (PBMCs), derived from a female LHON patient with bilateral reduced vision and carrying the pathogenic mutation 11778/ND4, display increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS), as revealed by flow cytometry, fluorometric measurements of nitrite/nitrate, and 3-nitrotyrosine immunodetection. Moreover, viability assays with the tetrazolium dye MTT showed that lymphoblasts from the same patient are more sensitive to prolonged NO exposure, leading to cell death. Taken together these findings suggest that oxidative and nitrosative stress cooperatively play an important role in driving LHON pathology when excess NO remains available over time in the cell environment. PMID:26881022

  17. High Mitochondrial DNA Copy Number Is a Protective Factor From Vision Loss in Heteroplasmic Leber's Hereditary Optic Neuropathy (LHON).

    Science.gov (United States)

    Bianco, Angelica; Bisceglia, Luigi; Russo, Luciana; Palese, Luigi L; D'Agruma, Leonardo; Emperador, Sonia; Montoya, Julio; Guerriero, Silvana; Petruzzella, Vittoria

    2017-04-01

    Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. It is characterized by as yet undisclosed genetic and environmental factors affecting the incomplete penetrance. We identified 27 LHON subjects who possess heteroplasmic primary LHON mutations. Mitochondrial DNA (mtDNA) copy number was evaluated. The presence of centrocecal scotoma, an edematous, hyperemic optic nerve head, and vascular tortuosity, as well as telangiectasia was recognized in affected subjects. We found higher cellular mtDNA content in peripheral blood cells of unaffected heteroplasmic mutation carriers with respect to the affected. The increase of cellular mtDNA content prevents complete loss of vision despite the presence of a heteroplasmic state of LHON primary mutation, suggesting that it is a key factor responsible for penetrance of LHON.

  18. Evidence for Detrimental Cross Interactions between Reactive Oxygen and Nitrogen Species in Leber’s Hereditary Optic Neuropathy Cells

    Directory of Open Access Journals (Sweden)

    Micol Falabella

    2016-01-01

    Full Text Available Here we have collected evidence suggesting that chronic changes in the NO homeostasis and the rise of reactive oxygen species bioavailability can contribute to cell dysfunction in Leber’s hereditary optic neuropathy (LHON patients. We report that peripheral blood mononuclear cells (PBMCs, derived from a female LHON patient with bilateral reduced vision and carrying the pathogenic mutation 11778/ND4, display increased levels of reactive oxygen species (ROS and reactive nitrogen species (RNS, as revealed by flow cytometry, fluorometric measurements of nitrite/nitrate, and 3-nitrotyrosine immunodetection. Moreover, viability assays with the tetrazolium dye MTT showed that lymphoblasts from the same patient are more sensitive to prolonged NO exposure, leading to cell death. Taken together these findings suggest that oxidative and nitrosative stress cooperatively play an important role in driving LHON pathology when excess NO remains available over time in the cell environment.

  19. Psychological morbidity in Leber’s hereditary optic neuropathy depends on phenotypic, social, economic, and genetic factors

    Directory of Open Access Journals (Sweden)

    Finsterer J

    2017-05-01

    Full Text Available Josef Finsterer,1 Sinda Zarrouk-Mahjoub2 1Krankenanstalt Rudolfstiftung, Vienna, Austria; 2University of Tunis El Manar, Genomics Platform, Pasteur Institute of Tunis, Tunis, Tunisia We have read with interest the article by Garcia et al1 about the effect of visual impairment on psychological well-being with regard to mood, interpersonal interactions, and career-related goals.1 Among the 103 Leber’s hereditary optic neuropathy (LHON patients, half became depressed with negative impacts on interpersonal relations and career goals. At diagnosis, older age corresponded to higher depression prevalence than young age. We have the following comments and concerns.View the original paper by Garcia and colleagues.  

  20. Acute Motor Axonal Neuropathy (Aman) With Motor Conduction Blocks In Childhood; Case Report.

    Science.gov (United States)

    Yildirim, Serhan; Adviye, Rahşan; Gül, Hakan Levent; Türk Börü, Ülkü

    2016-01-01

    Objective Acute motor axonal neuropathy (AMAN), characterized with decreased compound muscle action potentials (CMAP) and absence of demyelinating findings in electrophysiological studies, is a subtype of Guillain-Barre Syndrome (GBS). A 4 yr-old male patient presented with ascending weakness, dysarthria and dysphagia to İstanbul Dr. Lütfi Kırdar Kartal Training and Research Hospital Neurology outpatient for three days to in 2012. Dysphonia, restricted eye movements, flaccid tetraplegia and areflexia were found in neurological examination. There were motor conduction blocks in all peripheral nerves in electrophysiological studies.According to these findings the patient was diagnosed as Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP). Reduction of CMAP amplitudes in posterior tibial nerve, absence of CMAPs in median, ulnar and peroneal nerves and loss of motor conduction blocks were found in following electrophysiological studies. According to these findings, patient was diagnosed as AMAN. Motor conduction blocks may appear in early stage of AMAN and they disappear in later examinations. That's why electrophysiological studies must be repeated in patients with GBS.

  1. Recessive Distal Motor Neuropathy with Pyramidal signs in an Omani Kindred: Underlying Novel Mutation in the SIGMAR1 Gene.

    Science.gov (United States)

    Nandhagopal, Ramachandiran; Meftah, Douja; Al-Kalbani, Sami; Scott, Patrick

    2017-11-08

    Distal hereditary motor neuropathy (dHMN) due to sigma nonopiod intracellular receptor 1 gene (SIGMAR1) mutation (OMIM 601978.0003) is a rare neuromuscular disorder characterized by prominent amyotrophic distal limb weakness and co-existing pyramidal signs initially described in a Chinese family in the recent year. We report an extended consanguineous Omani family segregating dHMN with pyramidal signs in an autosomal recessive pattern and describe a novel mutation in the SIGMAR1 gene underlying this motor phenotype. We also provide an update on the reported phenotypic profile of SIGMAR1 mutations. We utilized homozygosity mapping and whole exome sequencing of leucocyte DNA obtained from three affected members of an Omani family who manifested with a length-dependent motor neuropathy and pyramidal signs. We identified a novel C>T transition at nucleotide position 238 (c.238C>T) in exon 2 of SIGMAR1 gene. Sanger sequencing and segregation analysis confirmed the presence of two copies of the variant in the affected subjects, unlike the unaffected healthy parents/sibling carrying at most a single copy. The T allele is predicted to cause a truncating mutation (p.Gln80*), likely flagging the mRNA for nonsense mediated decay (NMD) leading to a complete loss of function, thereby potentially contributing to the disease process. Our finding expands the spectrum of SIGMAR1 mutations causing recessive dHMN and indicates that this disorder is panethnic. SIGMAR1 mutation should be included in the diagnostic panel of a dHMN, especially if there are co-existing pyramidal signs and autosomal recessive inheritance. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  2. Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C.

    Science.gov (United States)

    Auranen, Mari; Toppila, Jussi; Suriyanarayanan, Saranya; Lone, Museer A; Paetau, Anders; Tyynismaa, Henna; Hornemann, Thorsten; Ylikallio, Emil

    2017-11-01

    Hereditary sensory neuropathy type 1 (HSAN1) may be the first genetic neuropathy amenable to a specific mechanism-based treatment, as L-serine supplementation can be used to lower the neurotoxic levels of 1-deoxysphingolipids (1-deoxySL) that cause the neurodegeneration. The treatment is so far untested in HSAN1C caused by variants in the serine palmitoyl transferase subunit 2 (SPTLC2) gene. The aim of this study was to establish whether oral L-serine lowers 1-deoxySL in a patient with HSAN1C, to perform a dose escalation to find the minimal effective dose, and to assess the safety profile and global metabolic effects of the treatment. Our patient underwent a 52-wk treatment in which the L-serine dose was titrated up to 400 mg/kg/day. She was followed up by repeated clinical examination, nerve conduction testing, and skin biopsies to document effects on small nerve fibers. Serum was assayed for 1-deoxySL and metabolomics analysis of 111 metabolites. We found a robust lowering of 1-deoxySL, which correlated in a near-linear fashion with increased serum L-serine levels. Metabolomics analysis showed a modest elevation in glycine and a marked reduction in the level of cytosine, whereas most of the other assayed metabolites did not change. There were no direct side effects from the treatment, but the patient developed a transitory toe ulceration during the course of the study. The Charcot-Marie-Tooth neuropathy score increased by 1 point. We conclude that oral supplementation of L-serine decreases 1-deoxySL in HSAN1C without major global effects on metabolism. L-serine is therefore a potential treatment for HSAN1C. © 2017 Auranen et al.; Published by Cold Spring Harbor Laboratory Press.

  3. Neuropatía óptica hereditaria de Leber Leber´s hereditary optic neuropathy

    Directory of Open Access Journals (Sweden)

    Yannara Elina Columbié Garbey

    2012-06-01

    Full Text Available La neuropatía óptica hereditaria de Leber es una enfermedad de herencia materna que se caracteriza por la pérdida subaguda, indolora y bilateral, aunque por lo general no siempre al unísono de la visión central. Predomina en hombres jóvenes y es causada por mutaciones puntuales del ADN mitocondrial. Esta es una de las neuropatías ópticas hereditarias más frecuentes y altamente invalidante, cuyo diagnóstico de certeza lo constituyen los estudios moleculares. El propósito de esta revisión es alertar en cuanto a su diagnóstico y posible incremento en condiciones ambientales favorecedoras. Se realizó una búsqueda automatizada de artículos científicos relacionados con el tema, en PUBMED e Hinari, que resultó en 37 publicaciones realizadas durante los años 1988-2010. Se estudiaron y discutieron aspectos de la enfermedad tales como antecedentes históricos, factores de riesgo, epidemiología, genética, características clínicas, diagnóstico y tratamiento; además de profundizar en su estado actual en nuestro contexto. En Cuba actualmente se conoce de la existencia de varias familias que padecen la neuropatía óptica hereditaria de Leber. El alza de la incidencia probablemente se debió a las condiciones medioambientales que favorecen o son factores de riesgo de esta entidad, como ocurrió durante la pasada epidemia de neuropatía óptica en Cuba. Cada día se producen más avances en el campo de la genética, que permiten identificar un número mayor de mutaciones asociadas a esta entidad. Esto unido al conocimiento de las características clínicas de la enfermedad ha permitido identificar las familias afectadas y actuar sobre los factores de riesgo.Leber´s hereditary optic neuropathy is a maternally inherited disease characterized by subacute, painless and bilateral loss of the central vision, although not always at the same time. It predominates in young men and is caused by mitochondrial DNA spot mutations. This is one of

  4. Fasciculations in human hereditary disease.

    Science.gov (United States)

    Finsterer, Josef; Aliyev, Rahim

    2015-06-01

    Fasciculations are a manifestation of peripheral nerve hyperexcitability in addition to myokymia, neuromyotonia, cramps, or tetany. Fasciculations occur in hereditary and non-hereditary diseases. Among the hereditary diseases, fasciculations are most frequently reported in familial amyotrophic lateral sclerosis (FALS), and spinal muscular atrophy (SMA). Among the non-hereditary diseases, fasciculations occur most frequently in peripheral nerve hyperexcitability syndromes (Isaac's syndrome, voltage-gated potassium channelopathy, cramp fasciculation syndrome, Morvan syndrome). If the cause of fasciculations remains unknown, they are called benign. Systematically reviewing the literature about fasciculations in hereditary disease shows that fasciculations can be a phenotypic feature in bulbospinal muscular atrophy (BSMA), GM2-gangliosidosis, triple-A syndrome, or hereditary neuropathy. Additionally, fasciculations have been reported in familial amyloidosis, spinocerebellar ataxias, Huntington's disease, Rett syndrome, central nervous system disease due to L1-cell adhesion molecule (L1CAM) mutations, Fabry's disease, or Gerstmann-Sträussler disease. Rarely, fasciculations may be a phenotypic feature in patients with mitochondrial disorders or other myopathies. Fasciculations are part of the phenotype in much more genetic disorders than commonly assumed. Fasciculations not only occur in motor neuron disease, but also in hereditary neuropathy, spinocerebellar ataxia, GM2-gangliosidosis, Huntington's disease, Rett syndrome, Fabry's disease, Gerstmann-Sträussler disease, mitochondrial disorders, or muscular dystrophies.

  5. A comparative study of brachial plexus sonography and magnetic resonance imaging in chronic inflammatory demyelinating neuropathy and multifocal motor neuropathy.

    Science.gov (United States)

    Goedee, H S; Jongbloed, B A; van Asseldonk, J-T H; Hendrikse, J; Vrancken, A F J E; Franssen, H; Nikolakopoulos, S; Visser, L H; van der Pol, W L; van den Berg, L H

    2017-10-01

    To compare the performance of neuroimaging techniques, i.e. high-resolution ultrasound (HRUS) and magnetic resonance imaging (MRI), when applied to the brachial plexus, as part of the diagnostic work-up of chronic inflammatory demyelinating neuropathy (CIDP) and multifocal motor neuropathy (MMN). Fifty-one incident, treatment-naive patients with CIDP (n = 23) or MMN (n = 28) underwent imaging of the brachial plexus using (i) a standardized MRI protocol to assess enlargement or T2 hyperintensity and (ii) bilateral HRUS to determine the extent of nerve (root) enlargement. We found enlargement of the brachial plexus in 19/51 (37%) and T2 hyperintensity in 29/51 (57%) patients with MRI and enlargement in 37/51 (73%) patients with HRUS. Abnormal results were only found in 6/51 (12%) patients with MRI and 12/51 (24%) patients with HRUS. A combination of the two imaging techniques identified 42/51 (83%) patients. We found no association between age, disease duration or Medical Research Council sum-score and sonographic nerve size, MRI enlargement or presence of T2 hyperintensity. Brachial plexus sonography could complement MRI in the diagnostic work-up of patients with suspected CIDP and MMN. Our results indicate that combined imaging studies may add value to the current diagnostic consensus criteria for chronic inflammatory neuropathies. © 2017 EAN.

  6. Motor Branch Biopsy of the Pronator Teres Muscle in a Patient with Painful Forearm Neuropathy

    Directory of Open Access Journals (Sweden)

    Tomomi Kinoshita

    2014-07-01

    Full Text Available Histological evaluation of a peripheral nerve is often the final diagnostic work-up for a neuropathy of unknown origin, and a distal sensory nerve is usually biopsied. Here, we report the case of a female patient with painful unilateral neuropathy in the upper arm. According to the histological evaluation of the pronator teres motor branch, vasculitis seemed to be the most probable cause of the condition, and steroid therapy improved the patients' symptoms. A biopsy of the motor branch of the pronator teres muscle nerve may be considered a valuable diagnostic option in selected cases with neuropathy affecting the upper limb, when performed in cooperation with neurologists and orthopedic surgeons.

  7. Diagnostic approach to peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Misra Usha

    2008-01-01

    Full Text Available Peripheral neuropathy refers to disorders of the peripheral nervous system. They have numerous causes and diverse presentations; hence, a systematic and logical approach is needed for cost-effective diagnosis, especially of treatable neuropathies. A detailed history of symptoms, family and occupational history should be obtained. General and systemic examinations provide valuable clues. Neurological examinations investigating sensory, motor and autonomic signs help to define the topography and nature of neuropathy. Large fiber neuropathy manifests with the loss of joint position and vibration sense and sensory ataxia, whereas small fiber neuropathy manifests with the impairment of pain, temperature and autonomic functions. Electrodiagnostic (EDx tests include sensory, motor nerve conduction, F response, H reflex and needle electromyography (EMG. EDx helps in documenting the extent of sensory motor deficits, categorizing demyelinating (prolonged terminal latency, slowing of nerve conduction velocity, dispersion and conduction block and axonal (marginal slowing of nerve conduction and small compound muscle or sensory action potential and dennervation on EMG. Uniform demyelinating features are suggestive of hereditary demyelination, whereas difference between nerves and segments of the same nerve favor acquired demyelination. Finally, neuropathy is classified into mononeuropathy commonly due to entrapment or trauma; mononeuropathy multiplex commonly due to leprosy and vasculitis; and polyneuropathy due to systemic, metabolic or toxic etiology. Laboratory investigations are carried out as indicated and specialized tests such as biochemical, immunological, genetic studies, cerebrospinal fluid (CSF examination and nerve biopsy are carried out in selected patients. Approximately 20% patients with neuropathy remain undiagnosed but the prognosis is not bad in them.

  8. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy

    NARCIS (Netherlands)

    van Schaik, I. N.; Bouche, P.; Illa, I.; Léger, J.-M.; van den Bergh, P.; Cornblath, D. R.; Evers, E. M. A.; Hadden, R. D. M.; Hughes, R. A. C.; Koski, C. L.; Nobile-Orazio, E.; Pollard, J.; Sommer, C.; van Doorn, P. A.

    2006-01-01

    Several diagnostic criteria for multifocal motor neuropathy have been proposed in recent years and a beneficial effect of intravenous immunoglobulin (IVIg) and various other immunomodulatory drugs has been suggested in several trials and uncontrolled studies. The objectives were to prepare consensus

  9. Diagnostic value of GM1 antibodies in motor neuron disorders and neuropathies: a meta-analysis

    NARCIS (Netherlands)

    van Schaik, I. N.; Bossuyt, P. M.; Brand, A.; Vermeulen, M.

    1995-01-01

    We performed a meta-analysis on the diagnostic value of IgM anti-GM1 antibodies. The reported frequencies of IgM anti-GM1 antibodies ranged from 0 to 100% for patients with multifocal motor neuropathy (MMN), from 0 to 33% in the Guillain-Barré syndrome, from 0 to 65% in amyotrophic lateral sclerosis

  10. A Case of Acute Motor and Sensory Axonal Neuropathy Following Hepatitis A Infection

    OpenAIRE

    Jo, Yoon-Sik; Han, Sang-Don; Choi, Jin-Yong; Kim, Ick Hee; Kim, Yong-Duk; Na, Sang-Jun

    2013-01-01

    Acute motor and sensory axonal neuropathy (AMSAN) are recently described subtypes of Guillain-Barre syndrome characterized by acute onset of distal weakness, loss of deep tendon reflexes, and sensory symptoms. A 21-yr-old male was transferred to our hospital due to respiration difficulties and progressive weakness. In laboratory findings, immunoglobulin M antibodies against hepatitis A were detected in blood and cerebrospinal fluid. The findings of motor nerve conduction studies showed marked...

  11. Measurement of Systemic Mitochondrial Function in Advanced Primary Open-Angle Glaucoma and Leber Hereditary Optic Neuropathy

    Science.gov (United States)

    Van Bergen, Nicole J; Crowston, Jonathan G.; Craig, Jamie E.; Burdon, Kathryn P.; Kearns, Lisa S.; Sharma, Shiwani; Hewitt, Alex W.; Mackey, David A.; Trounce, Ian A.

    2015-01-01

    Primary Open Angle Glaucoma (POAG) is a common neurodegenerative disease characterized by the selective and gradual loss of retinal ganglion cells (RGCs). Aging and increased intraocular pressure (IOP) are glaucoma risk factors; nevertheless patients deteriorate at all levels of IOP, implying other causative factors. Recent evidence presents mitochondrial oxidative phosphorylation (OXPHOS) complex-I impairments in POAG. Leber Hereditary Optic Neuropathy (LHON) patients suffer specific and rapid loss of RGCs, predominantly in young adult males, due to complex-I mutations in the mitochondrial genome. This study directly compares the degree of OXPHOS impairment in POAG and LHON patients, testing the hypothesis that the milder clinical disease in POAG is due to a milder complex-I impairment. To assess overall mitochondrial capacity, cells can be forced to produce ATP primarily from mitochondrial OXPHOS by switching the media carbon source to galactose. Under these conditions POAG lymphoblasts grew 1.47 times slower than controls, whilst LHON lymphoblasts demonstrated a greater degree of growth impairment (2.35 times slower). Complex-I enzyme specific activity was reduced by 18% in POAG lymphoblasts and by 29% in LHON lymphoblasts. We also assessed complex-I ATP synthesis, which was 19% decreased in POAG patients and 17% decreased in LHON patients. This study demonstrates both POAG and LHON lymphoblasts have impaired complex-I, and in the majority of aspects the functional defects in POAG were milder than LHON, which could reflect the milder disease development of POAG. This new evidence places POAG in the spectrum of mitochondrial optic neuropathies and raises the possibility for new therapeutic targets aimed at improving mitochondrial function. PMID:26496696

  12. A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology

    Energy Technology Data Exchange (ETDEWEB)

    Mackey, D. (Royal Children' s Hospital, Melbourne (Australia)); Howell, N. (Univ. of Texas, Galveston (United States))

    1992-12-01

    The Tas2 and Vic2 Australian families are affected with a variant of Leber hereditary optic neuropathy (LHON). The risk of developing the optic neuropathy shows strict maternal inheritance, and the opthalmological changes in affected family members are characteristic of LHON. However, in contrast to the common form of the disease, members of these two families show a high frequency of vision recovery. To ascertain the mitochondrial genetic etiology of the LHON in these families, both (a) the nucleotide sequences of the seven mitochondrial genes encoding subunits of respiratory-chain complex I and (b) the mitochondrial cytochrome b gene were determined for representatives of both families. Neither family carries any of the previously identified primary mitochondrial LHON mutations: ND4/11778, ND1/3460, or ND1/4160. Instead, both LHON families carry multiple nucleotide changes in the mitochondrial complex I genes, which produce conservative amino acid changes. From the available sequence data, it is inferred that the Vic2 and Tas2 LHON families are phylogenetically related to each other and to a cluster of LHON families in which mutations in the mitochondrial cytochrome b gene have been hypothesized to play a primary etiological role. However, sequencing analysis establishes that the Vic2 and Tas2 LHON families do not carry these cytochrome b mutations. There are two hypotheses to account for the unusual mitochondrial genetic etiology of the LHON in the Tas2 and Vic2 LHON families. One possibility is that there is a primary LHON mutation within the mitochondrial genome but that it is at a site that was not included in the sequencing analyses. Alternatively, the disease in these families may result from the cumulative effects of multiple secondary LHON mutations that have less severe phenotypic consequences. 29 refs., 3 figs., 3 tabs.

  13. Measurement of Systemic Mitochondrial Function in Advanced Primary Open-Angle Glaucoma and Leber Hereditary Optic Neuropathy.

    Science.gov (United States)

    Van Bergen, Nicole J; Crowston, Jonathan G; Craig, Jamie E; Burdon, Kathryn P; Kearns, Lisa S; Sharma, Shiwani; Hewitt, Alex W; Mackey, David A; Trounce, Ian A

    2015-01-01

    Primary Open Angle Glaucoma (POAG) is a common neurodegenerative disease characterized by the selective and gradual loss of retinal ganglion cells (RGCs). Aging and increased intraocular pressure (IOP) are glaucoma risk factors; nevertheless patients deteriorate at all levels of IOP, implying other causative factors. Recent evidence presents mitochondrial oxidative phosphorylation (OXPHOS) complex-I impairments in POAG. Leber Hereditary Optic Neuropathy (LHON) patients suffer specific and rapid loss of RGCs, predominantly in young adult males, due to complex-I mutations in the mitochondrial genome. This study directly compares the degree of OXPHOS impairment in POAG and LHON patients, testing the hypothesis that the milder clinical disease in POAG is due to a milder complex-I impairment. To assess overall mitochondrial capacity, cells can be forced to produce ATP primarily from mitochondrial OXPHOS by switching the media carbon source to galactose. Under these conditions POAG lymphoblasts grew 1.47 times slower than controls, whilst LHON lymphoblasts demonstrated a greater degree of growth impairment (2.35 times slower). Complex-I enzyme specific activity was reduced by 18% in POAG lymphoblasts and by 29% in LHON lymphoblasts. We also assessed complex-I ATP synthesis, which was 19% decreased in POAG patients and 17% decreased in LHON patients. This study demonstrates both POAG and LHON lymphoblasts have impaired complex-I, and in the majority of aspects the functional defects in POAG were milder than LHON, which could reflect the milder disease development of POAG. This new evidence places POAG in the spectrum of mitochondrial optic neuropathies and raises the possibility for new therapeutic targets aimed at improving mitochondrial function.

  14. Results of Mitochondrial DNA Sequence Analysis in Patients with Clinically Diagnosed Leber’s Hereditary Optic Neuropathy

    Directory of Open Access Journals (Sweden)

    Haluk Esgin

    2012-09-01

    Full Text Available Objective: To investigate possible mitochondrial DNA (mtDNA mutations in patients with Leber’s hereditary optic neuropathy (LHON in order to provide a precise diagnosis and genetic counseling.Material and Methods: Between 1982 and 2007, ten patients were clinically diagnosed with LHON and six of these patients agreed to be involved in this study. Six healthy individuals were also included as a control group. mtDNA was isolated from peripheral blood samples and polymerase chain reaction and mtDNA sequence analysis were performed. Results: In one of the six patients, a homoplasmic mutant m.11778G>A mutation was detected. All of the clinically diagnosed LHON patients and the control groups had the m.14212C>T and m.14580G>A single nucleotide polymorphisms (SNPs. The m.11719A>G SNP was detected in three of six patients and four of the controls. Two of the six patients had the m.3197T>C SNP and, in addition, the m.14258G>A SNP was found in one of these two patients, while neither of these mutations were present in the control group.Conclusion: The clinical diagnosis of LHON could be supported by molecular genetics only in one patient by the detection of one mutation. The m.3197T>C and m.14258G>A SNPs should be considered as potential mtDNA mutations due to the fact that they were detected in the patient group. These mutations should be investigated further in large case groups for suspected gene loci that could lead to optic neuropathy.

  15. Measurement of Systemic Mitochondrial Function in Advanced Primary Open-Angle Glaucoma and Leber Hereditary Optic Neuropathy.

    Directory of Open Access Journals (Sweden)

    Nicole J Van Bergen

    Full Text Available Primary Open Angle Glaucoma (POAG is a common neurodegenerative disease characterized by the selective and gradual loss of retinal ganglion cells (RGCs. Aging and increased intraocular pressure (IOP are glaucoma risk factors; nevertheless patients deteriorate at all levels of IOP, implying other causative factors. Recent evidence presents mitochondrial oxidative phosphorylation (OXPHOS complex-I impairments in POAG. Leber Hereditary Optic Neuropathy (LHON patients suffer specific and rapid loss of RGCs, predominantly in young adult males, due to complex-I mutations in the mitochondrial genome. This study directly compares the degree of OXPHOS impairment in POAG and LHON patients, testing the hypothesis that the milder clinical disease in POAG is due to a milder complex-I impairment. To assess overall mitochondrial capacity, cells can be forced to produce ATP primarily from mitochondrial OXPHOS by switching the media carbon source to galactose. Under these conditions POAG lymphoblasts grew 1.47 times slower than controls, whilst LHON lymphoblasts demonstrated a greater degree of growth impairment (2.35 times slower. Complex-I enzyme specific activity was reduced by 18% in POAG lymphoblasts and by 29% in LHON lymphoblasts. We also assessed complex-I ATP synthesis, which was 19% decreased in POAG patients and 17% decreased in LHON patients. This study demonstrates both POAG and LHON lymphoblasts have impaired complex-I, and in the majority of aspects the functional defects in POAG were milder than LHON, which could reflect the milder disease development of POAG. This new evidence places POAG in the spectrum of mitochondrial optic neuropathies and raises the possibility for new therapeutic targets aimed at improving mitochondrial function.

  16. The pattern of retinal ganglion cell dysfunction in Leber hereditary optic neuropathy.

    Science.gov (United States)

    Majander, A; Robson, A G; João, C; Holder, G E; Chinnery, P F; Moore, A T; Votruba, M; Stockman, A; Yu-Wai-Man, P

    2017-09-01

    Leber inherited optic neuropathy (LHON) is characterized by subacute bilateral loss of central vision due to dysfunction and loss of retinal ganglion cells (RGCs). Comprehensive visual electrophysiological investigations (including pattern reversal visual evoked potentials, pattern electroretinography and the photopic negative response) performed on 13 patients with acute and chronic LHON indicate early impairment of RGC cell body function and severe axonal dysfunction. Temporal, spatial and chromatic psychophysical tests performed on 7 patients with acute LHON and 4 patients with chronic LHON suggest severe involvement or loss of the midget, parasol and bistratified RGCs associated with all three principal visual pathways. Copyright © 2017. Published by Elsevier B.V.

  17. Diagnostic signs of motor neuropathy in MR neurography: Nerve lesions and muscle denervation

    Energy Technology Data Exchange (ETDEWEB)

    Schwarz, Daniel; Pham, Mirko; Bendszus, Martin; Baeumer, Philipp [Heidelberg University Hospital, Department of Neuroradiology, Heidelberg (Germany); Weiler, Markus [Heidelberg University Hospital, Department of Neurology, Heidelberg (Germany); German Cancer Research Center (DKFZ), Clinical Cooperation Unit Neurooncology, Heidelberg (Germany); Heiland, Sabine [Heidelberg University Hospital, Section of Experimental Radiology, Department of Neuroradiology, Heidelberg (Germany)

    2015-05-01

    To investigate the diagnostic contribution of T2-w nerve lesions and of muscle denervation in peripheral motor neuropathies by magnetic resonance neurography (MRN). Fifty-one patients with peripheral motor neuropathies underwent high-resolution MRN by large coverage axial T2-w sequences of the upper arm, elbow, and forearm. Images were evaluated by two blinded readers for T2-w signal alterations of median, ulnar, and radial nerves, and for denervation in respective target muscle groups. All 51 patients displayed nerve lesions in at least one of three nerves, and 43 out of 51 patients showed denervation in at least one target muscle group of these nerves. In 21 out of 51 patients, the number of affected nerves matched the number of affected target muscle groups. In the remaining 30 patients, T2-w lesions were encountered more frequently than target muscle group denervation. In 153 nerve-muscle pairs, 72 showed denervation, but only one had increased muscle signal without a lesion in the corresponding nerve. MRN-based diagnosis of peripheral motor neuropathies is more likely by visualization of peripheral nerve lesions than by denervation in corresponding target muscles. Increased muscular T2-w signal without concomitant nerve lesions should raise suspicion of an etiology other than peripheral neuropathy. (orig.)

  18. Mitochondrial dysfunction due to Leber's hereditary optic neuropathy as a cause of visual loss during assessment for epilepsy surgery.

    Science.gov (United States)

    Niehusmann, Pitt; Surges, Rainer; von Wrede, Randi D; Elger, Christian E; Wellmer, Jörg; Reimann, Jens; Urbach, Horst; Vielhaber, Stefan; Bien, Christian G; Kunz, Wolfram S

    2011-01-01

    Assessment for epilepsy surgery may require invasive measures such as implantation of intracranial electrodes or the Wada test. These investigations are commonly well tolerated. However, complications, including visual disturbances of various etiologies, have been reported. Here we describe two patients with pharmacoresistant temporal lobe epilepsy (TLE) who displayed loss of vision in the context of presurgical assessment and in whom mutations associated with Leber's hereditary optic neuropathy (LHON) were detected. Genetic analysis revealed in one patient the frequent mitochondrial G11778A LHON mutation in ND4. In the second patient, the mitochondrial C4640A mutation in ND2 was detected. This rare LHON mutation enhanced the sensitivity of the patient's muscle and brain tissue to amobarbital, a known blocker of the mitochondrial respiratory chain. Mitochondrial dysfunction has been reported in epilepsy. Thus, the presence of LHON mutations can be a rare cause of visual disturbances in patients with epilepsy and may have predisposed to development of epilepsy. Copyright © 2010 Elsevier Inc. All rights reserved.

  19. Gene therapy for mitochondrial diseases: Leber Hereditary Optic Neuropathy as the first candidate for a clinical trial.

    Science.gov (United States)

    Cwerman-Thibault, Hélène; Augustin, Sébastien; Ellouze, Sami; Sahel, José-Alain; Corral-Debrinski, Marisol

    2014-03-01

    Mitochondrial disorders cannot be ignored anymore in most medical disciplines; indeed their minimum estimated prevalence is superior to 1 in 5000 births. Despite the progress made in the last 25 years on the identification of gene mutations causing mitochondrial pathologies, only slow progress was made towards their effective treatments. Ocular involvement is a frequent feature in mitochondrial diseases and corresponds to severe and irreversible visual handicap due to retinal neuron loss and optic atrophy. Interestingly, three clinical trials for Leber Congenital Amaurosis due to RPE65 mutations are ongoing since 2007. Overall, the feasibility and safety of ocular Adeno-Associated Virus delivery in adult and younger patients and consistent visual function improvements have been demonstrated. The success of gene-replacement therapy for RPE65 opens the way for the development of similar approaches for a broad range of eye disorders, including those with mitochondrial etiology such as Leber Hereditary Optic Neuropathy (LHON). Copyright © 2013 Académie des sciences. Published by Elsevier SAS. All rights reserved.

  20. Human extraocular muscles in mitochondrial diseases: comparing chronic progressive external ophthalmoplegia with Leber’s hereditary optic neuropathy

    Science.gov (United States)

    Carta, A; Carelli, V; D’Adda, T; Ross-Cisneros, F N; Sadun, A A

    2005-01-01

    Aims: To compare the ultrastructural aspects of human extraocular muscles in two types of mitochondrial disease: chronic progressive external ophthalmoplegia (CPEO) and Leber’s hereditary optic neuropathy (LHON). Methods: Muscle samples of the medial rectus obtained from surgery in a sporadic case of CPEO associated with deleted mitochondrial DNA, and post mortem in a case of 3460/ND1 LHON were processed for electron microscopy (EM). The medial rectus from an autoptic time to fixation matched control was used to exclude postmortem artefacts. Results: The CPEO specimen revealed focal areas of disruption and abnormalities of mitochondria in some muscle fibres, creating a “mosaic-like” pattern. In the LHON specimen a diffuse increase in both number and size of mitochondria (mean diameter 0.85 μm v 0.65 μm of control, pCPEO and LHON reveals marked differences. A “mosaic-like” pattern caused by a selective damage of muscle fibres was evident in CPEO, whereas a diffuse increase in mitochondria with preservation of myofibrils characterised the LHON case. These ultrastructural changes may relate to the different expression of the two diseases, resulting in ophthalmoplegia in CPEO and normal eye movements in LHON. PMID:15965159

  1. Leber's hereditary optic neuropathy is associated with mitochondrial ND1 T3394C mutation

    Energy Technology Data Exchange (ETDEWEB)

    Liang, Min [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Guan, Minqiang [Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Zhao, Fuxing; Zhou, Xiangtian [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Yuan, Meixia [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Tong, Yi [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005 (China); Yang, Li [Division of Human Genetics, Cincinnati Children' s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229 (United States); Wei, Qi-Ping; Sun, Yan-Hong [Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine and Pharmacology, Beijing 100078 (China); Lu, Fan [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Qu, Jia, E-mail: jqu@wzmc.net [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); and others

    2009-06-05

    We report here the clinical, genetic and molecular characterization of four Chinese families with Leber's hereditary optic neuropathy (LHON). There were variable severity and age-of-onset in visual impairment among these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of complete mitochondrial genomes in these pedigrees showed the homoplasmic T3394C (Y30H) mutation, which localized at a highly conserved tyrosine at position 30 of ND1, and distinct sets of mtDNA polymorphisms belonging to haplogroups D4b and M9a. The occurrence of T3394C mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. However, there was the absence of functionally significant mtDNA mutations in these four Chinese pedigrees carrying the T3394C mutation. Therefore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of the LHON-associated T3394C mutation.

  2. Leber's hereditary optic neuropathy is associated with mitochondrial ND6 T14502C mutation

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Fuxin [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Guan, Minqiang [Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Zhou, Xiangtian [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Yuan, Meixia; Liang, Ming [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Liu, Qi [Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Liu, Yan; Zhang, Yongmei [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Yang, Li [Division of Human Genetics, Cincinnati Children' s Hospital Medical Center, Cincinnati, OH 45229 (United States); Tong, Yi [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005 (China); Wei, Qi-Ping; Sun, Yan-Hong [Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine and Pharmacology, Beijing 100078 (China); Qu, Jia, E-mail: jqu@wzmc.net [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325003 (China); and others

    2009-11-20

    We report here the clinical, genetic, and molecular characterization of three Chinese families with Leber's hereditary optic neuropathy (LHON). There were variable severity and age of onset in visual impairment among these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of complete mitochondrial genomes in these pedigrees showed the homoplasmic T14502C (I58V) mutation, which localized at a highly conserved isoleucine at position 58 of ND6, and distinct sets of mtDNA polymorphisms belonging to haplogroups M10a, F1a1, and H2. The occurrence of T14502C mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. Here, mtDNA variants I187T in the ND1, A122V in CO1, S99A in the A6, and V254I in CO3 exhibited an evolutionary conservation, indicating a potential modifying role in the development of visual impairment associated with T14502C mutation in those families. Furthermore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic manifestation of the LHON-associated T14502C mutation in these Chinese families.

  3. Minocycline, a possible neuroprotective agent in Leber's hereditary optic neuropathy (LHON): studies of cybrid cells bearing 11,778 mutation.

    Science.gov (United States)

    Haroon, Mohammad Fahad; Fatima, Ambrin; Schöler, Susanne; Gieseler, Anne; Horn, Thomas F W; Kirches, Elmar; Wolf, Gerald; Kreutzmann, Peter

    2007-12-01

    Leber's hereditary optic neuropathy (LHON) is a retinal neurodegenerative disorder caused by mitochondrial DNA point mutations. Complex I of the respiratory chain affected by the mutation results in a decrease in ATP and an increase of reactive oxygen species production. Evaluating the efficacy of minocycline in LHON, the drug increased the survival of cybrid cells in contrast to the parental cells after thapsigargin-induced calcium overload. Similar protection was observed by treatment with cyclosporine A, a blocker of the mitochondrial permeability transition pore (mPTP). Ratiometric Ca(2+) imaging reveals that acetylcholine/thapsigargin triggered elevation of the cytosolic calcium concentration is alleviated by minocycline and cyclosporine A. The mitochondrial membrane potential of LHON cybrids was significantly conserved and the active-caspase-3/procaspase-3 ratio was decreased in both treatments. Our observations show that minocycline inhibits permeability transition induced by thapsigargin in addition to its antioxidant effects. In relation with its high safety profile, these results would suggest minocycline as a promising neuroprotective agent in LHON.

  4. Leber's hereditary optic neuropathy (LHON) pathogenic mutations induce mitochondrial-dependent apoptotic death in transmitochondrial cells incubated with galactose medium.

    Science.gov (United States)

    Ghelli, Anna; Zanna, Claudia; Porcelli, Anna Maria; Schapira, Anthony H V; Martinuzzi, Andrea; Carelli, Valerio; Rugolo, Michela

    2003-02-07

    Leber's hereditary optic neuropathy (LHON), a maternally inherited form of central vision loss, is associated with mitochondrial DNA pathogenic point mutations affecting different subunits of complex I. We here report that osteosarcoma-derived cytoplasmic hybrids (cybrid) cell lines harboring one of the three most frequent LHON pathogenic mutations, at positions 11778/ND4, 3460/ND1, and 14484/ND6, undergo cell death when galactose replaces glucose in the medium, contrary to control cybrids that maintain some growth capabilities. This is a well known way to produce a metabolic stress, forcing the cells to rely on the mitochondrial respiratory chain to produce ATP. We demonstrate that LHON cybrid cell death is apoptotic, showing chromatin condensation and nuclear DNA laddering. Moreover, we also document the mitochondrial involvement in the activation of the apoptotic cascade, as shown by the increased release of cytochrome c into the cytosol in LHON cybrid cells as compared with controls. Cybrids bearing the 3460/ND1 and 14484/ND6 mutations seemed more readily prone to undergo apoptosis as compared with the 11778/ND4 mutation. In conclusion, LHON cybrid cells forced by the reduced rate of glycolytic flux to utilize oxidative metabolism are sensitized to an apoptotic death through a mechanism involving mitochondria.

  5. Inner retinal contributions to the multifocal electroretinogram: patients with Leber's hereditary optic neuropathy (LHON). Multifocal ERG in patients with LHON.

    Science.gov (United States)

    Kurtenbach, Anne; Leo-Kottler, Beate; Zrenner, Eberhart

    2004-05-01

    In this study we examine the multifocal electroretinogram (mfERG) recorded from patients suffering from Leber's hereditary optic neuropathy (LHON), a degeneration of the ganglion cell and nerve fibre layers of the retina. We compared the mfERGs recorded from 11 patients with LHON, to those from 11 control subjects. The pattern ERG (PERG) was additionally performed with 9 of the patients. MfERGs were recorded and analysed using the VERIS 3.01 system with a stimulus of 103 equal-sized hexagons. For analysis, hexagons were grouped according to distance from the optic nerve head (ONH) and according to distance from the fovea. Two significant differences were found between the waveforms of the two groups: In the first order kernel, the control group showed a component around 34 ms that decreased with distance from the ONH. This component was reduced in the LHON group of subjects. In the second order (first slice) kernel, the patient group was missing features that decrease with distance from the fovea in the control group. PERG amplitudes showed a significant correlation with the amplitude of the second order mfERG kernel. The results show that the damage to ganglion cells and nerve fibres caused by LHON can be detected in mfERG recordings and indicate that activity from the inner retina can contribute significantly to first and second order waveforms.

  6. Idebenone protects against retinal damage and loss of vision in a mouse model of Leber's hereditary optic neuropathy.

    Directory of Open Access Journals (Sweden)

    Fabrice D Heitz

    Full Text Available Leber's hereditary optic neuropathy (LHON is an inherited disease caused by mutations in complex I of the mitochondrial respiratory chain. The disease is characterized by loss of central vision due to retinal ganglion cell (RGC dysfunction and optic nerve atrophy. Despite progress towards a better understanding of the disease, no therapeutic treatment is currently approved for this devastating disease. Idebenone, a short-chain benzoquinone, has shown promising evidence of efficacy in protecting vision loss and in accelerating recovery of visual acuity in patients with LHON. It was therefore of interest to study suitable LHON models in vitro and in vivo to identify anatomical correlates for this protective activity. At nanomolar concentrations, idebenone protected the rodent RGC cell line RGC-5 against complex I dysfunction in vitro. Consistent with the reported dosing and observed effects in LHON patients, we describe that in mice, idebenone penetrated into the eye at concentrations equivalent to those which protected RGC-5 cells from complex I dysfunction in vitro. Consequently, we next investigated the protective effect of idebenone in a mouse model of LHON, whereby mitochondrial complex I dysfunction was caused by exposure to rotenone. In this model, idebenone protected against the loss of retinal ganglion cells, reduction in retinal thickness and gliosis. Furthermore, consistent with this protection of retinal integrity, idebenone restored the functional loss of vision in this disease model. These results support the pharmacological activity of idebenone and indicate that idebenone holds potential as an effective treatment for vision loss in LHON patients.

  7. Autosomal dominant hereditary spastic paraplegia with axonal sensory motor polyneuropathy maps to chromosome 21q 22.3.

    Science.gov (United States)

    Peddareddygari, Leema Reddy; Hanna, Philip A; Igo, Robert P; Luo, Yuqun A; Won, Sungho; Hirano, Michio; Grewal, Raji P

    2016-01-01

    Hereditary spastic paraplegia (HSP) are a genetically and clinically heterogeneous group of disorders. At present, 19 autosomal dominant loci for HSP have been mapped. We ascertained an American family of European descent segregating an autosomal dominant HSP associated with peripheral neuropathy. A genome wide scan was performed with 410 microsatellite repeat marker (Weber lab screening set 16) and following linkage and haplotype analysis, fine mapping was performed. Established genes or loci for HSP were excluded by direct sequencing or haplotype analysis. All established loci for HSP were excluded. Fine mapping suggested a locus on chromosome 21q22.3 flanked by markers D21S1411 and D21S1446 with a maximum logarithm of odds score of 2.05 and was supported by haplotype analysis. A number of candidate genes in this region were analyzed and no disease-producing mutations were detected. We present the clinical and genetic analysis of an American family with autosomal dominant HSP with axonal sensory motor polyneuropathy mapping to a novel locus on chromosome 21q22.3 designated SPG56.

  8. Tinetti and Berg balance scales correlate with disability in hereditary peripheral neuropathies: a preliminary study.

    Science.gov (United States)

    Monti Bragadin, M; Francini, L; Bellone, E; Grandis, M; Reni, L; Canneva, S; Gemelli, C; Ursino, G; Maggi, G; Mori, L; Schenone, A

    2015-08-01

    The combination of distal muscle weakness, sensory defects and feet deformities leads to disequilibrium in patients affected by Charcot-Marie-Tooth (CMT) neuropathy. Studies relating the outcome of balance scales and clinical severity of CMT are lacking. To evaluate the accuracy of the Tinetti Balance scale (TBS) and Berg Balance scale (BBS) in identifying balance disorders and quantifying disease severity in CMT patients. Observational study. University of Genoa-IRCCS AOU San Martino IST-Department of Neurology, Italy. Nineteen individuals with a diagnosis of CMT (12 females, 7 males, age 41.26±12.42). All subjects underwent an evaluation with both TBS and BBS. Disability was quantified with CMT neuropathy score (CMTNS). Moreover, a complete neurophysiological study was performed. Distal lower limbs strength was evaluated with MRC scale. Pearson rank order correlation was used to determine the correlation between the scores on the two tests and to identify an eventual correlation between TBS or BBS and the CMTNS. Both scales showed a highly significant negative correlation with the CMTNS (r=-0.78, P<0.0005 and r=-0.77, P<0.001, respectively) and distal weakness on the anterior tibial muscles (AT) (TBS: AT left: r=0.65, P<0.005 and AT right: 0.59, P<0.01; BBS: AT left r=+0.71, P<0.001 and AT right r=+0.66, P<0.005). We found also a highly significant, positive correlation between the two different balance scales (r=+0.9, P<0.0001). TBS and BBS strongly correlate with disease disability and distal muscular weakness. Both TBS and BBS may play a relevant role in the assessment of disability in patients affected by CMT. Further studies are needed to validate our results in a larger population.

  9. Hereditary motor and autonomic neuronopathy 1 maps to chromosome 20q13.2-13.3

    Directory of Open Access Journals (Sweden)

    W. Marques Jr.

    2004-11-01

    Full Text Available The spinal muscular atrophies (SMA or hereditary motor neuronopathies result from the continuous degeneration and death of spinal cord lower motor neurons, leading to progressive muscular weakness and atrophy. We describe a large Brazilian family exhibiting an extremely rare, late-onset, dominant, proximal, and progressive SMA accompanied by very unusual manifestations, such as an abnormal sweating pattern, and gastrointestinal and sexual dysfunctions, suggesting concomitant involvement of the autonomic nervous system. We propose a new disease category for this disorder, `hereditary motor and autonomic neuronopathy', and attribute the term, `survival of motor and autonomic neurons 1' (SMAN1 to the respective locus that was mapped to a 14.5 cM region on chromosome 20q13.2-13.3 by genetic linkage analysis and haplotype studies using microsatellite polymorphic markers. This locus lies between markers D20S120 and D20S173 showing a maximum LOD score of 4.6 at D20S171, defining a region with 33 known genes, including several potential candidates. Identifying the SMAN1 gene should not only improve our understanding of the molecular mechanisms underlying lower motor neuron diseases but also help to clarify the relationship between motor and autonomic neurons.

  10. The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V.

    Science.gov (United States)

    Irobi, Joy; Van den Bergh, Peter; Merlini, Luciano; Verellen, Christine; Van Maldergem, Lionel; Dierick, Ines; Verpoorten, Nathalie; Jordanova, Albena; Windpassinger, Christian; De Vriendt, Els; Van Gerwen, Veerle; Auer-Grumbach, Michaela; Wagner, Klaus; Timmerman, Vincent; De Jonghe, Peter

    2004-09-01

    Silver syndrome is a rare autosomal dominant neurodegenerative disorder characterized by marked amyotrophy and weakness of small hand muscles and spasticity in the lower limbs. The locus for Silver syndrome (SPG17) was assigned to a 13 cM region on chromosome 11q12-q14 in a single large pedigree. We recently found heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy (BSCL2, seipin) gene causing SPG17 and distal hereditary motor neuropathy type V (distal HMN V). Here we report the clinical features of two families with heterozygous BSCL2 mutations. Interestingly, both families show a clinical phenotype different from classical Silver syndrome, and in some patients the phenotype is also different from distal HMN V. Patients in the first family had marked spasticity in the lower limbs and very striking distal amyotrophy that always started in the legs. Patients in the second family had distal amyotrophy sometimes starting and predominating in the legs, but no pyramidal tract signs. These observations broaden the clinical phenotype of disorders associated with BSCL2 mutations, having consequences for molecular genetic testing.

  11. Contactin-1 and Neurofascin-155/-186 Are Not Targets of Auto-Antibodies in Multifocal Motor Neuropathy.

    Directory of Open Access Journals (Sweden)

    Kathrin Doppler

    Full Text Available Multifocal motor neuropathy is an immune mediated disease presenting with multifocal muscle weakness and conduction block. IgM auto-antibodies against the ganglioside GM1 are detectable in about 50% of the patients. Auto-antibodies against the paranodal proteins contactin-1 and neurofascin-155 and the nodal protein neurofascin-186 have been detected in subgroups of patients with chronic inflammatory demyelinating polyneuropathy. Recently, auto-antibodies against neurofascin-186 and gliomedin were described in more than 60% of patients with multifocal motor neuropathy. In the current study, we aimed to validate this finding, using a combination of different assays for auto-antibody detection. In addition we intended to detect further auto-antibodies against paranodal proteins, specifically contactin-1 and neurofascin-155 in multifocal motor neuropathy patients' sera. We analyzed sera of 33 patients with well-characterized multifocal motor neuropathy for IgM or IgG anti-contactin-1, anti-neurofascin-155 or -186 antibodies using enzyme-linked immunosorbent assay, binding assays with transfected human embryonic kidney 293 cells and murine teased fibers. We did not detect any IgM or IgG auto-antibodies against contactin-1, neurofascin-155 or -186 in any of our multifocal motor neuropathy patients. We conclude that auto-antibodies against contactin-1, neurofascin-155 and -186 do not play a relevant role in the pathogenesis in this cohort with multifocal motor neuropathy.

  12. MRI shows thickening and altered diffusion in the median and ulnar nerves in multifocal motor neuropathy

    DEFF Research Database (Denmark)

    Haakma, Wieke; Jongbloed, Bas A.; Froeling, Martijn

    2017-01-01

    Objectives To study disease mechanisms in multifocal motor neuropathy (MMN) with magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) of the median and ulnar nerves. Methods We enrolled ten MMN patients, ten patients with amyotrophic lateral sclerosis (ALS) and ten healthy controls...... is compatible with changes in the myelin sheath structure, whereas lowered AD values suggest axonal dysfunction. These findings suggest that myelin and axons are diffusely involved in MMN pathogenesis....

  13. Longitudinal study of a heteroplasmic 3460 Leber hereditary optic neuropathy family by multiplexed primer-extension analysis and nucleotide sequencing

    Energy Technology Data Exchange (ETDEWEB)

    Ghosh, S.S.; Fahy, E. [Applied Genetics, San Diego, CA (United States); Bodis-Wollner, I. [State Univ. of New York College of Optometry, New York, NY (United States)] [and others

    1996-02-01

    Nucleotide-sequencing and multiplexed primer-extension assays have been used to quantitate the mutant-allele frequency in 14 maternal relatives, spanning three generations, from a family that is heteroplasmic for the primary Leber hereditary optic neuropathy (LHON) mutation at nucleotide 3460 of the mitochondrial genome. There was excellent agreement between the values that were obtained with the two different methods. The longitudinal study shows that the mutant-allele frequency was constant within individual family members over a sampling period of 3.5 years. Second, although there was an overall increase in the mutant-allele frequency in successive generations, segregation in the direction of the mutant allele was not invariant, and there was one instance in which there was a significant decrease in the frequency from parent to offspring. From these two sets of results, and from previous studies of heteroplasmic LHON families, we conclude that there is no evidence for a marked selective pressure that determines the replication, segregation, or transmission of primary LHON mutations to white blood cells and platelets. Instead, the mtDNA molecules are most likely to replicate and segregate under conditions of random drift at the cellular level. Finally, the pattern of transmission in this maternal lineage is compatible with a developmental bottleneck model in which the number of mitochondrial units of segregation in the female germ line is relatively small in relation to the number of mtDNA molecules within a cell. However, this is not an invariant pattern for humans, and simple models of mitochondrial gene transmission are inappropriate at the present time. 37 refs., 4 figs., 1 tab.

  14. Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage

    Energy Technology Data Exchange (ETDEWEB)

    Brown, M.D.; Sun, F.; Wallace, D.C. [Emory Univ. School of Medicine, Atlanta, GA (United States)

    1997-02-01

    Leber hereditary optic neuropathy (LHON) is a type of blindness caused by mtDNA mutations. Three LHON mtDNA mutations at nucleotide positions 3460, 11778, and 14484 are specific for LHON and account for 90% of worldwide cases and are thus designated as {open_quotes}primary{close_quotes} LHON mutations. Fifteen other {open_quotes}secondary{close_quotes} LHON mtDNA mutations have been identified, but their pathogenicity is unclear. mtDNA haplotype and phylogenetic analysis of the primary LHON mutations in North American Caucasian patients and controls has shown that, unlike the 3460 and 11778 mutations, which are distributed throughout the European-derived (Caucasian) mtDNA phylogeny, patients containing the 14484 mutation tended to be associated with European mtDNA haplotype J. To investigate this apparent clustering, we performed {chi}{sup 2}-based statistical analyses to compare the distribution of LHON patients on the Caucasian phylogenetic tree. Our results indicate that, unlike the 3460 and 11778 mutations, the 14484 mutation was not distributed on the phylogeny in proportion to the frequencies of the major Caucasian mtDNA haplogroups found in North America. The 14484 mutation was next shown to occur on the haplogroup J background more frequently that expected, consistent with the observation that {approximately}75% of worldwide 14484-positive LHON patients occur in association with haplogroup J. The 11778 mutation also exhibited a moderate clustering on haplogroup J. These observations were supported by statistical analysis using all available mutation frequencies reported in the literature. This paper thus illustrates the potential importance of genetic background in certain mtDNA-based diseases, speculates on a pathogenic role for a subset of LHON secondary mutations and their interaction with primary mutations, and provides support for a polygenic model for LHON expression in some cases. 18 refs., 3 tabs.

  15. Mitochondrial DNA mutation m.10680G > A is associated with Leber hereditary optic neuropathy in Chinese patients

    Science.gov (United States)

    2012-01-01

    Background Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder with gender biased and incomplete penetrance. The majority of LHON patients are caused by one of the three primary mutations (m.3460G > A, m.11778G > A and m.14484T > C). Rare pathogenic mutations have been occasionally reported in LHON patients. Methods We screened mutation m.10680G > A in the MT-ND4L gene in 774 Chinese patients with clinical features of LHON but lacked the three primary mutations by using allele specific PCR (AS-PCR). Patients with m.10680G > A were further determined entire mtDNA genome sequence. Results The optimal AS-PCR could detect as low as 10% heteroplasmy of mutation m.10680G > A. Two patients (Le1263 and Le1330) were identified to harbor m.10680G > A. Analysis of the complete mtDNA sequences of the probands suggested that they belonged to haplogroups B4a1 and D6a1. There was no other potentially pathogenic mutation, except for a few private yet reported variants in the MT-ND1 and MT-ND5 genes, in the two lineages. A search in reported mtDNA genome data set (n = 9277; excluding Chinese LHON patients) identified no individual with m.10680G > A. Frequency of m.10680G > A in Chinese LHON patients analyzed in this study and our previous studies (3/784) was significantly higher than that of the general populations (0/9277) (P = 0.0005). Conclusion Taken together, we speculated that m.10680G > A may be a rare pathogenic mutation for LHON in Chinese. This mutation should be included in future clinical diagnosis. PMID:22400981

  16. Cigarette toxicity triggers Leber's hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways

    Science.gov (United States)

    Giordano, L; Deceglie, S; d'Adamo, P; Valentino, M L; La Morgia, C; Fracasso, F; Roberti, M; Cappellari, M; Petrosillo, G; Ciaravolo, S; Parente, D; Giordano, C; Maresca, A; Iommarini, L; Del Dotto, V; Ghelli, A M; Salomao, S R; Berezovsky, A; Belfort, R; Sadun, A A; Carelli, V; Loguercio Polosa, P; Cantatore, P

    2015-01-01

    Leber's hereditary optic neuropathy (LHON), the most frequent mitochondrial disease, is associated with mitochondrial DNA (mtDNA) point mutations affecting Complex I subunits, usually homoplasmic. This blinding disorder is characterized by incomplete penetrance, possibly related to several genetic modifying factors. We recently reported that increased mitochondrial biogenesis in unaffected mutation carriers is a compensatory mechanism, which reduces penetrance. Also, environmental factors such as cigarette smoking have been implicated as disease triggers. To investigate this issue further, we first assessed the relationship between cigarette smoke and mtDNA copy number in blood cells from large cohorts of LHON families, finding that smoking was significantly associated with the lowest mtDNA content in affected individuals. To unwrap the mechanism of tobacco toxicity in LHON, we exposed fibroblasts from affected individuals, unaffected mutation carriers and controls to cigarette smoke condensate (CSC). CSC decreased mtDNA copy number in all cells; moreover, it caused significant reduction of ATP level only in mutated cells including carriers. This implies that the bioenergetic compensation in carriers is hampered by exposure to smoke derivatives. We also observed that in untreated cells the level of carbonylated proteins was highest in affected individuals, whereas the level of several detoxifying enzymes was highest in carriers. Thus, carriers are particularly successful in reactive oxygen species (ROS) scavenging capacity. After CSC exposure, the amount of detoxifying enzymes increased in all cells, but carbonylated proteins increased only in LHON mutant cells, mostly from affected individuals. All considered, it appears that exposure to smoke derivatives has a more deleterious effect in affected individuals, whereas carriers are the most efficient in mitigating ROS rather than recovering bioenergetics. Therefore, the identification of genetic modifiers that

  17. Mitochondrial DNA mutation m.10680G > A is associated with Leber hereditary optic neuropathy in Chinese patients

    Directory of Open Access Journals (Sweden)

    Zhang A-Mei

    2012-03-01

    Full Text Available Abstract Background Leber hereditary optic neuropathy (LHON is a mitochondrial disorder with gender biased and incomplete penetrance. The majority of LHON patients are caused by one of the three primary mutations (m.3460G > A, m.11778G > A and m.14484T > C. Rare pathogenic mutations have been occasionally reported in LHON patients. Methods We screened mutation m.10680G > A in the MT-ND4L gene in 774 Chinese patients with clinical features of LHON but lacked the three primary mutations by using allele specific PCR (AS-PCR. Patients with m.10680G > A were further determined entire mtDNA genome sequence. Results The optimal AS-PCR could detect as low as 10% heteroplasmy of mutation m.10680G > A. Two patients (Le1263 and Le1330 were identified to harbor m.10680G > A. Analysis of the complete mtDNA sequences of the probands suggested that they belonged to haplogroups B4a1 and D6a1. There was no other potentially pathogenic mutation, except for a few private yet reported variants in the MT-ND1 and MT-ND5 genes, in the two lineages. A search in reported mtDNA genome data set (n = 9277; excluding Chinese LHON patients identified no individual with m.10680G > A. Frequency of m.10680G > A in Chinese LHON patients analyzed in this study and our previous studies (3/784 was significantly higher than that of the general populations (0/9277 (P = 0.0005. Conclusion Taken together, we speculated that m.10680G > A may be a rare pathogenic mutation for LHON in Chinese. This mutation should be included in future clinical diagnosis.

  18. Motor activation in SPG4-linked hereditary spastic paraplegia

    DEFF Research Database (Denmark)

    Scheuer, KH; Nielsen, JE; Krabbe, Katja

    2006-01-01

    : Thirteen patients and 13 normal controls matched for age, gender and handedness underwent O15-labelled water positron emission tomography during (1) right ankle flexion-extension, (2) right shoulder flexion-extension and (3) rest. Within-group comparisons of movement vs. rest (simple main effects......) and between-group comparisons of movement vs. rest (group x behavioural state interaction) were performed using a random effects approach and statistical parametric mapping (SPM99). RESULTS: Patterns of motor activation were generally comparable between groups during both tasks, although patients had...

  19. Stem Cell Ophthalmology Treatment Study (SCOTS: bone marrow-derived stem cells in the treatment of Leber′s hereditary optic neuropathy

    Directory of Open Access Journals (Sweden)

    Jeffrey N Weiss

    2016-01-01

    Full Text Available The Stem Cell Ophthalmology Treatment Study (SCOTS is currently the largest-scale stem cell ophthalmology trial registered at ClinicalTrials.gov (identifier: NCT01920867. SCOTS utilizes autologous bone marrow-derived stem cells (BMSCs to treat optic nerve and retinal diseases. Treatment approaches include a combination of retrobulbar, subtenon, intravitreal, intra-optic nerve, subretinal, and intravenous injection of autologous BMSCs according to the nature of the disease, the degree of visual loss, and any risk factors related to the treatments. Patients with Leber′s hereditary optic neuropathy had visual acuity gains on the Early Treatment Diabetic Retinopathy Study (ETDRS of up to 35 letters and Snellen acuity improvements from hand motion to 20/200 and from counting fingers to 20/100. Visual field improvements were noted. Macular and optic nerve head nerve fiber layer typically thickened. No serious complications were seen. The increases in visual acuity obtained in our study were encouraging and suggest that the use of autologous BMSCs as provided in SCOTS for ophthalmologic mitochondrial diseases including Leber′s hereditary optic neuropathy may be a viable treatment option.

  20. Transgenic expression of neuronal dystonin isoform 2 partially rescues the disease phenotype of the dystonia musculorum mouse model of hereditary sensory autonomic neuropathy VI

    Science.gov (United States)

    Ferrier, Andrew; Sato, Tadasu; De Repentigny, Yves; Gibeault, Sabrina; Bhanot, Kunal; O'Meara, Ryan W.; Lynch-Godrei, Anisha; Kornfeld, Samantha F.; Young, Kevin G.; Kothary, Rashmi

    2014-01-01

    A newly identified lethal form of hereditary sensory and autonomic neuropathy (HSAN), designated HSAN-VI, is caused by a homozygous mutation in the bullous pemphigoid antigen 1 (BPAG1)/dystonin gene (DST). The HSAN-VI mutation impacts all major neuronal BPAG1/dystonin protein isoforms: dystonin-a1, -a2 and -a3. Homozygous mutations in the murine Dst gene cause a severe sensory neuropathy termed dystonia musculorum (dt). Phenotypically, dt mice are similar to HSAN-VI patients, manifesting progressive limb contractures, dystonia, dysautonomia and early postnatal death. To obtain a better molecular understanding of disease pathogenesis in HSAN-VI patients and the dt disorder, we generated transgenic mice expressing a myc-tagged dystonin-a2 protein under the regulation of the neuronal prion protein promoter on the dtTg4/Tg4 background, which is devoid of endogenous dystonin-a1 and -a2, but does express dystonin-a3. Restoring dystonin-a2 expression in the nervous system, particularly within sensory neurons, prevented the disorganization of organelle membranes and microtubule networks, attenuated the degeneration of sensory neuron subtypes and ameliorated the phenotype and increased life span in these mice. Despite these improvements, complete rescue was not observed likely because of inadequate expression of the transgene. Taken together, this study provides needed insight into the molecular basis of the dt disorder and other peripheral neuropathies including HSAN-VI. PMID:24381311

  1. Acute motor axonal neuropathy in a child with atypical presentation: a case report.

    Science.gov (United States)

    Lee, Kyung Soo; Han, Seung Hoon

    2015-01-01

    Acute motor axonal neuropathy (AMAN) is a variant of Guillain-Barre syndrome. It has been reported to have no sensory symptoms and is diagnosed by typical electrophysiological findings of low-amplitude or unobtainable compound muscle action potentials with normal sensory nerve action potentials. However, the authors experienced atypical case of general electrophysiological findings of AMAN with pain and paresthesia and presented it. This case implies that clinician should be on the alert to atypical sensory symptoms from the classical presentation of AMAN even if the patient is diagnosed with AMAN electrophysiologically and should consider proper treatment options based on clinical presentations.

  2. Autoantibody pathogenicity in a multifocal motor neuropathy induced pluripotent stem cell-derived model.

    Science.gov (United States)

    Harschnitz, Oliver; van den Berg, Leonard H; Johansen, Lill Eva; Jansen, Marc D; Kling, Sandra; Vieira de Sá, Renata; Vlam, Lotte; van Rheenen, Wouter; Karst, Henk; Wierenga, Corette J; Pasterkamp, R Jeroen; van der Pol, W Ludo

    2016-07-01

    We investigated the pathogenicity of immunoglobulin M (IgM) anti-GM1 antibodies in serum from patients with multifocal motor neuropathy (MMN) using human induced pluripotent stem cell (iPSC)-derived motor neurons (MNs). iPSCs were generated from fibroblasts and differentiated into MNs. We studied the binding of IgM to MNs, their complement-activating properties, and effects on structural integrity using fluorescence and electron microscopy. Live cell imaging was used to study effects of antibody binding on MNs in the presence and absence of complement. IgM antibody binding to MNs was detected using sera from MMN patients with and without detectable anti-GM1 IgM antibody titers in enzyme-linked immunosorbent assay, but not with sera from (disease) controls. Competition and depletion experiments showed that antibodies specifically bound to GM1 on iPSC-derived MNs. Binding of these antibodies disrupted calcium homeostasis by both complement-dependent and complement-independent pathways. MNs showed marked axonal damage after complement activation, and reduced antibody pathogenicity following treatment with immunoglobulin preparations. Our data provide evidence for the pathogenicity of anti-GM1 IgM antibodies in MMN patients and link their presence to the clinical characteristics of axonal damage and immunoglobulin responsiveness. This iPSC-derived disease model will facilitate diagnosis, studies on autoantibody pathogenicity, drug development, and screening in immune-mediated neuropathies. Ann Neurol 2016;80:71-88. © 2016 American Neurological Association.

  3. MRI shows thickening and altered diffusion in the median and ulnar nerves in multifocal motor neuropathy.

    Science.gov (United States)

    Haakma, Wieke; Jongbloed, Bas A; Froeling, Martijn; Goedee, H Stephan; Bos, Clemens; Leemans, Alexander; van den Berg, Leonard H; Hendrikse, Jeroen; van der Pol, W Ludo

    2017-05-01

    To study disease mechanisms in multifocal motor neuropathy (MMN) with magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) of the median and ulnar nerves. We enrolled ten MMN patients, ten patients with amyotrophic lateral sclerosis (ALS) and ten healthy controls (HCs). Patients underwent MRI (in a prone position) and nerve conduction studies. DTI and fat-suppressed T2-weighted scans of the forearms were performed on a 3.0T MRI scanner. Fibre tractography of the median and ulnar nerves was performed to extract diffusion parameters: fractional anisotropy (FA), mean (MD), axial (AD) and radial (RD) diffusivity. Cross-sectional areas (CSA) were measured on T2-weighted scans. Forty-five out of 60 arms were included in the analysis. AD was significantly lower in MMN patients (2.20 ± 0.12 × 10-3 mm2/s) compared to ALS patients (2.31 ± 0.17 × 10-3 mm2/s; p motor neuropathy (MMN). • Diffusion tensor imaging allows non-invasive evaluation of the forearm nerves in MMN. • Nerve thickening and lowered diffusion parameters suggests myelin and axonal changes. • This study can help to provide insight into pathological mechanisms of MMN.

  4. Evidence against an X-linked locus close to DXS7 determining visual loss susceptibility in British and Italian families with Leber hereditary optic neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Sweeney, M.G.; Davis, M.B.; Lashwood, A.; Brockington, M.; Harding, A.E. (Institute of Neurology, Queen Square, London (United Kingdom)); Toscano, A. (Clinica Neurologica, Messina (Italy))

    1992-10-01

    Leber hereditary optic neuropathy (LHON) is associated with mutations of mtDNA, but two features of LHON pedigrees are not explicable solely on the basis of mitochondrial inheritance. There is a large excess of affected males, and not all males at risk develop the disease. These observations could be explained by the existence of an X-linked visual loss susceptibility gene. This hypothesis was supported by linkage studies in Finland, placing the susceptibility locus at DXS7, with a maximum lod score of 2.48 at a recombination fraction of 0. Linkage studies in 1 Italian and 12 British families with LHON, analyzed either together or separately depending on the associated mtDNA mutation, have excluded the presence of such a locus from an interval of about 30 cM around DXS7 in these kindreds, with a total lod score of -26.51 at a recombination fraction of 0. 17 refs., 2 figs., 1 tab.

  5. Detection of the mtDNA 14484 mutation on an African-specific haplotype: Implications about its role in causing Leber hereditary optic neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Torroni, A.; Petrozzi, M.; Terracina, M. [Universita` di Roma (Italy)] [and others

    1996-07-01

    Leber hereditary optic neuropathy (LHON) is a maternally transmitted disease whose primary clinical manifestation is acute or subacute bilateral loss of central vision leading to central scotoma and blindness. To date, LHON has been associated with 18 mtDNA missense mutations, even though, for many of these mutations, it remains unclear whether they cause the disease, contribute to the pathology, or are nonpathogenic mtDNA polymorphisms. On the basis of numerous criteria, which include the specificity for LHON, the frequency in the general population, and the penetrance within affected pedigrees, the detection of associated defects in the respiratory chain, mutations at three nucleotide positions (nps), 11778 (G{r_arrow}A), 3460 (G{r_arrow}A), and 14484 (T{r_arrow}C) have been classified as high-risk and primary LHON mutations. Overall, these three mutations encompass {ge}90% of the LHON cases. 29 refs., 1 fig.

  6. Mitochondrial Gene Therapy Improves Respiration, Biogenesis, and Transcription in G11778A Leber's Hereditary Optic Neuropathy and T8993G Leigh's Syndrome Cells

    Science.gov (United States)

    Bergquist, Kristen; Young, Kisha; Gnaiger, Erich; Rao, Raj R.

    2012-01-01

    Abstract Many incurable mitochondrial disorders result from mutant mitochondrial DNA (mtDNA) and impaired respiration. Leigh's syndrome (LS) is a fatal neurodegenerative disorder of infants, and Leber's hereditary optic neuropathy (LHON) causes blindness in young adults. Treatment of LHON and LS cells harboring G11778A and T8993G mutant mtDNA, respectively, by >90%, with healthy donor mtDNA complexed with recombinant human mitochondrial transcription factor A (rhTFAM), improved mitochondrial respiration by ∼1.2-fold in LHON cells and restored >50% ATP synthase function in LS cells. Mitochondrial replication, transcription, and translation of key respiratory genes and proteins were increased in the short term. Increased NRF1, TFAMB1, and TFAMA expression alluded to the activation of mitochondrial biogenesis as a mechanism for improving mitochondrial respiration. These results represent the development of a therapeutic approach for LHON and LS patients in the near future. PMID:22390282

  7. Partial mitochondrial complex I inhibition induces oxidative damage and perturbs glutamate transport in primary retinal cultures. Relevance to Leber Hereditary Optic Neuropathy (LHON).

    Science.gov (United States)

    Beretta, Simone; Wood, John P M; Derham, Barry; Sala, Gessica; Tremolizzo, Lucio; Ferrarese, Carlo; Osborne, Neville N

    2006-11-01

    Leber Hereditary Optic Neuropathy (LHON) is a maternally inherited form of visual loss, due to selective degeneration of retinal ganglion cells. Despite the established aetiological association between LHON and mitochondrial DNA mutations affecting complex I of the electron transport chain, the pathophysiology of this disorder remains obscure. Primary rat retinal cultures were exposed to increasing concentrations of rotenone to titrate complex I inhibition. Neural cells were more sensitive than Müller glial cells to rotenone toxicity. Rotenone induced an increase in mitochondrial-derived free radicals and lipid peroxidation. Sodium-dependent glutamate uptake, which is mostly mediated by the glutamate transporter GLAST expressed by Müller glial cells, was reduced dose-dependently by rotenone with no changes in GLAST expression. Our findings suggest that complex I-derived free radicals and disruption of glutamate transport might represent key elements for explaining the selective retinal ganglion cell death in LHON.

  8. Clinical and Paraclinical Indicators of Motor System Impairment in Hereditary Spastic Paraplegia: A Pilot Study.

    Science.gov (United States)

    Martinuzzi, Andrea; Montanaro, Domenico; Vavla, Marinela; Paparella, Gabriella; Bonanni, Paolo; Musumeci, Olimpia; Brighina, Erika; Hlavata, Hana; Rossi, Giuseppe; Aghakhanyan, Gayane; Martino, Nicola; Baratto, Alessandra; D'Angelo, Maria Grazia; Peruch, Francesca; Fantin, Marianna; Arnoldi, Alessia; Citterio, Andrea; Vantaggiato, Chiara; Rizzo, Vincenzo; Toscano, Antonio; Bresolin, Nereo; Bassi, Maria Teresa

    2016-01-01

    Hereditary spastic paraplegias (HSP) are a composite and genetically heterogeneous group of conditions mainly expressed by the impairment of the central motor system ("pure" forms). The involvement of other components of the central nervous system or of other systems is described in the "complicate" forms. The definition of an investigation protocol capable, by assembling clinical and paraclinical indicators to fully represent the extent of the motor system impairment, would help both the clinical handling of these conditions and contribute to our understanding of their pathogenesis. We applied a clinical and paraclinical protocol which included tools exploring motor and non motor functioning, neurophysiology and MRI to a composite cohort of 70 molecularly defined HSP patients aged 3 to 65, to define for each indicator its significance in detailing the presence and the severity of the pathology. Clinically increased deep tendon reflexes and lower limb (LL) weakness are constant findings in all patients. The "complicated" forms are characterized by peripheral motor impairment, cognitive and cerebellar involvement. The Spastic Paraplegia Rating Scale efficiently reflects the severity of functional problems and correlates with disease duration. Neurophysiology consistently documents the impairment of the central motor pathway to the LLs. Nevertheless, the upper extremities and sensory system involvement is a frequent finding. MRI diffusion tensor imaging (DTI) highlighted a significant alteration of FA and MD. Combining the sampling of the various portion of the cortico-spinal tract (CST) DTI consistently discriminated patients from controls. We propose a graded clinical and paraclinical protocol for HSP phenotype definition, indicating for each tool the discriminative and descriptive capacity. Our protocol applied to 9 different forms of HSP showed that the functional impairment often extends beyond the CST. The novel DTI approach may add significant elements in

  9. Clinical and Paraclinical Indicators of Motor System Impairment in Hereditary Spastic Paraplegia: A Pilot Study.

    Directory of Open Access Journals (Sweden)

    Andrea Martinuzzi

    Full Text Available Hereditary spastic paraplegias (HSP are a composite and genetically heterogeneous group of conditions mainly expressed by the impairment of the central motor system ("pure" forms. The involvement of other components of the central nervous system or of other systems is described in the "complicate" forms. The definition of an investigation protocol capable, by assembling clinical and paraclinical indicators to fully represent the extent of the motor system impairment, would help both the clinical handling of these conditions and contribute to our understanding of their pathogenesis.We applied a clinical and paraclinical protocol which included tools exploring motor and non motor functioning, neurophysiology and MRI to a composite cohort of 70 molecularly defined HSP patients aged 3 to 65, to define for each indicator its significance in detailing the presence and the severity of the pathology.Clinically increased deep tendon reflexes and lower limb (LL weakness are constant findings in all patients. The "complicated" forms are characterized by peripheral motor impairment, cognitive and cerebellar involvement. The Spastic Paraplegia Rating Scale efficiently reflects the severity of functional problems and correlates with disease duration. Neurophysiology consistently documents the impairment of the central motor pathway to the LLs. Nevertheless, the upper extremities and sensory system involvement is a frequent finding. MRI diffusion tensor imaging (DTI highlighted a significant alteration of FA and MD. Combining the sampling of the various portion of the cortico-spinal tract (CST DTI consistently discriminated patients from controls.We propose a graded clinical and paraclinical protocol for HSP phenotype definition, indicating for each tool the discriminative and descriptive capacity. Our protocol applied to 9 different forms of HSP showed that the functional impairment often extends beyond the CST. The novel DTI approach may add significant

  10. Simultaneous occurrence of the 11778 (ND4) and the 9438 (COX III) mtDNA mutations in Leber hereditary optic neuropathy: Molecular, biochemical, and clinical findings

    Energy Technology Data Exchange (ETDEWEB)

    Oostra, R.J.; Bleeker-Wagemakers, E.M.; Zwart, R. [Ophthalmic Research Institute, Amsterdam (Netherlands)] [and others

    1995-10-01

    Three mtDNA point mutations at nucleotide position (np) 3460, at np 11778 and at np 14484, are thought to be of primary importance in the pathogenesis of Leber hereditary optic neuropathy (LHON), a maternally inherited disease characterized by subacute central vision loss. These mutations are present in genes coding for subunits of complex I (NADH dehydrogenase) of the respiratory chain, occur exclusively in LHON maternal pedigrees, and have never been reported to occur together. Johns and Neufeld postulated that an mtDNA mutation at np 9438, in the gene coding for one of the subunits (COX III) of complex IV (cytochrome c oxidase), was also of primary importance. Johns and Neufeld (1993) found this mutation, which changed a conserved glycine to a serine, in 5 unrelated LHON probands who did not carry one of the presently known primary mutations, but they did not find it in 400 controls. However, the role of this sequence variant has been questioned in the Journal when it has been found to occur in apparently healthy African and Cuban individuals. Subsequently, Johns et al. described this mutation in two Cuban individuals presenting with optic and peripheral neuropathy. 22 refs., 1 fig., 1 tab.

  11. Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP)

    Science.gov (United States)

    2013-01-01

    Background Hereditary spastic paraplegias (HSPs) are characterised by lower limb spasticity due to degeneration of the corticospinal tract. We set out for an electrophysiological characterisation of motor and sensory tracts in patients with HSP. Methods We clinically and electrophysiologically examined a cohort of 128 patients with genetically confirmed or clinically probable HSP. Motor evoked potentials (MEPs) to arms and legs, somato-sensory evoked potentials of median and tibial nerves, and nerve conduction studies of tibial, ulnar, sural, and radial nerves were assessed. Results Whereas all patients showed clinical signs of spastic paraparesis, MEPs were normal in 27% of patients and revealed a broad spectrum with axonal or demyelinating features in the others. This heterogeneity can at least in part be explained by different underlying genotypes, hinting for distinct pathomechanisms in HSP subtypes. In the largest subgroup, SPG4, an axonal type of damage was evident. Comprehensive electrophysiological testing disclosed a more widespread affection of long fibre tracts involving peripheral nerves and the sensory system in 40%, respectively. Electrophysiological abnormalities correlated with the severity of clinical symptoms. Conclusions Whereas HSP is primarily considered as an upper motoneuron disorder, our data suggest a more widespread affection of motor and sensory tracts in the central and peripheral nervous system as a common finding in HSP. The distribution patterns of electrophysiological abnormalities were associated with distinct HSP genotypes and could reflect different underlying pathomechanisms. Electrophysiological measures are independent of symptomatic treatment and may therefore serve as a reliable biomarker in upcoming HSP trials. PMID:24107482

  12. [The analysis of mitochondrial DNA haplogroups and variants for Leber's hereditary optic neuropathy in Chinese families carrying the m.14484T >C mutation].

    Science.gov (United States)

    Meng, Xiangjuan; Zhu, Jinping; Gao, Min; Zhang, Sai; Zhao, Fuxin; Zhang, Juanjuan; Liu, Xiaoling; Wei, Qiping; Tong, Yi; Zhang, Minglian; Qu, Jia; Guan, Minxin

    2014-04-01

    The m.14484T>C mutation in mitochondrial ND6 gene (MT-ND6) is a primary mutation underlying the development of Leber's hereditary optic neuropathy (LHON) , but by itself not enough to cause visual loss. To explore the role of mitochondrial haplogroups on the expression of LHON for the people carrying the m.14484T>C mutation, we performed systematic and extended mutational screening of MT-ND6 gene in a cohort of 1177 Han Chinese patients with LHON. A total of 67 affected subjects carried the homoplasmic m.14484T>C mutation, accounting for 5.7% of this LHON population. The penetrances of optic neuropathy among 51 pedigrees carrying the m.14484T>C mutation ranged from 5.6% to 100.0%, with the average of 21.5%. The sequence analysis of entire mitochondrial genomes of 51 probands exhibited distinct sets of polymorphisms belonging to 18 Eastern Asian haplogroups. The frequencies of haplogroup A and haplogroup F were sig-nificantly less in the LHON mtDNA samples than those in 106 Chinese controls. On the other hand, the haplogroup M10a accounted for 9.8% of the patient's mtDNA samples but was absent in 106 Chinese controls. Strikingly, the average pene-trance (46.13%) of optic neuropathy for the pedigrees carrying mitochondrial haplogroup M10a was higher than those car-rying other mtDNA haplogroups. These observations indicated that mitochondrial haplogroup M10a may increase the risk of visual loss.

  13. Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5).

    Science.gov (United States)

    Kim, Hee-Jin; Sohn, Kwang-Min; Shy, Michael E; Krajewski, Karen M; Hwang, Miok; Park, June-Hee; Jang, Sue-Yon; Won, Hong-Hee; Choi, Byung-Ok; Hong, Sung Hwa; Kim, Byoung-Joon; Suh, Yeon-Lim; Ki, Chang-Seok; Lee, Soo-Youn; Kim, Sun-Hee; Kim, Jong-Won

    2007-09-01

    We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy, one of Asian and one of European descent. The disease is inherited in an X-linked recessive manner, and the affected male patients invariably develop sensorineural hearing loss of prelingual type followed by gating disturbance and visual loss. The family of European descent was reported in 1967 as having Rosenberg-Chutorian syndrome, and recently a Korean family with the same symptom triad was identified with a novel disease locus CMTX5 on the chromosome band Xq21.32-q24. PRPS1 (phosphoribosyl pyrophosphate synthetase 1) is an isoform of the PRPS gene family and is ubiquitously expressed in human tissues, including cochlea. The enzyme mediates the biochemical step critical for purine metabolism and nucleotide biosynthesis. The mutations identified were E43D, in patients with Rosenberg-Chutorian syndrome, and M115T, in the Korean patients with CMTX5. We also showed decreased enzyme activity in patients with M115T. PRPS1 is the first CMT gene that encodes a metabolic enzyme, shedding a new light on the understanding of peripheral nerve-specific metabolism and also suggesting the potential of PRPS1 as a target for drugs in prevention and treatment of peripheral neuropathy by antimetabolite therapy.

  14. Nerve sonography in multifocal motor neuropathy and chronic inflammatory demyelinating polyneuropathy

    Directory of Open Access Journals (Sweden)

    D. S. Druzhinin

    2016-01-01

    Full Text Available The quantitative ultrasound characteristics (USC of the median, ulnar nerve at different levels and the spinal nerves in patients with multifocal motor neuropathy (MMN; n=13; 40,4 ± 12,6 years old and chronic inflammatory demyelinating polyneuropathy (CIDP; n = 7; 47,3 ± 11,2 year old did not reveal statistical difference in cross sectional area (CSA between analyzed groups. Patients with MMN have more pronounced asymmetry of CSA in comparison with CIDP patients which have a symmetrical pattern of diffuse nerve involvement. Quantitative USC has shown to be not informative enough in differentiation of MMN and CIDP. The qualitative analysis (QA according to 3 described types of nerve changes has shown that CIDP is characterized by the prevalence of type 3 pattern (85.8 % while MMN – by type 2 (69.2 %. The sensitivity and specificity of proposed QA patterns in nerve USC need to be analyzed in additional investigations. 

  15. A comparative study of brachial plexus sonography and magnetic resonance imaging in chronic inflammatory demyelinating neuropathy and multifocal motor neuropathy

    NARCIS (Netherlands)

    Goedee, H S; Jongbloed, B A; van Asseldonk, J.T.H.; Hendrikse, J|info:eu-repo/dai/nl/266590268; Vrancken, A F J E|info:eu-repo/dai/nl/30354693X; Franssen, H|info:eu-repo/dai/nl/072250313; Nikolakopoulos, S; Visser, L H; van der Pol, W L|info:eu-repo/dai/nl/203721721; van den Berg, L H|info:eu-repo/dai/nl/288255216

    2017-01-01

    BACKGROUND AND PURPOSE: To compare the performance of neuroimaging techniques, i.e. high-resolution ultrasound (HRUS) and magnetic resonance imaging (MRI), when applied to the brachial plexus, as part of the diagnostic work-up of chronic inflammatory demyelinating neuropathy (CIDP) and multifocal

  16. Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder?

    Science.gov (United States)

    De Jonghe, P; Auer-Grumbach, M; Irobi, J; Wagner, K; Plecko, B; Kennerson, M; Zhu, D; De Vriendt, E; Van Gerwen, V; Nicholson, G; Hartung, H-P; Timmerman, V

    2002-06-01

    Autosomal dominant juvenile amyotrophic lateral sclerosis (ALS) is a rare disorder and so far only one family has been reported. Genetic linkage studies mapped the disease locus to chromosome 9q34 (ALS4). The diagnosis of ALS in this family is based on the clinical signs with almost exclusively lower motor neurone pathology in combination with less prominent pyramidal tract signs. Atypical features include normal life expectancy, the absence of bulbar involvement and the symmetrical distal distribution of atrophy and weakness. We performed a molecular genetic study in three families that we had diagnosed as having distal hereditary motor neuronopathy, i.e. distal spinal muscular atrophy or spinal Charcot-Marie-Tooth syndrome, and found linkage to the ALS4 locus. The clinical phenotype in these three families, of different geographic origin (Austria, Belgium and England), is strikingly similar to the autosomal dominant juvenile ALS family except for a younger onset age in two of the distal hereditary motor neuronopathy families. These data suggest that ALS4 and distal hereditary motor neuronopathy with pyramidal tract signs may be one and the same disorder.

  17. Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy

    Science.gov (United States)

    Vaccari, Ilaria; Carbone, Antonietta; Previtali, Stefano Carlo; Mironova, Yevgeniya A.; Alberizzi, Valeria; Noseda, Roberta; Rivellini, Cristina; Bianchi, Francesca; Del Carro, Ubaldo; D'Antonio, Maurizio; Lenk, Guy M.; Wrabetz, Lawrence; Giger, Roman J.; Meisler, Miriam H.; Bolino, Alessandra

    2015-01-01

    Mutations of FIG4 are responsible for Yunis-Varón syndrome, familial epilepsy with polymicrogyria, and Charcot-Marie-Tooth type 4J neuropathy (CMT4J). Although loss of the FIG4 phospholipid phosphatase consistently causes decreased PtdIns(3,5)P2 levels, cell-specific sensitivity to partial loss of FIG4 function may differentiate FIG4-associated disorders. CMT4J is an autosomal recessive neuropathy characterized by severe demyelination and axonal loss in human, with both motor and sensory involvement. However, it is unclear whether FIG4 has cell autonomous roles in both motor neurons and Schwann cells, and how loss of FIG4/PtdIns(3,5)P2-mediated functions contribute to the pathogenesis of CMT4J. Here, we report that mice with conditional inactivation of Fig4 in motor neurons display neuronal and axonal degeneration. In contrast, conditional inactivation of Fig4 in Schwann cells causes demyelination and defects in autophagy-mediated degradation. Moreover, Fig4-regulated endolysosomal trafficking in Schwann cells is essential for myelin biogenesis during development and for proper regeneration/remyelination after injury. Our data suggest that impaired endolysosomal trafficking in both motor neurons and Schwann cells contributes to CMT4J neuropathy. PMID:25187576

  18. Neurological associations in auditory neuropathy spectrum disorder: Results from a tertiary hospital in South India

    Directory of Open Access Journals (Sweden)

    Anjali Lepcha

    2015-01-01

    Full Text Available Aims: To find out the prevalence and types of neurological abnormalities associated in auditory neuropathy spectrum disorder in a large tertiary referral center. Settings and Design: A prospective clinical study was conducted on all patients diagnosed with auditory neuropathy spectrum disorder in the ear, nose, and throat (ENT and neurology departments during a 17-month period. Patients with neurological abnormalities on history and examination were further assessed by a neurologist to determine the type of disorder present. Results: The frequency of auditory neuropathy spectrum disorder was 1.12%. Sixty percent were found to have neurological involvement. This included cerebral palsy in children, peripheral neuropathy (PN, spinocerebellar ataxia, hereditary motor-sensory neuropathy, spastic paresis, and ponto-bulbar palsy. Neurological lesions did not present simultaneously with hearing loss in most patients. Sixty-six percent of patients with auditory neuropathy spectrum disorder were born of consanguineous marriages. Conclusions: There is a high prevalence of neurological lesions in auditory neuropathy spectrum disorder which has to be kept in mind while evaluating such patients. Follow-up and counselling regarding the appearance of neuropathies is therefore important in such patients. A hereditary etiology is indicated in a majority of cases of auditory neuropathy spectrum disorder.

  19. Mutation analysis of PMP22 in Slovak patients with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies.

    Science.gov (United States)

    Resko, Peter; Radvansky, Jan; Odnogova, Zuzana; Baldovic, Marian; Minarik, Gabriel; Polakova, Helena; Palffy, Roland; Kadasi, Ludevit

    2011-12-01

    Charcot-Marie-Tooth disease (CMT) and related peripheral neuropathies are the most commonly inherited neurological disorders in humans, characterized by clinical and genetic heterogeneity. The most prevalent clinical entities belonging to this group of disorders are CMT type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP). CMT1A and HNPP are predominantly caused by a 1.5 Mb duplication and deletion in the chromosomal region 17p11.2, respectively, and less frequently by other mutations in the peripheral myelin protein 22 (PMP22) gene. Despite being relatively common diseases, they haven't been previously studied in the Slovak population. Therefore, the aim of this study was to identify the spectrum and frequency of PMP22 mutations in the Slovak population by screening 119 families with CMT and 2 families with HNPP for causative mutations in this gene. The copy number determination of PMP22 resulted in the detection of CMT1A duplication in 40 families and the detection of HNPP deletion in 7 families, 6 of which were originally diagnosed as CMT. Consequent mutation screening of families without duplication or deletion using dHPLC and sequencing identified 6 single base changes (3 unpublished to date), from which only c.327C>A (Cys109X) present in one family was provably causative. These results confirm the leading role of PMP22 mutation analysis in the differential diagnosis of CMT and show that the spectrum and frequency of PMP22 mutations in the Slovak population is comparable to that seen in the global population.

  20. Hereditary spastic paraplegia caused by compound heterozygous mutations outside the motor domain of the KIF1A gene.

    Science.gov (United States)

    Krenn, M; Zulehner, G; Hotzy, C; Rath, J; Stogmann, E; Wagner, M; Haack, T B; Strom, T M; Zimprich, A; Zimprich, F

    2017-05-01

    Hereditary spastic paraplegia is a clinically and genetically heterogeneous group of rare, inherited disorders causing an upper motor neuron syndrome with (complex) or without (pure) additional neurological symptoms. Mutations in the KIF1A gene have already been associated with recessive and dominant forms of hereditary spastic paraplegia (SPG30) in a few cases. All family members included in the study were examined neurologically. Whole-exome sequencing was used in affected individuals to identify the responsible candidate gene. Conventional Sanger sequencing was conducted to validate familial segregation. A family of Macedonian origin with two affected siblings, one with slowly progressive and the other one with a more complex and rapidly progressing hereditary spastic paraplegia is reported. In both affected individuals, two novel pathogenic mutations outside the motor domain of the KIF1A gene were found (NM_001244008.1:c.2909G>A, p.Arg970His and c.1214dup, p.Asn405Lysfs*40) that segregate with the disease within the family establishing the diagnosis of autosomal recessive SPG30. This report provides the first evidence that mutations outside the motor domain of the gene can cause (recessive) SPG30 and extends the genotype-phenotype association for KIF1A-related diseases. © 2017 EAN.

  1. Development and validation of a novel PCR-RFLP based method for the detection of 3 primary mitochondrial mutations in Leber's hereditary optic neuropathy patients.

    Science.gov (United States)

    Eustace Ryan, Siobhan; Ryan, Fergus; Barton, David; O'Dwyer, Veronica; Neylan, Derek

    2015-01-01

    Leber's Hereditary Optic Neuropathy (LHON; MIM 535000) is one of the most commonly inherited optic neuropathies and it results in significant visual morbidity among young adults with a peak age of onset between the ages of 15-30. The worldwide incidence of LHON is approximately 1 in 31,000. 95 % of LHON patients will have one of 3 primary mitochondrial mutations, G3460A (A52T of ND1), G11778A (R340H of ND4) and T14484C (M64V of ND6). There is incomplete penetrance and a marked gender bias in the development of visual morbidity with approximately 50 % of male carriers and 10 % of female carriers developing optic neuropathy. Visual recovery can occur but is dependent on the mutation present with the highest level of visual recovery seen in patients who have the T14484C mutation. The 3 primary mutations are typically identified by individual end-point PCR-restriction fragment length polymorphism (RFLP) or individual targeted bi-directional Sanger sequencing reactions. The purpose of this study was to design a simple multiplex PCR-RFLP that could detect these 3 primary LHON mutations in one assay. PCR primers were designed to incorporate a MaeIII restriction site in the presence of 3460A and 14484C mutations with the 11778A mutation naturally incorporating a MaeIII site. A multiplex PCR-RFLP assay was developed to detect the 3 common mutations in a single assay. Synthetic LHON controls based on the mitochondrial genome harbouring the 3 common mutations were synthesized and cloned into plasmids to act as reliable assay controls. DNA from previously tested patients and the synthetic LHON controls were subjected to the multiplex PCR-RFLP assay. The RFLP products were detected by agarose gel electrophoresis. The novel PCR-RFLP assay accurately detects the 3 primary mutations both in patient DNA and in synthesized DNA control samples with a simple visual mutation detection procedure. The synthesized DNA was demonstrated to be a robust control for the detection of LHON

  2. Non-motor symptoms in patients with hereditary spastic paraplegia caused by SPG4 mutations.

    Science.gov (United States)

    Servelhere, K R; Faber, I; Saute, J A M; Moscovich, M; D'Abreu, A; Jardim, L B; Teive, H A G; Lopes-Cendes, I; Franca, M C

    2016-02-01

    Non-motor manifestations are frequently overlooked in degenerative disorders and little is known about their frequency and clinical relevance in SPG4 hereditary spastic paraplegia (SPG4-HSP). Thirty patients with SPG4-HSP and 30 healthy controls answered the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, Brief Pain Inventory and Beck Depression Inventory. Student's t test was used to compare groups and linear regression was used to assess correlations. Patients had higher fatigue scores than controls (31.0 ± 16.5 vs. 14.5 ± 16.0, P = 0.002) as well as pain (3.4 ± 2.7 vs. 1.0 ± 1.6, P = 0.001) and depression (12.7 ± 8.9 vs. 4.4 ± 3.8, P < 0.001, respectively). Fatigue was associated with depression and possibly with disease severity (P = 0.008 and 0.07, respectively). Fatigue, pain and depression are frequent and often severe manifestations in patients with SPG4-HSP. © 2016 EAN.

  3. Cortical excitability changes distinguish the motor neuron disease phenotypes from hereditary spastic paraplegia.

    Science.gov (United States)

    Geevasinga, N; Menon, P; Sue, C M; Kumar, K R; Ng, K; Yiannikas, C; Kiernan, M C; Vucic, S

    2015-05-01

    Cortical hyperexcitability has been identified as an important pathogenic mechanism in motor neuron disease (MND). The issue as to whether cortical hyperexcitability is a common process across the MND phenotypes, including amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), remains unresolved. Separately, the clinical distinction between PLS and 'mimic disorders' such as hereditary spastic paraparesis (HSP) may be difficult, potentially delaying diagnosis. Consequently, the aim of the present study was to determine the nature and spectrum of cortical excitability changes across the MND phenotypes, and to determine whether the presence of cortical dysfunction distinguishes PLS from HSP. Cortical excitability studies were undertaken on a cohort of 14 PLS, 82 ALS and 13 HSP patients with mutations in the spastin gene. Cortical hyperexcitability, as heralded by reduction of short interval intracortical inhibition (PLS 0.26%, -3.8% to 1.4%; ALS -0.15%, -3.6% to 7.0%; P < 0.01) and cortical silent period duration (CSPPLS 172.2 ± 5.4 ms; CSPALS 178.1 ± 5.1 ms; P < 0.001), along with an increase in intracortical facilitation was evident in ALS and PLS phenotypes, although appeared more frequently in ALS. Inexcitability of the motor cortex was more frequent in PLS (PLS 71%, ALS 24%, P < 0.0001). Cortical excitability was preserved in HSP. Cortical dysfunction appears to be an intrinsic process across the MND phenotypes, with cortical inexcitability predominating in PLS and cortical hyperexcitability predominating in ALS. Importantly, cortical excitability was preserved in HSP, thereby suggesting that the presence of cortical dysfunction could help differentiate PLS from HSP in a clinical setting. © 2015 EAN.

  4. Cell therapy using retinal progenitor cells shows therapeutic effect in a chemically-induced rotenone mouse model of Leber hereditary optic neuropathy.

    Science.gov (United States)

    Mansergh, Fiona C; Chadderton, Naomi; Kenna, Paul F; Gobbo, Oliviero L; Farrar, G Jane

    2014-11-01

    Primary mitochondrial disorders occur at a prevalence of one in 10 000; ∼50% of these demonstrate ocular pathology. Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial disorder. LHON results from retinal ganglion cell pathology, which leads to optic nerve degeneration and blindness. Over 95% of cases result from one of the three common mutations in mitochondrial genes MTND1, MTND4 and MTND6, which encode elements of the complex I respiratory chain. Various therapies for LHON are in development, for example, intravitreal injection of adeno-associated virus carrying either the yeast NDI1 gene or a specific subunit of mammalian Complex I have shown visual improvement in animal models. Given the course of LHON, it is likely that in many cases prompt administration may be necessary before widespread cell death. An alternative approach for therapy may be the use of stem cells to protect visual function; this has been evaluated by us in a rotenone-induced model of LHON. Freshly dissected embryonic retinal cells do not integrate into the ganglion cell layer (GCL), unlike similarly obtained photoreceptor precursors. However, cultured retinal progenitor cells can integrate in close proximity to the GCL, and act to preserve retinal function as assessed by manganese-enhanced magnetic resonance imaging, optokinetic responses and ganglion cell counts. Cell therapies for LHON therefore represent a promising therapeutic approach, and may be of particular utility in treating more advanced disease.

  5. A Meta-analysis of the association between different genotypes (G11778A, T14484C and G3460A) of Leber hereditary optic neuropathy and visual prognosis.

    Science.gov (United States)

    Guo, Dong-Yu; Wang, Xia-Wei; Hong, Nan; Gu, Yang-Shun

    2016-01-01

    To analyze the influences of different genotypes (G11778A, T14484C and G3460A) of Leber hereditary optic neuropathy (LHON) on visual prognosis. After a systematic literature search, all relevant studies evaluating the association between the three primary mutations of LHON and visual prognosis were included. All statistical tests were calculated with Revman 5.2 and STATA 12.0. Ten independent studies were included finally. A significant association between the three primary mutations and prognostic vision over 0.3 were found in G11778A versus T14484C [odds ratio (OR)=0.10, 95% confidence interval (CI)=0.05-0.17, P0.05). From pairwise comparison, we conclude that these three different genotypes of LHON are related to patients' visual prognosis. The T14484C patients might have a best prognostic vision, G3460A second, and G11778A worst. And there is little relation between the three different genotypes and patients' vision, age of onset and sex ratio.

  6. Mitochondrial tRNAThr 15891C>G mutation was not associated with Leber's hereditary optic neuropathy in Han Chinese patients.

    Science.gov (United States)

    Jiang, Zhaochang; Yu, Jinfang; Xia, Bohou; Zhuo, Guangchao

    2016-01-01

    Mutations in mitochondrial DNA (mtDNA) were the most important causes of Leber's hereditary optic neuropathy (LHON). To date, approximately 25 LHON-associated mtDNA mutations have been identified in various ethnic populations. Three primary mutations, the 3460G > A, 11778G > A and 14484T > C, in genes encoding the subunits of respiratory chain complex I, were the most common LHON-associated mtDNA mutations. Moreover, secondary mutations in mt-tRNA genes have been reported increasingly to be associated with LHON, simply due to the high mutation rates of mt-tRNAs. There is a lack of functional analysis and a poor genetic evaluation of a certain mt-tRNA mutation, which failed to meet the classic pathogenicity scoring system. As a result, how to classify a pathogenic mutation in mt-tRNA gene became important for both geneticist and clinician to diagnosis the LHON or the suspicious of LHON. In this study, we reassessed the role of a point mutation in mt-tRNA(Thr) gene which had been reported to be a mutation associated with LHON, the pathogenicity of this mutation has been discussed in this context.

  7. X-inactivation patterns in female Leber`s hereditary optic neuropathy patients do not support a strong X-linked determinant

    Energy Technology Data Exchange (ETDEWEB)

    Pegoraro, E.; Hoffman, E.P. [Univ. of Pittsburgh School of Medicine, PA (United States); Carelli, V.; Cortelli, P. [Univ. of Bologna (Italy)] [and others

    1996-02-02

    Leber`s hereditary optic neuropathy (LHON) accounts for about 3% of the cases of blindness in young adult males. The underlying mitochondrial pathogenesis of LHON has been well studied, with specific mitochondrial DNA (mtDNA) mutations of structural genes described and well characterized. However, enigmatic aspects of the disease are not explained by mutation data, such as the higher proportion of affected males, the later onset of the disease in females, and the presence of unaffected individuals with a high proportion of mutant mtDNA. A hypothesis which has been put forward to explain the unusual disease expression is a dual model of mtDNA and X-linked nuclear gene inheritance. If a nuclear X-linked modifier gene influences the expression of the mitochondrial-linked mutant gene then the affected females should be either homozygous for the nuclear determinant, or if heterozygous, lyonization should favor the mutant X. In order to determine if an X-linked gene predisposes to LHON phenotype we studied X-inactivation patterns in 35 females with known mtDNA mutations from 10 LHON pedigrees. Our results do not support a strong X-linked determinant in LHON cause: 2 of the 10 (20%) manifesting carriers showed skewing of X-inactivation, as did 3 of the 25 (12%) nonmanifesting carriers. 39 refs., 2 figs., 1 tab.

  8. X chromosome-linked and mitochondrial gene control of Leber hereditary optic neuropathy: Evidence from segregation analysis for dependence on X chromosome inactivation

    Energy Technology Data Exchange (ETDEWEB)

    Xiangdong Bu; Rotter, J.I. (Cedars-Sinai Medical Center, Los Angeles, CA (United States) Univ. of California, Los Angeles (United States))

    1991-09-15

    Leber hereditary optic neuropathy (LHON) has been shown to involve mutation(s) of mitochondrial DNA, yet there remain several confusing aspects of its inheritance not explained by mitochondrial inheritance alone, including male predominance, reduced penetrance, and a later age of onset in females. By extending segregation analysis methods to disorders that involve both a mitochondrial and a nuclear gene locus, the authors show that the available pedigree data for LHON are most consistent with a two-locus disorder, with one responsible gene being mitochondrial and the other nuclear and X chromosome-linked. Furthermore, they have been able to extend the two-locus analytic method and demonstrate that a proportion of affected females are likely heterozygous at the X chromosome-linked locus and are affected due to unfortunate X chromosome inactivation, thus providing an explanation for the later age of onset in females. The estimated penetrance for a heterozygous female is 0.11{plus minus}0.02. The calculated frequency of the X chromosome-linked gene for LHON is 0.l08. Among affected females, 60% are expected to be heterozygous, and the remainder are expected to be homozygous at the responsible X chromosome-linked locus.

  9. Novel frameshift and splice site mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with hereditary sensory neuropathy type IV.

    Science.gov (United States)

    Verpoorten, Nathalie; Claeys, Kristl G; Deprez, Liesbet; Jacobs, An; Van Gerwen, Veerle; Lagae, Lieven; Arts, Willem Frans; De Meirleir, Linda; Keymolen, Kathelijn; Ceuterick-de Groote, Chantal; De Jonghe, Peter; Timmerman, Vincent; Nelis, Eva

    2006-01-01

    Congenital insensitivity to pain with anhidrosis or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is the first human genetic disorder implicated in the neurotrophin signal transduction pathway. HSAN IV is characterized by absence of reaction to noxious stimuli, recurrent episodes of fever, anhidrosis, self-mutilating behavior and often mental retardation. Mutations in the neurotrophic tyrosine kinase, receptor, type 1 (NTRK1) are associated with this disorder. Here we report four homozygous mutations, two frameshift (p.Gln626fsX6 and p.Gly181fsX58), one missense (p.Arg761Trp) and one splice site (c.359+5G>T) mutation in four HSAN IV patients. The splice site mutation caused skipping of exons 2 and 3 in patient's mRNA resulting in an in-frame deletion of the second leucine-rich motif. NTRK1 mutations are only rarely reported in the European population. This report extends the spectrum of NTRK1 mutations observed in patients diagnosed with HSAN IV.

  10. Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates.

    Science.gov (United States)

    Lafreniere, Ronald G; MacDonald, Marcia L E; Dube, Marie-Pierre; MacFarlane, Julie; O'Driscoll, Mary; Brais, Bernard; Meilleur, Sebastien; Brinkman, Ryan R; Dadivas, Owen; Pape, Terry; Platon, Christele; Radomski, Chris; Risler, Jenni; Thompson, Jay; Guerra-Escobio, Ana-Maria; Davar, Gudarz; Breakefield, Xandra O; Pimstone, Simon N; Green, Roger; Pryse-Phillips, William; Goldberg, Y Paul; Younghusband, H Banfield; Hayden, Michael R; Sherrington, Robin; Rouleau, Guy A; Samuels, Mark E

    2004-05-01

    Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons. We identified two large pedigrees segregating the disorder in an isolated population living in Newfoundland and performed a 5-cM genome scan. Linkage analysis identified a locus mapping to 12p13.33 with a maximum LOD score of 8.4. Haplotype sharing defined a candidate interval of 1.06 Mb containing all or part of seven annotated genes, sequencing of which failed to detect causative mutations. Comparative genomics revealed a conserved ORF corresponding to a novel gene in which we found three different truncating mutations among five families including patients from rural Quebec and Nova Scotia. This gene, termed "HSN2," consists of a single exon located within intron 8 of the PRKWNK1 gene and is transcribed from the same strand. The HSN2 protein may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells.

  11. Coexistence of mutations in keratin 10 (KRT10) and the mitochondrial genome in a patient with ichthyosis with confetti and Leber's hereditary optic neuropathy.

    Science.gov (United States)

    Kalinska-Bienias, Agnieszka; Pollak, Agnieszka; Kowalewski, Cezary; Lechowicz, Urszula; Stawinski, Piotr; Gergont, Aleksandra; Kosinska, Joanna; Pronicka, Ewa; Kowalski, Pawel; Wozniak, Katarzyna; Ploski, Rafal

    2017-09-25

    Ichthyosis with confetti (IWC) is a severe congenital genodermatosis characterized by ichthyosiform erythroderma since birth and confetti-like spots of normal skin appearing in childhood as a results of revertant mosaicism. This disorder is caused by mutations in KRT10 or KRT1 genes. We report a 16-year-old boy who presented ichthyosiform erythroderma with severe desquamation since birth and gradually worsening psycho-neurological symptoms (mental retardation, ataxia, dystonia, hypoacusis). The patient conspicuously lacked typical confetti-like spots at the age of 16. The molecular diagnostics by the whole exome sequencing showed a novel de novo (c.1374-2A>C) mutation in the KRT10 gene responsible for the development of IWC (KRT10 defect was confirmed by immunofluorescent study). Concurrently, the m.14484T>C mutation in mitochondrial MTND6 gene (characteristic for Leber's hereditary optic neuropathy or LHON) was detected in patient, his mother and brother. LHON causes frequent inherited blindness typically appearing during young adult life whose expression can be triggered by additional factors such as smoking or alcohol exposure. We speculate the effects of KRT10 and LHON mutations influence each other-skin inflammatory reaction due to severe ichthyosis might trigger the development of psychoneurological abnormalities whereas the mitochondrial mutation may reduce revertant mosaicism phenomenon resulting in the lack of confetti-like spots characteristic for IWC. However, based on a single case we should be cautious about attributing phenotypes to digenic mechanisms without functional data. © 2017 Wiley Periodicals, Inc.

  12. Optimization of a genotyping screening based on hydrolysis probes to detect the main mutations related to Leber hereditary optic neuropathy (LHON).

    Science.gov (United States)

    Martins, Fábio Tadeu Arrojo; Miranda, Paulo Maurício do Amor Divino; Fernandes, Marcela Scabello Amaral; Maciel-Guerra, Andréa Trevas; Sartorato, Edi Lúcia

    2017-01-01

    Leber hereditary optic neuropathy (LHON) is a mitochondrial inherited disease characterized by bilateral vision problems, such as reduced visual acuity, dyschromatopsia, and central or centrocecal scotoma. Of these cases, 95% are caused by three mutations in mitochondrial DNA (mtDNA): m.G11778A, followed by m.T14484C and m.G3460A. The remaining 5% of cases of LHON are caused by rare mutations also present in mtDNA. Although conventional molecular tools for molecular screening of LHON are becoming popular, in most cases these tools are still expensive and time-consuming and are difficult to reproduce. Therefore, to meet the need for more accurate, faster, and cheaper techniques for molecular screening, as well as make it more accessible, we used the high-throughput method TaqMan(®) OpenArray(™) Genotyping platform for developing a customized high-throughput assay for the three main mutations related to LHON. The assay was performed for 87 individuals diagnosed with LHON or acquired optic neuropathy of unknown origin. The three main mutations were screened using the customized assay with the TaqMan(®) OpenArray(™) Genotyping platform, and all reactions were performed in triplicate. The positive and negative results were revalidated with restriction fragment length polymorphism PCR (RFLP-PCR) and Sanger sequencing. The main mutations related to LHON were detected in 34 patients with genotyping reactions, of which 27 cases had the m.G11778A mutation, and seven had the m.T14484C mutation. The TaqMan(®) OpenArray(™) Genotyping platform was shown to be an effective tool for molecular screening of the most common mutations related to LHON without presenting false positive or negative results for the analyzed mutations. In addition, this tool can be considered a cheaper, faster, and more accurate alternative for molecular screening of LHON mutations than PCR and Sanger sequencing, as 94 genotyping reactions can be performed within 6 h and specific Taq

  13. Optimization of a genotyping screening based on hydrolysis probes to detect the main mutations related to Leber hereditary optic neuropathy (LHON)

    Science.gov (United States)

    Miranda, Paulo Maurício do Amor Divino; Fernandes, Marcela Scabello Amaral; Maciel-Guerra, Andréa Trevas; Sartorato, Edi Lúcia

    2017-01-01

    Purpose Leber hereditary optic neuropathy (LHON) is a mitochondrial inherited disease characterized by bilateral vision problems, such as reduced visual acuity, dyschromatopsia, and central or centrocecal scotoma. Of these cases, 95% are caused by three mutations in mitochondrial DNA (mtDNA): m.G11778A, followed by m.T14484C and m.G3460A. The remaining 5% of cases of LHON are caused by rare mutations also present in mtDNA. Although conventional molecular tools for molecular screening of LHON are becoming popular, in most cases these tools are still expensive and time-consuming and are difficult to reproduce. Therefore, to meet the need for more accurate, faster, and cheaper techniques for molecular screening, as well as make it more accessible, we used the high-throughput method TaqMan® OpenArray™ Genotyping platform for developing a customized high-throughput assay for the three main mutations related to LHON. Methods The assay was performed for 87 individuals diagnosed with LHON or acquired optic neuropathy of unknown origin. The three main mutations were screened using the customized assay with the TaqMan® OpenArray™ Genotyping platform, and all reactions were performed in triplicate. The positive and negative results were revalidated with restriction fragment length polymorphism PCR (RFLP-PCR) and Sanger sequencing. Results The main mutations related to LHON were detected in 34 patients with genotyping reactions, of which 27 cases had the m.G11778A mutation, and seven had the m.T14484C mutation. Conclusions The TaqMan® OpenArray™ Genotyping platform was shown to be an effective tool for molecular screening of the most common mutations related to LHON without presenting false positive or negative results for the analyzed mutations. In addition, this tool can be considered a cheaper, faster, and more accurate alternative for molecular screening of LHON mutations than PCR and Sanger sequencing, as 94 genotyping reactions can be performed within 6 h

  14. MRI shows thickening and altered diffusion in the median and ulnar nerves in multifocal motor neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Haakma, Wieke [University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands); Aarhus University, Department of Forensic Medicine and Comparative Medicine Lab, Aarhus (Denmark); Jongbloed, Bas A.; Goedee, H.S.; Berg, Leonard H. van den; Pol, W.L. van der [University Medical Center Utrecht, Brain Centre Rudolf Magnus, Department of Neurology and Neurosurgery, Utrecht (Netherlands); Froeling, Martijn; Bos, Clemens; Hendrikse, Jeroen [University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands); Leemans, Alexander [University Medical Center Utrecht, Image Sciences Institute, Utrecht (Netherlands)

    2017-05-15

    To study disease mechanisms in multifocal motor neuropathy (MMN) with magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) of the median and ulnar nerves. We enrolled ten MMN patients, ten patients with amyotrophic lateral sclerosis (ALS) and ten healthy controls (HCs). Patients underwent MRI (in a prone position) and nerve conduction studies. DTI and fat-suppressed T2-weighted scans of the forearms were performed on a 3.0T MRI scanner. Fibre tractography of the median and ulnar nerves was performed to extract diffusion parameters: fractional anisotropy (FA), mean (MD), axial (AD) and radial (RD) diffusivity. Cross-sectional areas (CSA) were measured on T2-weighted scans. Forty-five out of 60 arms were included in the analysis. AD was significantly lower in MMN patients (2.20 ± 0.12 x 10{sup -3} mm{sup 2}/s) compared to ALS patients (2.31 ± 0.17 x 10{sup -3} mm{sup 2}/s; p < 0.05) and HCs (2.31± 0.17 x 10{sup -3} mm{sup 2}/s; p < 0.05). Segmental analysis showed significant restriction of AD, RD and MD (p < 0.005) in the proximal third of the nerves. CSA was significantly larger in MMN patients compared to ALS patients and HCs (p < 0.01). Thickening of nerves is compatible with changes in the myelin sheath structure, whereas lowered AD values suggest axonal dysfunction. These findings suggest that myelin and axons are diffusely involved in MMN pathogenesis. (orig.)

  15. A Simple Oligonucleotide Biochip Capable of Rapidly Detecting Known Mitochondrial DNA Mutations in Chinese Patients with Leber’S Hereditary Optic Neuropathy (LHON)

    Science.gov (United States)

    Du, Wei-Dong; Chen, Gang; Cao, Hui-Min; Jin, Qing-Hui; Liao, Rong-Feng; He, Xiang-Cheng; Chen, Da-Ben; Huang, Shu-Ren; Zhao, Hui; Lv, Yong-Mei; Tang, Hua-Yang; Tang, Xian-Fa; Wang, Yong-Qing; Sun, Song; Zhao, Jian-Long; Zhang, Xue-Jun

    2011-01-01

    Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disease. Clinically, no efficient assay protocols have been available. In this study, we aimed to develop an oligonucleotide biochip specialized for detection of known base substitution mutations in mitochondrial DNA causing LHON and to investigate frequencies of LHON relevant variants in Anhui region of China. Thirty-two pairs of oligonucleotide probes matched with the mutations potentially linked to LHON were covalently immobilized. Cy5-lablled targets were amplified from blood DNA samples by a multiplex PCR method. Two kinds of primary mutations 11778 G > A and 14484 T > C from six confirmed LHON patients were interrogated to validate this biochip format. Further, fourteen Chinese LHON pedigrees and twenty-five unrelated healthy individuals were investigated by the LHON biochip, direct sequencing and pyrosequencing, respectively. The biochip was found to be able efficiently to discriminate homoplasmic and heteroplasmic mtDNA mutations in LHON. Biochip analysis revealed that twelve of eighteen LHON symptomatic cases from the 14 Chinese pedigree harbored the mutations either 11778G > A, 14484T > C or 3460G > A, respectively, accounting for 66.7%. The mutation 11778G > A in these patients was homoplasmic and prevalent (55.5%, 10 of 18 cases). The mutations 3460G > A and 3394T > C were found to co-exist in one LHON case. The mutation 13708G > A appeared in one LHON pedigree. Smaller amount of sampling and reaction volume, easier target preparation, fast and high-throughput were the main advantages of the biochip over direct DNA sequencing and pyrosequencing. Our findings suggested that primary mutations of 11778G > A, 14484T > C or 3460G > A are main variants of mtDNA gene leading to LHON in China. The biochip would easily be implemented in clinical diagnosis. PMID:21694444

  16. A simple oligonucleotide biochip capable of rapidly detecting known mitochondrial DNA mutations in Chinese patients with Leber's hereditary optic neuropathy (LHON).

    Science.gov (United States)

    Du, Wei-Dong; Chen, Gang; Cao, Hui-Min; Jin, Qing-Hui; Liao, Rong-Feng; He, Xiang-Cheng; Chen, Da-Ben; Huang, Shu-Ren; Zhao, Hui; Lv, Yong-Mei; Tang, Hua-Yang; Tang, Xian-Fa; Wang, Yong-Qing; Sun, Song; Zhao, Jian-Long; Zhang, Xue-Jun

    2011-01-01

    Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disease. Clinically, no efficient assay protocols have been available. In this study, we aimed to develop an oligonucleotide biochip specialized for detection of known base substitution mutations in mitochondrial DNA causing LHON and to investigate frequencies of LHON relevant variants in Anhui region of China. Thirty-two pairs of oligonucleotide probes matched with the mutations potentially linked to LHON were covalently immobilized. Cy5-lablled targets were amplified from blood DNA samples by a multiplex PCR method. Two kinds of primary mutations 11778 G > A and 14484 T > C from six confirmed LHON patients were interrogated to validate this biochip format. Further, fourteen Chinese LHON pedigrees and twenty-five unrelated healthy individuals were investigated by the LHON biochip, direct sequencing and pyrosequencing, respectively. The biochip was found to be able efficiently to discriminate homoplasmic and heteroplasmic mtDNA mutations in LHON. Biochip analysis revealed that twelve of eighteen LHON symptomatic cases from the 14 Chinese pedigree harbored the mutations either 11778G > A, 14484T > C or 3460G A, respectively, accounting for 66.7%. The mutation 11778G > A in these patients was homoplasmic and prevalent (55.5%, 10 of 18 cases). The mutations 3460G > A and 3394T > C were found to co-exist in one LHON case. The mutation 13708G > A appeared in one LHON pedigree. Smaller amount of sampling and reaction volume, easier target preparation, fast and high-throughput were the main advantages of the biochip over direct DNA sequencing and pyrosequencing. Our findings suggested that primary mutations of 11778G > A, 14484T > C or 3460G > A are main variants of mtDNA gene leading to LHON in China. The biochip would easily be implemented in clinical diagnosis.

  17. A Simple Oligonucleotide Biochip Capable of Rapidly Detecting Known Mitochondrial DNA Mutations in Chinese Patients with Leber’S Hereditary Optic Neuropathy (LHON

    Directory of Open Access Journals (Sweden)

    Wei-Dong Du

    2011-01-01

    Full Text Available Leber's hereditary optic neuropathy (LHON is a maternally transmitted disease. Clinically, no efficient assay protocols have been available. In this study, we aimed to develop an oligonucleotide biochip specialized for detection of known base substitution mutations in mitochondrial DNA causing LHON and to investigate frequencies of LHON relevant variants in Anhui region of China. Thirty-two pairs of oligonucleotide probes matched with the mutations potentially linked to LHON were covalently immobilized. Cy5-lablled targets were amplified from blood DNA samples by a multiplex PCR method. Two kinds of primary mutations 11778 G > A and 14484 T > C from six confirmed LHON patients were interrogated to validate this biochip format. Further, fourteen Chinese LHON pedigrees and twenty-five unrelated healthy individuals were investigated by the LHON biochip, direct sequencing and pyrosequencing, respectively. The biochip was found to be able efficiently to discriminate homoplasmic and heteroplasmic mtDNA mutations in LHON. Biochip analysis revealed that twelve of eighteen LHON symptomatic cases from the 14 Chinese pedigree harbored the mutations either 11778G > A, 14484T > C or 3460G > A, respectively, accounting for 66.7%. The mutation 11778G > A in these patients was homoplasmic and prevalent (55.5%, 10 of 18 cases. The mutations 3460G > A and 3394T > C were found to co-exist in one LHON case. The mutation 13708G > A appeared in one LHON pedigree. Smaller amount of sampling and reaction volume, easier target preparation, fast and high-throughput were the main advantages of the biochip over direct DNA sequencing and pyrosequencing. Our findings suggested that primary mutations of 11778G > A, 14484T > C or 3460G > A are main variants of mtDNA gene leading to LHON in China. The biochip would easily be implemented in clinical diagnosis.

  18. Multifocal VEP provide electrophysiological evidence of predominant dysfunction of the optic nerve fibers derived from the central retina in Leber's hereditary optic neuropathy.

    Science.gov (United States)

    Ziccardi, Lucia; Parisi, Vincenzo; Giannini, Daniela; Sadun, Federico; De Negri, Anna Maria; Barboni, Piero; La Morgia, Chiara; Sadun, Alfedo A; Carelli, Valerio

    2015-09-01

    To differentiate the bioelectrical cortical responses driven by axons from central and mid-peripheral retina in Leber's hereditary optic neuropathy (LHON) by using multifocal visual evoked potentials (mfVEP). Seventeen genetically confirmed LHON patients (33.35 ± 8.4 years, 17 eyes) and 22 age-matched controls (C) (38.2 ± 6.0 years, 22 eyes) were studied by mfVEP and optical coherence tomography. MfVEP P1 implicit time (P1 IT, ms) and response amplitude density of the N1-P1 components (N1-P1 RAD, nV/deg(2)) of the second order binary kernel were measured for five concentric retinal areas between the fovea and mid-periphery: 0-20 degrees (R1 to R5). Mean mfVEP P1 ITs and N1-P1 RADs at all five foveal eccentricities were significantly different (p LHON when compared to controls. In both groups, mean mfVEP responses obtained from R1 to R5 showed a progressive shortening of P1 ITs (linear fitting, LHON: r  = -0.95; C: r = -0.98) and decrease of N1-P1 RADs (exponential fitting, LHON: r (2) = 0.94; C: r (2) = 0.93). The slope of the linear fitting between mean mfVEP P1 ITs in the two groups was about three times greater in LHON than in controls (LHON: y = -13.33x +182.03; C: y = -4.528x +108.1). MfVEP P1 ITs detected in R1 and R2 (0-5 degrees) were significantly correlated (p LHON, discriminating a predominant involvement of axons driving responses from the central retina when compared to those serving the mid-peripheral retina.

  19. Fifteen novel mutations in the mitochondrial NADH dehydrogenase subunit 1, 2, 3, 4, 4L, 5 and 6 genes from Iranian patients with Leber's hereditary optic neuropathy (LHON).

    Science.gov (United States)

    Rezvani, Zahra; Didari, Elmira; Arastehkani, Ahoura; Ghodsinejad, Vadieh; Aryani, Omid; Kamalidehghan, Behnam; Houshmand, Massoud

    2013-12-01

    Leber's hereditary optic neuropathy (LHON) is an optic nerve dysfunction resulting from mutations in mitochondrial DNA (mtDNA), which is transmitted in a maternal pattern of inheritance. It is caused by three primary point mutations: G11778A, G3460A and T14484C; in the mitochondrial genome. These mutations are sufficient to induce the disease, accounting for the majority of LHON cases, and affect genes that encode for the different subunits of mitochondrial complexes I and III of the mitochondrial respiratory chain. Other mutations are secondary mutations associated with the primary mutations. The purpose of this study was to determine MT-ND variations in Iranian patients with LHON. In order to determine the prevalence and distribution of mitochondrial mutations in the LHON patients, their DNA was studied using PCR and DNA sequencing analysis. Sequencing of MT-ND genes from 35 LHON patients revealed a total of 44 nucleotide variations, in which fifteen novel variations-A14020G, A13663G, C10399T, C4932A, C3893G, C10557A, C12012A, C13934T, G4596A, T12851A, T4539A, T4941A, T13255A, T14353C and del A 4513-were observed in 27 LHON patients. However, eight patients showed no variation in the ND genes. These mutations contribute to the current database of mtDNA polymorphisms in LHON patients and may facilitate the definition of disease-related mutations in human mtDNA. This research may help to understand the disease mechanism and open up new diagnostic opportunities for LHON.

  20. ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes

    NARCIS (Netherlands)

    de Bot, S. T.; Veldink, J. H.; Vermeer, S.; Mensenkamp, A. R.; Brugman, F.; Scheffer, H.; van den Berg, L. H.; Kremer, H. P. H.; Kamsteeg, E. J.; van de Warrenburg, B. P.

    SPAST mutations are the most common cause of autosomal dominant hereditary spastic paraplegias (AD-HSPs), but many spastic paraplegia patients are found to carry no mutations in this gene. In order to assess the contribution of ATL1 and REEP1 in AD-HSP, we performed mutational analysis in 27

  1. Axonal neuropathy-associated TRPV4 regulates neurotrophic factor-derived axonal growth.

    Science.gov (United States)

    Jang, Yongwoo; Jung, Jooyoung; Kim, Hyungsup; Oh, Jungeun; Jeon, Ji Hyun; Jung, Saewoon; Kim, Kyung-Tai; Cho, Hawon; Yang, Dong-Jin; Kim, Sung Min; Kim, In-Beom; Song, Mi-Ryoung; Oh, Uhtaek

    2012-02-17

    Spinal muscular atrophy and hereditary motor and sensory neuropathies are characterized by muscle weakness and atrophy caused by the degenerations of peripheral motor and sensory nerves. Recent advances in genetics have resulted in the identification of missense mutations in TRPV4 in patients with these hereditary neuropathies. Neurodegeneration caused by Ca(2+) overload due to the gain-of-function mutation of TRPV4 was suggested as the molecular mechanism for the neuropathies. Despite the importance of TRPV4 mutations in causing neuropathies, the precise role of TRPV4 in the sensory/motor neurons is unknown. Here, we report that TRPV4 mediates neurotrophic factor-derived neuritogenesis in developing peripheral neurons. TRPV4 was found to be highly expressed in sensory and spinal motor neurons in early development as well as in the adult, and the overexpression or chemical activation of TRPV4 was found to promote neuritogenesis in sensory neurons as well as PC12 cells, whereas its knockdown and pharmacologic inhibition had the opposite effect. More importantly, nerve growth factor or cAMP treatment up-regulated the expression of phospholipase A(2) and TRPV4. Neurotrophic factor-derived neuritogenesis appears to be regulated by the phospholipase A(2)-mediated TRPV4 pathway. These findings show that TRPV4 mediates neurotrophic factor-induced neuritogenesis in developing peripheral nerves. Because neurotrophic factors are essential for the maintenance of peripheral nerves, these findings suggest that aberrant TRPV4 activity may lead to some types of pathology of sensory and motor nerves.

  2. Clinical pathological and genetic analysis of 2 cases of mitochondrial myopathy presented as acute motor axonal neuropathy

    Directory of Open Access Journals (Sweden)

    Hou-min YIN

    2014-06-01

    Full Text Available Background The main clinical manifestations of mitochondrial myopathy are chronic limb weakness and muscular soreness. Subclinical peripheral nerve injury is also reported, but acute axonal neuropathy.like syndrome concurrent with lactic acidosis is rare. In this paper the clinical features of 2 patients presenting as acute lactic acidosis and sudden muscle weakness were analyzed. Pathological changes and genetic mutations were detected.  Methods Electromyography (EMG and muscle biopsy were performed. Modified Gomori trichrome (MGT and succinodehydrogenase (SDH staining were used to identify pathological changes. Changes of ultra microstructure of muscular tissue were observed under electron microscope. Mitochondrial DNA (mtDNA full length sequencing was performed using 24 pairs of partially overlapping primers.  Results EMG showed a coexistence of neurogenic and myogenic changes. Dramatic decrease of motor nerve amplitude and moderately reduced sensory nerve amplitude were observed but nerve conduction velocity was normal in both patients. Impressive ragged red fibers were seen on MGT staining. Electron microscope showed dramatic mitochondrial abnormalities in Case 1 and paracrystaline inclusions in Case 2. mtDNA sequencing showed 3243A > G mutation in Case 1 and 8344A > G mutation in Case 2. Conclusions Mitochondrial myopathy can present as metabolic crisis like acute lactic acidosis, dyspnea and acute motor axonal neuropathy.like syndrome. It is a life.threatening phenotype that needs more attention. doi: 10.3969/j.issn.1672-6731.2014.06.007

  3. Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy : preparation for gene therapy clinical trial.

    Science.gov (United States)

    Lam, Byron L; Feuer, William J; Schiffman, Joyce C; Porciatti, Vittorio; Vandenbroucke, Ruth; Rosa, Potyra R; Gregori, Giovanni; Guy, John

    2014-04-01

    IMPORTANCE Establishing the natural history of G11778A Leber hereditary optic neuropathy (LHON) is important to determine the optimal end points to assess the safety and efficacy of a planned gene therapy trial. OBJECTIVE To use the results of the present natural history study of patients with G11778A LHON to plan a gene therapy clinical trial that will use allotopic expression by delivering a normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells via an adeno-associated virus vector injected into the vitreous. DESIGN, SETTING, AND PARTICIPANTS A prospective observational study initiated in 2008 was conducted in primary and referral institutional practice settings. Participants included 44 individuals with G11778A LHON, recruited between September 2008 and March 2012, who were evaluated every 6 months and returned for 1 or more follow-up visits (6-36 months) as of August 2012. EXPOSURES Complete neuro-ophthalmic examination and main measures. MAIN OUTCOMES AND MEASURES Visual acuity, automated visual field testing, pattern electroretinogram, and spectral-domain optical coherence tomography. RESULTS Clinical measures were stable during the follow-up period, and visual acuity was as good as or better than the other visual factors used for monitoring patients. Based on a criterion of 15 or more letters from the Early Treatment Diabetic Retinopathy Study chart, 13 eyes of 8 patients (18%) improved, but 24 months after the onset of symptoms, any further improvements were to no better than 20/100. Acuity recovery occurred in some patients despite continued marked retinal nerve fiber layer thinning indistinguishable from that in patients who did not recover visual acuity. CONCLUSIONS AND RELEVANCE Spontaneous improvement of visual acuity in patients with G11778A LHON is not common and is partial and limited when it occurs, so improvements in vision with adeno-associated virus-mediated gene therapy of a synthetic wild-type ND4 subunit gene should be

  4. The background of mitochondrial DNA haplogroup J increases the sensitivity of Leber's hereditary optic neuropathy cells to 2,5-hexanedione toxicity.

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    Anna Ghelli

    Full Text Available Leber's hereditary optic neuropathy (LHON is a maternally inherited blinding disease due to mitochondrial DNA (mtDNA point mutations in complex I subunit genes, whose incomplete penetrance has been attributed to both genetic and environmental factors. Indeed, the mtDNA background defined as haplogroup J is known to increase the penetrance of the 11778/ND4 and 14484/ND6 mutations. Recently it was also documented that the professional exposure to n-hexane might act as an exogenous trigger for LHON. Therefore, we here investigate the effect of the n-hexane neurotoxic metabolite 2,5-hexanedione (2,5-HD on cell viability and mitochondrial function of different cell models (cybrids and fibroblasts carrying the LHON mutations on different mtDNA haplogroups. The viability of control and LHON cybrids and fibroblasts, whose mtDNAs were completely sequenced, was assessed using the MTT assay. Mitochondrial ATP synthesis rate driven by complex I substrates was determined with the luciferine/luciferase method. Incubation with 2,5-HD caused the maximal loss of viability in control and LHON cells. The toxic effect of this compound was similar in control cells irrespective of the mtDNA background. On the contrary, sensitivity to 2,5-HD induced cell death was greatly increased in LHON cells carrying the 11778/ND4 or the 14484/ND6 mutation on haplogroup J, whereas the 11778/ND4 mutation in association with haplogroups U and H significantly improved cell survival. The 11778/ND4 mutation on haplogroup U was also more resistant to inhibition of complex I dependent ATP synthesis by 2,5-HD. In conclusion, this study shows that mtDNA haplogroups modulate the response of LHON cells to 2,5-HD. In particular, haplogroup J makes cells more sensitive to its toxic effect. This is the first evidence that an mtDNA background plays a role by interacting with an environmental factor and that 2,5-HD may be a risk element for visual loss in LHON. This proof of principle has broad

  5. A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy

    DEFF Research Database (Denmark)

    Zazo Seco, Celia; Castells-Nobau, Anna; Joo, Seol-Hee

    2017-01-01

    A consanguineous family from Pakistan was ascertained to have a novel deafness-dystonia syndrome with motor regression, ichthyosis-like features and signs of sensory neuropathy. By applying a combined strategy of linkage analysis and whole-exome sequencing in the presented family, a homozygous no...

  6. Motor and sensory neuropathy due to myelin infolding and paranodal damage in a transgenic mouse model of Charcot–Marie–Tooth disease type 1C

    Science.gov (United States)

    Lee, Samuel M.; Sha, Di; Mohammed, Anum A.; Asress, Seneshaw; Glass, Jonathan D.; Chin, Lih-Shen; Li, Lian

    2013-01-01

    Charcot–Marie–Tooth disease type 1C (CMT1C) is a dominantly inherited motor and sensory neuropathy. Despite human genetic evidence linking missense mutations in SIMPLE to CMT1C, the in vivo role of CMT1C-linked SIMPLE mutations remains undetermined. To investigate the molecular mechanism underlying CMT1C pathogenesis, we generated transgenic mice expressing either wild-type or CMT1C-linked W116G human SIMPLE. Mice expressing mutant, but not wild type, SIMPLE develop a late-onset motor and sensory neuropathy that recapitulates key clinical features of CMT1C disease. SIMPLE mutant mice exhibit motor and sensory behavioral impairments accompanied by decreased motor and sensory nerve conduction velocity and reduced compound muscle action potential amplitude. This neuropathy phenotype is associated with focally infolded myelin loops that protrude into the axons at paranodal regions and near Schmidt–Lanterman incisures of peripheral nerves. We find that myelin infolding is often linked to constricted axons with signs of impaired axonal transport and to paranodal defects and abnormal organization of the node of Ranvier. Our findings support that SIMPLE mutation disrupts myelin homeostasis and causes peripheral neuropathy via a combination of toxic gain-of-function and dominant-negative mechanisms. The results from this study suggest that myelin infolding and paranodal damage may represent pathogenic precursors preceding demyelination and axonal degeneration in CMT1C patients. PMID:23359569

  7. Carbamoylation correlates of cyanate neuropathy and cyanide poisoning: relevance to the biomarkers of cassava cyanogenesis and motor system toxicity.

    Science.gov (United States)

    Kimani, Samuel; Moterroso, Victor; Lasarev, Mike; Kipruto, Sinei; Bukachi, Fred; Maitai, Charles; David, Larry; Tshala-Katumbay, Desire

    2013-01-01

    We sought to elucidate the protein carbamoylation patterns associated with cyanate neuropathy relative to cyanide poisoning. We hypothesized that under a diet deficient in sulfur amino acids (SAA), the carbamoylation pattern associated with cyanide poisoning is similar to that of cyanate neuropathy. Male rats (6-8 weeks old) were fed a diet with all amino acids (AAA) or 75%-deficiency in SAA and treated with 2.5 mg/kg/body weight (bw) NaCN, or 50 mg/kg/bw NaOCN, or 1 μl/g/bw saline, for up to 6 weeks. Albumin and spinal cord proteins were analyzed using liquid chromatography mass spectrometry (LC-MS/MS). Only NaOCN induced motor deficits with significant levels of carbamoylation. At Day 14, we found a diet-treatment interaction effect on albumin carbamoylation (p = 0.07). At Day 28, no effect was attributed to diet (p = 0.71). Mean number of NaCN-carbamoylated sites on albumin was 47.4% higher relative to vehicle (95% CI:16.7-86.4%). Only NaOCN carbamoylated spinal cord proteins, prominently, under SAA-restricted diet. Proteins targets included myelin basic and proteolipid proteins, neurofilament light and glial fibrillary acidic proteins, and 2', 3' cyclic-nucleotide 3'-phosphodiesterase. Under SAA deficiency, chronic but not acute cyanide toxicity may share biomarkers and pathogenetic similarities with cyanate neuropathy. Prevention of carbamoylation may protect against the neuropathic effects of cyanate.

  8. Motor and functional evaluation of patients with spastic paraplegia, optic atrophy, and neuropathy (SPOAN Avaliação motora e funcional de pacientes com paraplegia espástica, atrofia óptica e neuropatia (SPOAN

    Directory of Open Access Journals (Sweden)

    Zodja Graciani

    2010-02-01

    Full Text Available Spastic paraplegia, optic atrophy, and neuropathy (SPOAN is an autosomal recessive complicated form of hereditary spastic paraplegia, which is clinically defined by congenital optic atrophy, infancy-onset progressive spastic paraplegia and peripheral neuropathy. In this study, which included 61 individuals (age 5-72 years, 42 females affected by SPOAN, a comprehensive motor and functional evaluation was performed, using modified Barthel index, modified Ashworth scale, hand grip strength measured with a hydraulic dynamometer and two hereditary spastic paraplegia scales. Modified Barthel index, which evaluate several functional aspects, was more sensitive to disclose disease progression than the spastic paraplegia scales. Spasticity showed a bimodal distribution, with both grades 1 (minimum and 4 (maximum. Hand grip strength showed a moderate inverse correlation with age. Combination of early onset spastic paraplegia and progressive polyneuropathy make SPOAN disability overwhelming.A paraplegia espástica, atrofia óptica e neuropatia (SPOAN é uma forma complicada de paraplegia espástica de herança autossômica recessiva, caracterizada por atrofia óptica congênita, paraplegia espástica progressiva de início na infância e neuropatia periférica. Este estudo avaliou o desempenho motor e funcional de 61 indivíduos com SPOAN (5 a 72 anos, por meio do índice de Barthel modificado, a escala modificada de Ashworth, da avaliação da força de preensão das mãos com dinamômetro hidráulico de Jamar e escalas de paraplegia espástica hereditária. O índice de Barthel modificado, que investiga aspectos funcionais, mostrou-se mais sensível para avaliar a progressão da doença do que as escalas de paraplegia espástica. A espasticidade apresentou distribuição bimodal, com o grau 1 (mínimo e 4 (máximo. A força de preensão mostrou correlação inversa moderada com a idade. A combinação de paraplegia espástica de início precoce com

  9. Localization and expression of ciliary neurotrophic factor (CNTF) in postmortem sciatic nerve from patients with motor neuron disease and diabetic neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Lee, D.A. [Univ. Medical Center, New Orleans, LA (United States); Gross, L.; Wittrock, D.A.; Windebank, A.J. [Mayo Clinic, Rochester, MN (United States)

    1996-08-01

    Ciliary neurotrophic factor (CNTF) is thought to play an important role in the maintenance of the mature motor system. The factor is found most abundantly in myelinating Schwann cells in the adult sciatic nerve. Lack of neuronal growth factors has been proposed as one possible etiology of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Growth factor replacement therapies are currently being evaluated as a treatment for motor neuron disease. In this report we determined whether the expression of CNTF in sciatic nerve differed in patients with motor neuron disease compared to controls or patients with another form of axonopathy. We identified 8 patients (7 with ALS and 1 with SMA) with motor neuron disease and 6 patients with diabetic motor neuropathy who had autopsy material available. Immunoperoxidase staining showed reduced CNTF expression in nerves of patients with motor neuron disease but not in patients with diabetic motor neuropathy. Decreased CNTF appears be associated with primary motor neuron disease rather than a generalized process of axon loss. This result supports suggestions that CNTF deficiency may be an important factor in the development of motor neuron disease. 20 refs., 4 figs., 1 tab.

  10. Visual prognosis better in eyes with less severe reduction of visual acuity one year after onset of Leber hereditary optic neuropathy caused by the 11,778 mutation.

    Science.gov (United States)

    Mashima, Yukihiko; Kigasawa, Kazuteru; Shinoda, Kei; Wakakura, Masato; Oguchi, Yoshihisa

    2017-10-18

    Patients with Leber hereditary optic neuropathy (LHON) have a progressive decrease of their visual acuity which can deteriorate to <0.1. Some patients can have a partial recovery of their vision in one or both eyes. One prognostic factor associated with a recovery of vision is an early-age onset. The purpose of this study was to determine other clinical factors that are predictive of a good visual recovery. Sixty-one Japanese LHON patients, with the 11,778 mutation and a mean age of 23.1 ± 12.1 years at the onset, were studied. All patients were initially examined at an acute stage of LHON and were followed for 3 to 10 years. At 1 year after the onset, the lowest visual acuity was <0.1 in all eyes. We studied the following parameters of patients with/without a final visual acuity of ≥ 0.2: sex; heavy consumption of cigarettes and alcohol; taking idebenone; mean age at onset; mean lowest visual acuity; and distribution of the lowest and the final visual acuity. Fifteen (24.6%) of the 61 patients or 25 (20.5%) of the 122 eyes had a recovery of their visual acuity to ≥ 0.2. The mean age at onset of these 15 patients with visual recovery to ≥ 0.2 was 17.5 ± 7.7 years, and that of the 46 patients without visual recovery to ≥ 0.2 was 25.0 ± 12.8 years (P = 0.02, Mann-Whitney U test). The mean lowest visual acuity of the 25 eyes with visual recovery ≥ 0.2 was 0.04, and that of the 97 eyes without visual recovery to ≥ 0.2 was 0.015 (P < 0.001, Mann-Whitney U test). Fifty percent (15/30) of the eyes whose lowest visual acuity was ≥ 0.04 during 1 year after the onset had a visual recovery to ≥ 0.2, while 11% (10/92) of the eyes whose the lowest visual acuity was ≤ 0.03 had a visual recovery to ≥ 0.2 (P < 0.001, χ (2) test). There were no significant differences in the other clinical factors. A final visual acuity of ≥ 0.2 was associated with a less severe reduction of the visual acuity at 1 year after the

  11. Cognitive dysfunction in hereditary spastic paraplegias and other motor neuron disorders

    Directory of Open Access Journals (Sweden)

    Ingrid Faber

    Full Text Available ABSTRACT Hereditary spastic paraplegia (HSP is a diverse group of single-gene disorders that share the predominant clinical feature of progressive lower limb spasticity and weakness. More than 70 different genetic subtypes have been described and all modes of inheritance are possible. Intellectual dysfunction in HSP is frequent in recessive forms but rare in dominant families. It may manifest by either mental retardation and/or cognitive decline. The latter may be subtle, restricted to executive dysfunction or may evolve to severe dementia. The cognitive profile is thought to depend largely on the genetic subtype of HSP, although wide phenotypic variability within the same genetic subtype and also within the same family can be found.

  12. Robotic gait training improves motor skills and quality of life in hereditary spastic paraplegia.

    Science.gov (United States)

    Bertolucci, F; Di Martino, S; Orsucci, D; Ienco, E Caldarazzo; Siciliano, G; Rossi, B; Mancuso, M; Chisari, C

    2015-01-01

    Gait impairment, balance problems and falls have a negative impact on independence in ADL and quality of life of patients affected by Hereditary Spastic Paraplegia (HSP). Since no pharmacological options are available, treatments rely mostly on rehabilitation therapy, although almost no data on this topic exist. Given the demonstrated effectiveness of robotics in improving gait and balance in various neurological diseases, aim of this study is to test the effectiveness of a robotic-aided program of gait training on balance, walking ability and quality of life in adult subjects affected by uncomplicated HSP. Thirteen patients affected by uncomplicated HSP were subjected to a six-week robotic-aided gait training protocol. Participants underwent a battery of 3 walking test, 1 balance test and 2 quality of life questionnaires. At the end of the treatment a significant improvement of balance, walking ability and quality of life was observed in almost all the tests. The improvements were maintained over a two-month follow-up period. Our study indicates that a robotic gait training is long term effective in improving balance and walking ability with a positive impact on quality of life in patients affected by uncomplicated form of HSP. As currently there is no specific treatment to prevent or reverse HSP progression, our contribution would be significant for the development of exercise recommendations in this rare disease.

  13. Clinical approach to optic neuropathies

    Science.gov (United States)

    Behbehani, Raed

    2007-01-01

    Optic neuropathy is a frequent cause of vision loss encountered by ophthalmologist. The diagnosis is made on clinical grounds. The history often points to the possible etiology of the optic neuropathy. A rapid onset is typical of demyelinating, inflammatory, ischemic and traumatic causes. A gradual course points to compressive, toxic/nutritional and hereditary causes. The classic clinical signs of optic neuropathy are visual field defect, dyschromatopsia, and abnormal papillary response. There are ancillary investigations that can support the diagnosis of optic neuropathy. Visual field testing by either manual kinetic or automated static perimetry is critical in the diagnosis. Neuro-imaging of the brain and orbit is essential in many optic neuropathies including demyelinating and compressive. Newer technologies in the evaluation of optic neuropathies include multifocal visual evoked potentials and optic coherence tomography. PMID:19668477

  14. Hereditary Pancreatitis

    Science.gov (United States)

    ... E-News Sign-Up Home Hereditary Pancreatitis Hereditary Pancreatitis Hereditary Pancreatitis (HP) is a rare genetic condition characterized by ... of pancreatic attacks, which can progress to chronic pancreatitis . Symptoms include abdominal pain, nausea, and vomiting. Onset ...

  15. Antibodies to Glycoproteins Shared by Human Peripheral Nerve and Campylobacter jejuni in Patients with Multifocal Motor Neuropathy

    Directory of Open Access Journals (Sweden)

    Ljubica Suturkova

    2013-01-01

    Full Text Available We have tested serum samples from 24 patients with multifocal motor neuropathy (MMN for reactivity to ganglioside GM1 and to Gal(β1–3GalNAc-bearing glycoproteins isolated from human peripheral nerve and from Campylobacter jejuni (Cj serotype O:19. IgM anti-GM1 antibodies were detected by ELISA in 11 patients (45.8% with MMN and in only one subject (4% from the control group. Western blots showed positive reactivity of sera from 6 patients (25% with MMN to several Gal(β1–3GalNAc-bearing glycoproteins from human peripheral nerve and from Cj O:19 isolates. Sera from three patients (12.5% with MMN showed positively reactive bands with similar electrophoretic mobility in all isolates (60–62 kDa, 48–51 kDa, 42 kDa, and 38 kDa. All six patients showed positive reactivity to 48–52 kDa protein isolated from human peripheral nerve. Increased titer of IgG antibodies to 60–62 kDa protein isolated from Cj O:19 associated with Guillain-Barré syndrome was detected in three patients, and their serum showed also IgG positive reactivity to peripheral nerve antigen with the same electrophoretic mobility. One of these patients had a previous history of Cj infection which suggests the possibility that Cj may be also involved in the pathogenesis of MMN.

  16. [Diabetic neuropathy].

    Science.gov (United States)

    Lechleitner, Monika; Abrahamian, Heidemarie; Francesconi, Claudia; Kofler, Markus

    2016-04-01

    These are the guidelines for diagnosis and treatment of diabetic neuropathy. This diabetic late complication comprises a number of mono- and polyneuropathies, plexopathies, radiculopathies and autonomic neuropathy. The position statement summarizes characteristic clinical symptoms and techniques for diagnostic assessment of diabetic neuropathy. Recommendations for the therapeutic management of diabetic neuropathy, especially for the control of pain in sensorimotor neuropathy, are provided.

  17. Nerve ultrasound in the differentiation of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis with predominant lower motor neuron disease (ALS/LMND).

    Science.gov (United States)

    Loewenbrück, Kai F; Liesenberg, Julia; Dittrich, Markus; Schäfer, Jochen; Patzner, Beate; Trausch, Beate; Machetanz, Jochen; Hermann, Andreas; Storch, Alexander

    2016-01-01

    The objective of the study was to investigate nerve ultrasound (US) in comparison to nerve conduction studies (NCS) for differential diagnosis of amyotrophic lateral sclerosis with predominant lower motoneuron disease(ALS/LMND) and multifocal motor neuropathy(MMN). A single-center, prospective, examiner-blinded cross-sectional diagnostic study in two cohorts was carried out. Cohort I: convenience sample of subjects diagnosed with ALS/LMND or MMN (minimal diagnostic criteria:possible ALS (revised EL-Escorial criteria), possible MMN (European Federation of Neurosciences guidelines).Cohort II: consecutive subjects with suspected diagnosis of either ALS/LMND or MMN. Diagnostic US and NCS models were developed based on ROC analysis of 28 different US and 32 different NCS values measured in cohort I. Main outcome criterion was sensitivity/specificity of these models between ALS/LMND and MMN in cohort II.Cohort I consisted of 16 patients with ALS/LMND and 8 patients with MMN. For cohort II, 30 patients were recruited, 8 with ALS/LMND, 5 with MMN, and 17 with other diseases. In cohort I, the three best US measures showed higher mean ± SD areas under the curve than the respective NCS measures (0.99 ± 0.01 vs. 0.79 ± 0.03, pALS/LMND and MMN. It might be superior to NCS in the diagnosis of MMN in hospital-admitted patients with this differential diagnosis.

  18. Metabolic neuropathies

    Science.gov (United States)

    Neuropathy - metabolic ... damage can be caused by many different things. Metabolic neuropathy may be caused by: A problem with ... is one of the most common causes of metabolic neuropathies. People who are at the highest risk ...

  19. Acquired immune demyelinating neuropathies.

    Science.gov (United States)

    Dimachkie, Mazen M; Saperstein, David S

    2014-10-01

    Acquired immune demyelinating neuropathies refer to a group of disorders that share overlapping sensory, motor, and autonomic clinical, laboratory, and electrodiagnostic features. It is important to recognize acquired immune demyelinating neuropathies as they are generally responsive to immunosuppressive or immunomodulatory therapies. This article reviews recently developed early prognostic tools in Guillain-Barré syndrome and discusses the evolving understanding of chronic demyelinating phenotypes with differing treatment responsiveness. While weakness and numbness progress over 2 to 4 weeks in Guillain-Barré syndrome, they continue to evolve beyond 8 weeks in chronic inflammatory demyelinating polyradiculoneuropathy and over 4 to 8 weeks in subacute inflammatory demyelinating polyradiculoneuropathy. Acquired immune demyelinating neuropathies present uncommonly as variants with predominance of ocular, bulbar, sensory, autonomic, or motor manifestations in addition to regional variants, such as paraparetic acquired immune demyelinating neuropathies. Establishing the correct diagnosis is important as these immune disorders differ in response to corticosteroids and other immunosuppressive therapies.

  20. A de novo dominant mutation in KIF1A associated with axonal neuropathy, spasticity and autism spectrum disorder.

    Science.gov (United States)

    Tomaselli, Pedro J; Rossor, Alexander M; Horga, Alejandro; Laura, Matilde; Blake, Julian C; Houlden, Henry; Reilly, Mary M

    2017-08-23

    Mutations in the kinesin family member 1A (KIF1A) gene have been associated with a wide range of phenotypes including recessive mutations causing hereditary sensory neuropathy and hereditary spastic paraplegia and de novo dominant mutations causing a more complex neurological disorder affecting both the central and peripheral nervous system. We identified by exome sequencing a de novo dominant missense variant, (c.38G>A, p.R13H), within an ATP binding site of the kinesin motor domain in a patient manifesting a complex phenotype characterized by autism spectrum disorder (ASD), spastic paraplegia and axonal neuropathy. The presence of ASD distinguishes this case from previously reported patients with de novo dominant mutations in KIF1A. © 2017 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society.

  1. Neuropathies optiques héréditaires

    DEFF Research Database (Denmark)

    Milea, D; Verny, C

    2012-01-01

    Hereditary optic neuropathies are a group of heterogeneous conditions affecting both optic nerves, with an autosomal dominant, autosomal recessive, X-related or mitochondrial transmission. The two most common non-syndromic hereditary optic neuropathies (Leber's hereditary optic neuropathy...... and autosomal dominant optic atrophy) are very different in their clinical presentation and their genetic transmission, leading however to a common, non-specific optic nerve atrophy. Beyond the optic atrophy-related visual loss, which is the clinical hallmark of this group of diseases, other associated...

  2. The effects of isometric exercises and stretching on postural stability in Non–Insulin Dependent Diabetes Mellitus patients with diffuse symmetrical sensory motor neuropathy

    Directory of Open Access Journals (Sweden)

    S. Nenkova

    2009-02-01

    Full Text Available The purpose of this study was to explore the effects of isometric exercises and stretching on postural stability in Non – Insulin Dependent Diabetes Mellitus (NIDDM patients with diffuse symmetrical sensory motor neuropathy. Patients were assigned to an experimental group and amatched control group. The experimental group received isometric exer-cises and stretching three times weekly for 12 weeks in addition to routine medication and dietary advice. A t the end of this period, this group wascompared with the control group, which received routine medication anddietary advice only. Measurements of muscle strength of quadriceps, ham-strings, ankle plantar and dorsiflexors, and Romberg’s test for postural sta-bility were carried out before and after the 12 weeks intervention. The study showed that isometric exercises and stretching for the lower extremities improved postural stability (p = 0.00and strength of the quadriceps (p = 0.001 hamstrings (p = 0.001 dorsiflexors (p = 0.001 plantarflexors (p = 0.001in NIDDM patients with diffuse symmetrical sensory motor neuropathy. This exercise regimen also had a loweringeffect on blood glucose level (p = 0.00.  In conclusion it seems that the simple exercise intervention described in thisstudy may be of benefit to these patients if incorporated into their management programmes.

  3. Profiling the Mitochondrial Proteome of Leber’s Hereditary Optic Neuropathy (LHON) in Thailand: Down-Regulation of Bioenergetics and Mitochondrial Protein Quality Control Pathways in Fibroblasts with the 11778G>A Mutation

    Science.gov (United States)

    Tun, Aung Win; Chaiyarit, Sakdithep; Kaewsutthi, Supannee; Katanyoo, Wanphen; Chuenkongkaew, Wanicha; Kuwano, Masayoshi; Tomonaga, Takeshi; Peerapittayamongkol, Chayanon; Thongboonkerd, Visith; Lertrit, Patcharee

    2014-01-01

    Leber’s Hereditary Optic Neuropathy (LHON) is one of the commonest mitochondrial diseases. It causes total blindness, and predominantly affects young males. For the disease to develop, it is necessary for an individual to carry one of the primary mtDNA mutations 11778G>A, 14484T>C or 3460G>A. However these mutations are not sufficient to cause disease, and they do not explain the characteristic features of LHON such as the higher prevalence in males, incomplete penetrance, and relatively later age of onset. In order to explore the roles of nuclear encoded mitochondrial proteins in development of LHON, we applied a proteomic approach to samples from affected and unaffected individuals from 3 pedigrees and from 5 unrelated controls. Two-dimensional electrophoresis followed by MS/MS analysis in the mitochondrial lysate identified 17 proteins which were differentially expressed between LHON cases and unrelated controls, and 24 proteins which were differentially expressed between unaffected relatives and unrelated controls. The proteomic data were successfully validated by western blot analysis of 3 selected proteins. All of the proteins identified in the study were mitochondrial proteins and most of them were down regulated in 11778G>A mutant fibroblasts. These proteins included: subunits of OXPHOS enzyme complexes, proteins involved in intermediary metabolic processes, nucleoid related proteins, chaperones, cristae remodelling proteins and an anti-oxidant enzyme. The protein profiles of both the affected and unaffected 11778G>A carriers shared many features which differed from those of unrelated control group, revealing similar proteomic responses to 11778G>A mutation in both affected and unaffected individuals. Differentially expressed proteins revealed two broad groups: a cluster of bioenergetic pathway proteins and a cluster involved in protein quality control system. Defects in these systems are likely to impede the function of retinal ganglion cells, and may

  4. Characterization of a Leber's hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m.11778G>A and m.14484T>C of the mitochondrial DNA.

    Science.gov (United States)

    Catarino, Claudia B; Ahting, Uwe; Gusic, Mirjana; Iuso, Arcangela; Repp, Birgit; Peters, Katrin; Biskup, Saskia; von Livonius, Bettina; Prokisch, Holger; Klopstock, Thomas

    2017-09-01

    Leber's hereditary optic neuropathy (LHON) is an inherited mitochondrial disease that usually leads to acute or subacute bilateral central vision loss. In 95% of cases, LHON is caused by one of three primary mutations of the mitochondrial DNA (mtDNA), m.11778G>A in the MT-ND4 gene, m.14484T>C in the MT-ND6 gene, or m.3460G>A in the MT-ND1 gene. Here we characterize clinically, genetically, and biochemically a LHON family with multiple patients harboring two of these primary LHON mutations, m.11778G>A homoplasmic and m.14484T>C heteroplasmic. The unusually low male-to-female ratio of affected family members is also seen among the other patients previously reported with two primary LHON mutations m.11778G>A and m.14484T>C. While the index patient had very late onset of symptoms at 75years and severe visual loss, her two daughters had both onset in childhood (6 and 9years), with moderate to mild visual loss. A higher degree of heteroplasmy of the m.14484T>C mutation was found to correlate with an earlier age at onset in this family. Ours is the first LHON family harboring two primary LHON mutations where functional studies were performed in several affected family members. A more pronounced bioenergetic defect was found to correlate with an earlier age at onset. The patient with the earliest age at onset had a more significant complex I dysfunction than all controls, including the LHON patient with only the m.11778G>A mutation, suggesting a synergistic effect of the two primary LHON mutations in this patient. Copyright © 2017 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  5. Leber's Hereditary Optic Neuropathy is Associated with Compound Primary Mutations of Mitochondrial ND1 m.3635G > A and ND6 m.14502 T > C.

    Science.gov (United States)

    Jin, Xin; Wang, Lifeng; Gong, Yan; Chen, Bing; Wang, Yanhua; Chen, Tingjun; Wei, Shihui

    2015-01-01

    To describe the clinical and molecular characteristics of a Chinese Leber hereditary optic neuropathy (LHON) pedigree with compound mitochondrial DNA (mtDNA) mutations of m.3635G > A and m.14502T > C. A total of 22 individuals (2 affected, 20 unaffected) from a five-generation Chinese family with LHON underwent comprehensive ophthalmic examination, including visual acuity, slit lamp examination, fundoscopy, visual field examination and visual evoked potentials (VEP). The complete mtDNA genome of the two patients were amplified by polymerase chain reaction, sequenced using a Bigdye terminator v3.1 cycle sequencing kit and analyzed on an ABI 3700XL Genetic Analyzer. Two LHON patients in the family presented typical features of LHON: painless and progressive deterioration of bilateral vision, bilateral optic atrophy, centrocecal scotomata in both eyes and significant prolonged P100 latency and low amplitude potential in VEP. Compound primary mtDNA mutations of m.3635G > A and m.14502T > C were identified in these two patients and another 12 living matrilineal members of the pedigree. Haplogroup analysis showed the patients in this LHON family belonged to the N9b1 haplogroup. Modeled mutant structure showed the mutations altered the molecular local space conformation on the surface of ND1 and ND6. Compound mtDNA mutations of m.3635G > A and m.14502T > C presented with low penetration, and the patients with these compound mutations exhibited mild visual impairment. The biological information analysis suggested that m.14502T > C might play a protective role in LHON associated with m.3635G > A. The haplogroup analysis indicated that the mtDNA haplogroup might be an important factor affecting the expression of LHON associated with m.3635G > A and/or m.14502T > C.

  6. Profiling the mitochondrial proteome of Leber's Hereditary Optic Neuropathy (LHON) in Thailand: down-regulation of bioenergetics and mitochondrial protein quality control pathways in fibroblasts with the 11778G>A mutation.

    Science.gov (United States)

    Tun, Aung Win; Chaiyarit, Sakdithep; Kaewsutthi, Supannee; Katanyoo, Wanphen; Chuenkongkaew, Wanicha; Kuwano, Masayoshi; Tomonaga, Takeshi; Peerapittayamongkol, Chayanon; Thongboonkerd, Visith; Lertrit, Patcharee

    2014-01-01

    Leber's Hereditary Optic Neuropathy (LHON) is one of the commonest mitochondrial diseases. It causes total blindness, and predominantly affects young males. For the disease to develop, it is necessary for an individual to carry one of the primary mtDNA mutations 11778G>A, 14484T>C or 3460G>A. However these mutations are not sufficient to cause disease, and they do not explain the characteristic features of LHON such as the higher prevalence in males, incomplete penetrance, and relatively later age of onset. In order to explore the roles of nuclear encoded mitochondrial proteins in development of LHON, we applied a proteomic approach to samples from affected and unaffected individuals from 3 pedigrees and from 5 unrelated controls. Two-dimensional electrophoresis followed by MS/MS analysis in the mitochondrial lysate identified 17 proteins which were differentially expressed between LHON cases and unrelated controls, and 24 proteins which were differentially expressed between unaffected relatives and unrelated controls. The proteomic data were successfully validated by western blot analysis of 3 selected proteins. All of the proteins identified in the study were mitochondrial proteins and most of them were down regulated in 11778G>A mutant fibroblasts. These proteins included: subunits of OXPHOS enzyme complexes, proteins involved in intermediary metabolic processes, nucleoid related proteins, chaperones, cristae remodelling proteins and an anti-oxidant enzyme. The protein profiles of both the affected and unaffected 11778G>A carriers shared many features which differed from those of unrelated control group, revealing similar proteomic responses to 11778G>A mutation in both affected and unaffected individuals. Differentially expressed proteins revealed two broad groups: a cluster of bioenergetic pathway proteins and a cluster involved in protein quality control system. Defects in these systems are likely to impede the function of retinal ganglion cells, and may lead

  7. Profiling the mitochondrial proteome of Leber's Hereditary Optic Neuropathy (LHON in Thailand: down-regulation of bioenergetics and mitochondrial protein quality control pathways in fibroblasts with the 11778G>A mutation.

    Directory of Open Access Journals (Sweden)

    Aung Win Tun

    Full Text Available Leber's Hereditary Optic Neuropathy (LHON is one of the commonest mitochondrial diseases. It causes total blindness, and predominantly affects young males. For the disease to develop, it is necessary for an individual to carry one of the primary mtDNA mutations 11778G>A, 14484T>C or 3460G>A. However these mutations are not sufficient to cause disease, and they do not explain the characteristic features of LHON such as the higher prevalence in males, incomplete penetrance, and relatively later age of onset. In order to explore the roles of nuclear encoded mitochondrial proteins in development of LHON, we applied a proteomic approach to samples from affected and unaffected individuals from 3 pedigrees and from 5 unrelated controls. Two-dimensional electrophoresis followed by MS/MS analysis in the mitochondrial lysate identified 17 proteins which were differentially expressed between LHON cases and unrelated controls, and 24 proteins which were differentially expressed between unaffected relatives and unrelated controls. The proteomic data were successfully validated by western blot analysis of 3 selected proteins. All of the proteins identified in the study were mitochondrial proteins and most of them were down regulated in 11778G>A mutant fibroblasts. These proteins included: subunits of OXPHOS enzyme complexes, proteins involved in intermediary metabolic processes, nucleoid related proteins, chaperones, cristae remodelling proteins and an anti-oxidant enzyme. The protein profiles of both the affected and unaffected 11778G>A carriers shared many features which differed from those of unrelated control group, revealing similar proteomic responses to 11778G>A mutation in both affected and unaffected individuals. Differentially expressed proteins revealed two broad groups: a cluster of bioenergetic pathway proteins and a cluster involved in protein quality control system. Defects in these systems are likely to impede the function of retinal ganglion

  8. [Frequency of hereditary neurologic diseases. A clinical study].

    Science.gov (United States)

    Leone, M; Baldini, S; Voltolin, G; Norat, M; Bottacchi, E

    1993-09-01

    The nervous system is affected in 30% of hereditary monogenic disorders and as many as 500 single-gene disorders display major neurologic symptoms. We have studied the frequency of hereditary neurological diseases to assess their importance in daily hospital activity. Only single-gene hereditary diseases with central or peripheral nervous system involvement were considered; thus chromosomal diseases and diseases with multifactorial etiology were excluded. We surveyed admission to in- and out-patient departments of Neurology, Pediatrics, and Dermatology of the Aosta Regional Hospital for the calendar years 1982-1991, collecting 229 cases, 95 women and 134 men. Out-patient departments held 126 patients, the others came from in-patient departments. Admission to the neurological in-patient department were 1.8% of total neurological admissions in the same period. Each diagnosis was assigned to the code number of the International Classification of Diseases (ICD-IX Revision, 1975). We found 33 different phenotypes. Most frequent diagnoses were: essential tremor (89 patients), hereditary sensory-motor neuropathy (HSMN) type I (28), Huntington's chorea (13), progressive muscular dystrophy limb-girdle type (8), neurofibromatosis type I (9), HSMN type II (9), spinocerebellar ataxia (9), hereditary spastic paraplegia (7), spinal muscular atrophy type IV (5), myotonic dystrophy (5), cerebellar ataxia (4), HSMN type III (4), spinal muscular atrophy type II and III (3), tuberous sclerosis (3). Essential tremor mostly affected persons in the over-50 age groups. On the contrary, the other neurologic monogenic diseases were diagnosed in all ages with the following age-group breakdown: 0-9, 11%; 10-19, 16%; 20-29, 15%; 30-39, 8%; 40-49, 11%; 50-59, 19%; 60-69, 14%, 70+, 7%. Consistently with the general rule, autosomic recessive diseases have the earliest onset and autosomic dominant ones the latest; HSMN, spinal muscular atrophy and Huntington's chorea were the disorders diagnosed

  9. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of multifocal motor neuropathy. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision

    NARCIS (Netherlands)

    van Schaik, Ivo N.; Leger, Jean-Marc; Nobile-Orazio, Eduardo; Cornblath, David R.; Hadden, Robert D. M.; Koski, Carol L.; Pollard, John D.; Sommer, Claudia; Illa, Isabel; van den Bergh, Peter; van Dorrn, Pieter A.

    2010-01-01

    A European Federation of Neurological Societies/Peripheral Nerve Society consensus guideline on the definition, investigation, and treatment of multifocal motor neuropathy (MMN) was published in 2006. The aim is to revise this guideline. Disease experts considered references retrieved from MEDLINE

  10. Intramuscular viral delivery of paraplegin rescues peripheral axonopathy in a model of hereditary spastic paraplegia

    Science.gov (United States)

    Pirozzi, Marinella; Quattrini, Angelo; Andolfi, Gennaro; Dina, Giorgia; Malaguti, Maria Chiara; Auricchio, Alberto; Rugarli, Elena I.

    2006-01-01

    Degeneration of peripheral motor axons is a common feature of several debilitating diseases including complicated forms of hereditary spastic paraplegia. One such form is caused by loss of the mitochondrial energy-dependent protease paraplegin. Paraplegin-deficient mice display a progressive degeneration in several axonal tracts, characterized by the accumulation of morphological abnormal mitochondria. We show that adenoassociated virus–mediated (AAV-mediated) intramuscular delivery of paraplegin halted the progression of neuropathological changes and rescued mitochondrial morphology in the peripheral nerves of paraplegin-deficient mice. One single injection before onset of symptoms improved the motor performance of paraplegin-deficient mice for up to 10 months, indicating that the peripheral neuropathy contributes to the clinical phenotype. This study provides a proof of principle that gene transfer may be an effective therapeutic option for patients with paraplegin deficiency and demonstrates that AAV vectors can be successfully employed for retrograde delivery of an intracellular protein to spinal motor neurons, opening new perspectives for several hereditary axonal neuropathies of the peripheral nerves. PMID:16357941

  11. Leber’s Inherited Optic Neuropathy: A Large Family

    Directory of Open Access Journals (Sweden)

    Taylan Pekoz

    2012-04-01

    Full Text Available Leber's hereditary optic neuropathy characterized by loss of central vision is often seen in men and a maternally inherited disease. Here, admitted to our clinic with complaints of unilateral visual loss was diagnosed as Leber's hereditary optic neuropathy which was confirmed by the presence of a mutation at 3460G>A position. [Cukurova Med J 2012; 37(2.000: 121-124

  12. A smooth transition protocol for patients with multifocal motor neuropathy going from intravenous to subcutaneous immunoglobulin therapy: an open-label proof-of-concept study.

    Science.gov (United States)

    Misbah, Siraj A; Baumann, Andreas; Fazio, Raffaella; Dacci, Patrizia; Schmidt, Dirk S; Burton, Janet; Sturzenegger, Matthias

    2011-06-01

    Intravenous immunoglobulin (IVIG) is the first-line therapy for multifocal motor neuropathy (MMN). This open-label multi-centre study (NCT00701662) assessed the efficacy, safety, and convenience of subcutaneous immunoglobulin (SCIG) in patients with MMN over 6 months, as an alternative to IVIG. Eight MMN patients (42-66 years), on stable IVIG dosing, received weekly SCIG at doses equivalent to previous IVIG using a "smooth transition protocol". Primary efficacy endpoint was the change from baseline to week 24 in muscle strength. Disability, motor function, and health-related quality of life (HRQL) endpoints were also assessed. One patient deteriorated despite dose increase and was withdrawn. Muscle strength, disability, motor function, and health status were unchanged in all seven study completers who rated home treatment as extremely good. Four experienced 18 adverse events, of which only two were moderate. This study suggests that MMN patients with stable clinical course on regular IVIG can be switched to SCIG at the same monthly dose without deterioration and with a sustained overall improvement in HRQL. © 2011 Peripheral Nerve Society.

  13. Intrathecal administration of IGF-I by AAVrh10 improves sensory and motor deficits in a mouse model of diabetic neuropathy

    Directory of Open Access Journals (Sweden)

    Judit Homs

    2014-01-01

    Full Text Available Different adeno-associated virus (AAV serotypes efficiently transduce neurons from central and peripheral nervous systems through various administration routes. Direct administration of the vectors to the cerebrospinal fluid (CSF could be an efficient and safe strategy. Here, we show that lumbar puncture of a nonhuman AAV leads to wide and stable distribution of the vector along the spinal cord in adult mice. AAVrh10 efficiently and specifically infects neurons, both in dorsal root ganglia (60% total sensory neurons and in the spinal cord (up to one-third of α-motor neurons. As a proof of concept, we demonstrate the efficacy of AAVrh10 in a mouse model of diabetic neuropathy, in which intrathecal delivery of the vector coding for insulin-like growth factor (IGF-I favored the release of the therapeutic protein into the CSF through its expression by sensory and motor neurons. IGF-I–treated diabetic animals showed increased vascular endothelial growth factor expression, activation of Akt/PI3K pathway, and stimulated nerve regeneration and myelination in injured limbs. Moreover, we achieved restoration of nerve conduction velocities in both sensory and motor nerves by AAVrh10, whereas we reached only sensory nerve improvement with AAV1. Our results indicate that intrathecal injection of AAVrh10 is a promising tool to design gene therapy approaches for sensorimotor diseases.

  14. Intrathecal administration of IGF-I by AAVrh10 improves sensory and motor deficits in a mouse model of diabetic neuropathy.

    Science.gov (United States)

    Homs, Judit; Pagès, Gemma; Ariza, Lorena; Casas, Caty; Chillón, Miguel; Navarro, Xavier; Bosch, Assumpció

    2014-01-01

    Different adeno-associated virus (AAV) serotypes efficiently transduce neurons from central and peripheral nervous systems through various administration routes. Direct administration of the vectors to the cerebrospinal fluid (CSF) could be an efficient and safe strategy. Here, we show that lumbar puncture of a nonhuman AAV leads to wide and stable distribution of the vector along the spinal cord in adult mice. AAVrh10 efficiently and specifically infects neurons, both in dorsal root ganglia (60% total sensory neurons) and in the spinal cord (up to one-third of α-motor neurons). As a proof of concept, we demonstrate the efficacy of AAVrh10 in a mouse model of diabetic neuropathy, in which intrathecal delivery of the vector coding for insulin-like growth factor (IGF-I) favored the release of the therapeutic protein into the CSF through its expression by sensory and motor neurons. IGF-I-treated diabetic animals showed increased vascular endothelial growth factor expression, activation of Akt/PI3K pathway, and stimulated nerve regeneration and myelination in injured limbs. Moreover, we achieved restoration of nerve conduction velocities in both sensory and motor nerves by AAVrh10, whereas we reached only sensory nerve improvement with AAV1. Our results indicate that intrathecal injection of AAVrh10 is a promising tool to design gene therapy approaches for sensorimotor diseases.

  15. Colour vision defects in asymptomatic carriers of the Leber's hereditary optic neuropathy (LHON) mtDNA 11778 mutation from a large Brazilian LHON pedigree: a case-control study.

    Science.gov (United States)

    Quiros, P A; Torres, R J; Salomao, S; Berezovsky, A; Carelli, V; Sherman, J; Sadun, F; De Negri, A; Belfort, R; Sadun, A A

    2006-02-01

    To determine if asymptomatic carriers from a previously identified large pedigree of the Leber's hereditary optic neuropathy (LHON) 11778 mtDNA mutation have colour vision deficits. As part of a comprehensive analysis of over 200 members of a large Brazilian LHON pedigree spanning seven generations, colour vision tests were obtained from 91 members. Colour vision was tested one eye at a time using the Farnsworth-Munsell 100 (FM-100) hue colour vision test. The test was administered under uniform conditions, taking into account: ambient light levels, daylight colour temperature of 6700 kelvin, and neutral uniform background. Tests were scored using the FM-100 MS-Excel computer scoring program. Defects were determined and categorised as tritan, deutan, or protan. Categorisation of each dyschromatopsia was based on review of demonstrated axis computer generated plots and age adjusted error scores which coincided with Verriest 95% confidence intervals. Only the axis with the greatest magnitude error score was used to classify the defect. 55 of the 91 test subjects were LHON mtDNA 11778 J haplotype mutation carriers, proved by mtDNA analysis. The remaining 36 subjects were age matched non-blood relatives (off pedigree), who served as controls. 27 of 55 carriers (49.10%) were shown to have colour vision defects in one or both eyes. 13 of the 27 (48%) abnormal tests in the carrier group were tritan defects and the remaining 14 (52%) were deutan defects. Nine of the 27 (33%) abnormals in the carrier group were identified as having bilateral defects. Six of these were deutan, and the remaining three were tritan dyschromatopsias. Only six of the 36 (16.66%) age matched controls were found to have any type of dyschromatopsia. Five (83.3%) of these were deutan defects. The remaining one was a tritan defect. The difference between the two groups using a chi(2) test with one degree of freedom was statistically significant with a p value less that 0.001. Until now, LHON has

  16. Colour vision defects in asymptomatic carriers of the Leber's hereditary optic neuropathy (LHON) mtDNA 11778 mutation from a large Brazilian LHON pedigree: a case‐control study

    Science.gov (United States)

    Quiros, P A; Torres, R J; Salomao, S; Berezovsky, A; Carelli, V; Sherman, J; Sadun, F; De Negri, A; Belfort, R; Sadun, A A

    2006-01-01

    Aims To determine if asymptomatic carriers from a previously identified large pedigree of the Leber's hereditary optic neuropathy (LHON) 11778 mtDNA mutation have colour vision deficits. Methods As part of a comprehensive analysis of over 200 members of a large Brazilian LHON pedigree spanning seven generations, colour vision tests were obtained from 91 members. Colour vision was tested one eye at a time using the Farnsworth‐Munsell 100 (FM‐100) hue colour vision test. The test was administered under uniform conditions, taking into account: ambient light levels, daylight colour temperature of 6700 kelvin, and neutral uniform background. Tests were scored using the FM‐100 MS‐Excel computer scoring program. Defects were determined and categorised as tritan, deutan, or protan. Categorisation of each dyschromatopsia was based on review of demonstrated axis computer generated plots and age adjusted error scores which coincided with Verriest 95% confidence intervals. Only the axis with the greatest magnitude error score was used to classify the defect. 55 of the 91 test subjects were LHON mtDNA 11778 J haplotype mutation carriers, proved by mtDNA analysis. The remaining 36 subjects were age matched non‐blood relatives (off pedigree), who served as controls. Results 27 of 55 carriers (49.10%) were shown to have colour vision defects in one or both eyes. 13 of the 27 (48%) abnormal tests in the carrier group were tritan defects and the remaining 14 (52%) were deutan defects. Nine of the 27 (33%) abnormals in the carrier group were identified as having bilateral defects. Six of these were deutan, and the remaining three were tritan dyschromatopsias. Only six of the 36 (16.66%) age matched controls were found to have any type of dyschromatopsia. Five (83.3%) of these were deutan defects. The remaining one was a tritan defect. The difference between the two groups using a χ2 test with one degree of freedom was statistically significant with a p value less that 0

  17. Peripheral neuropathy: the importance of rare subtypes

    Science.gov (United States)

    Callaghan, Brian C.; Price, Ray S.; Chen, Kevin S.; Feldman, Eva L.

    2016-01-01

    Importance Peripheral neuropathy is a prevalent condition that usually warrants a thorough history and examination, but limited diagnostic evaluation. Rare localizations of peripheral neuropathy, however, often require more extensive diagnostic testing and different treatments. Objective To describe rare localizations of peripheral neuropathy, including the appropriate diagnostic evaluation and available treatments. Evidence Review References were identified from PubMed searches with an emphasis on systematic reviews and randomized clinical trials. Articles were also identified through the use of the author's own files. Search terms included common rare neuropathy localizations and their causes, as well as epidemiology, pathophysiology, diagnosis, and treatment. Findings Diffuse, non-length dependent neuropathies, multiple mononeuropathies, polyradiculopathies, plexopathies, and radiculoplexus neuropathies are rare peripheral neuropathy localizations that often require extensive diagnostic testing. Atypical neuropathy features, such as acute/subacute onset, asymmetry, and/or motor predominant signs, are frequently present. The most common diffuse, non-length dependent neuropathies are Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and amyotrophic lateral sclerosis (ALS). Effective disease modifying therapies exist for many diffuse, non-length dependent neuropathies including GBS, CIDP, MMN, and some paraprotein-associated demyelinating neuropathies. Vasculitic neuropathy (multiple mononeuropathy) also has efficacious treatment options, but definitive evidence of a treatment effect for IgM anti-MAG neuropathy and diabetic amyoptrophy (radiculoplexus neuropathy) is lacking. Conclusions and Relevance Recognition of rare localizations of periperhal neuropathy is essential given the implications for diagnostic testing and treatment. Electrodiagnostic studies are an important early step in the

  18. Autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J

    1980-01-01

    In order to elucidate the physiological significance of autonomic neuropathy in juvenile diabetics, cardiovascular, hormonal and metabolic functions have been investigated in three groups of juvenile diabetics: One group had no signs of neuropathy, one group had presumably slight autonomic...... neuropathy (reduced beat-to-beat variation in heart rate during hyperventilation) and one group had clinically severe autonomic neuropathy, defined by presence of orthostatic hypotension. In all three experimental situations we found sympathetic dysfunction causing cardiovascular and/or hormonal...... maladjustments in patients with autonomic neuropathy. Regarding metabolic functions we found normal responses to graded exercise and insulin-induced hypoglycemia in patients with autonomic neuropathy in spite of blunted catecholamine responses, suggesting increased sensitivity of glycogen stores and adipose...

  19. Diabetic Neuropathy

    Science.gov (United States)

    ... SEARCH Definition Treatment Prognosis Clinical Trials Organizations Publications Definition Diabetic neuropathy is a peripheral nerve disorder caused by diabetes or poor blood sugar control. The most common ...

  20. Penicillamin-induced neuropathy in rheumatoid arthritis

    DEFF Research Database (Denmark)

    Pedersen, P B; Hogenhaven, H

    1990-01-01

    A case of penicillamin-induced severe polyradiculopathy in rheumatoid arthritis is presented. The neuropathy was of demyelinating type, purely motor, proximal and clinically fully reversible when the drug ceased. In case of a progressive neuropathy, during penicillamin treatment, this adverse eff...... effect should be born in mind, and discontinuation of the drug considered.......A case of penicillamin-induced severe polyradiculopathy in rheumatoid arthritis is presented. The neuropathy was of demyelinating type, purely motor, proximal and clinically fully reversible when the drug ceased. In case of a progressive neuropathy, during penicillamin treatment, this adverse...

  1. Diabetic Neuropathies

    Science.gov (United States)

    Russell, James W.; Zilliox, Lindsay A.

    2014-01-01

    Purpose of Review: This article provides an overview for understanding the diagnosis, pathogenesis, and management of diabetic neuropathy. Recent Findings: New information about the pathogenesis of diabetic neuropathy continues to emerge, which will lead to identifying new drug targets. It is clear that the natural history of diabetic neuropathy is changing and the rate of progression is slowing. This is likely because of a combination of earlier diagnosis, improved glycemic management, and improved control of related complications such as hyperlipidemia and hypertension. Early diagnosis is critical, and small fiber neuropathy or subclinical diabetic neuropathy may be reversed or significantly improved with appropriate intervention. The American Academy of Neurology recently published guidelines for the treatment of painful diabetic neuropathy. Summary: Diabetic neuropathy is common and can present with varied clinical presentations discussed in this article. Although treatment currently focuses on pain management, attention should be paid to potential risk factors for neuropathy. For example, glycemic control, hyperlipidemia, and hypertension should be managed with diet, exercise, and medications. Class I or II clinical studies indicate that pregabalin, duloxetine, amitriptyline, gabapentin, and opioids are effective in the management of diabetic neuropathic pain. PMID:25299279

  2. [Atypical neuropathies associated with diabetes].

    Science.gov (United States)

    Lozeron, P

    2014-12-01

    Diabetes is the leading cause of neuropathy worldwide and, due to the epidemic progression of the affection, prevalence of diabetic neuropathies will increase in the near future. Beside the typical diabetic neuropathy pattern and the common entrapment neuropathies, several unusual clinical forms have been described with either a symmetrical or an asymmetrical pattern. Treatment-induced neuropathy is an acute sensory affection most commonly related to acute glycemic control. Pain is debilitating and associated with vegetative dysfunction. Prevention is important, as resolution is often incomplete. Several patterns or asymmetrical neuropathies of inflammatory and ischemic origin were described long ago in the lower limb. They are debilitating, most often painful and require steroid treatment. Other patterns affecting the thoracolumbar region or the upper limbs or involving a painless motor deficit must be identified as specific treatments are sometimes needed. An association between diabetes and chronic inflammatory demyelinating polyneuropathy has not been demonstrated but diagnosis may be suggested due to the misleading low conduction velocities seen in classical diabetic neuropathy. Like any other patient, the diabetic patient may present a neuropathy unrelated to diabetes. To facilitate patient care, neurologists should be aware of such clinical entities. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  3. MRI in Leber's hereditary optic neuropathy

    DEFF Research Database (Denmark)

    Matthews, Lucy; Enzinger, Christian; Fazekas, Franz

    2015-01-01

    mechanism involving mitochondrial dysfunction. OBJECTIVE: The primary aim was to define MRI features of LMS and LHON, and to assess the proportions of individuals displaying features typical of MS. Secondarily, we investigated the effect of gender on the risk of developing white matter lesions...... in the context of LHON. METHODS: A blinded standardised review of conventional brain MRIs of 30 patients with MS, 31 patients with LHON and 11 patients with LMS was conducted by three independent experts in the field. MS-like MRI features were assessed. RESULTS: All patients with LMS and 26% of patients...... with LHON had white matter lesions. Of these, all patients with LMS and 25% with LHON were found to have an MRI appearance typical of MS. Female patients with LHON had a significantly greater risk of having white matter lesions consistent with MS compared with male patients (relative risk 8.3). CONCLUSIONS...

  4. Genetics Home Reference: Leber hereditary optic neuropathy

    Science.gov (United States)

    ... disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA to their children. Often, people who develop the features of LHON ...

  5. Treatment strategies for chemotherapy-induced peripheral neuropathy: potential role of exercise

    Directory of Open Access Journals (Sweden)

    Karen Y. Wonders

    2011-12-01

    Full Text Available Chemotherapy-induced peripheral neuropathy (CIPN is a common, dose-limiting effect of cancer therapy that often has negative implications on a patient’s quality of life. The pain associated with CIPN has long been recognized as one of the most difficult types of pain to treat. Historically, much effort has been made to explore pharmacological therapies aimed at reducing symptoms of CIPN. While many of these agents provide a modest relief in the symptoms of peripheral neuropathy, many have been shown to have additional negative side effects for cancer patients. Therefore, the authors suggest exercise rehabilitation as one lifestyle modification that may positively impact the lives of patients with CIPN. To our knowledge, there are currently no published clinical trials examining the role of exercise in preserving neurological function following chemotherapy. However, investigations using low-to-moderate intensity exercise as an intervention in patients with diabetic peripheral neuropathy and hereditary motor and sensory neuropathies have produced promising results. Given that cancer patients appear to tolerate exercise, it seems plausible that exercise rehabilitation could be used as an effective strategy to minimize CIPN-induced detriments to quality of life.

  6. A Meta-analysis of the association between different genotypes(G11778A, T14484C and G3460A ) of Leber hereditary optic neuropathy and visual prognosis

    National Research Council Canada - National Science Library

    Dong-Yu Guo Xia-Wei Wang Nan Hong Yang-Shun Gu

    2016-01-01

    ...) of Leber hereditary optic neuropathy(LHON) on visual prognosis. METHODS: After a systematic literature search,all relevant studies evaluating the association between the three primary mutations of LHON and visual prognosis...

  7. [Small cell lung cancer associated with subacute sensori-motor neuropathy in a patient whose symptoms subsided during chemotherapy].

    Science.gov (United States)

    Tsushima, K; Koyama, S; Chino, M; Ichiyoshi, T

    1998-09-01

    A 71-year-old man was referred to us with diplopia, left peripheral facial nerve dysfunction, ataxic gait and dysesthesia of the extremities. Neurological examination revealed mild reduction of sensation to pinprick and light touch in the left dominant lower leg. His standing position was wide based, and he showed Romberg's sign. The patient also presented signs of left peripheral facial, bilateral abducent, and left oculomotor nerve dysfunction. Serum levels of CEA, CA 19-9, and proGRP were high. 67Gallium scintigraphy showed an accumulation of radioactivity at the hilum of the right lung, and the findings of bronchofiberscopy were compatible with the diagnosis of small cell lung cancer. Because the symptoms gradually worsened to the point that the patient could not move by himself, chemotherapy and radiotherapy were initiated 3 months after the onset of symptoms. While under chemotherapy, symptoms of neuropathy subsided and the patient was able to walk with the aid of a walking stick. Although all symptoms were indicative of carcinomatous neuropathy, no antineuronal antibodies were detected in the patient's serum by immunohistochemical techniques. However, because the lung cancer deteriorated gradually despite therapy, the patient died of respiratory failure. At autopsy, tumor metastases were found in the pericardium, left lung, both adrenal glands, right hilum lymph nodes, and mediasternal lymph nodes. No microscopic signs of metastases were found in the frontal, parietal, temporal, or occipital lobes, or in the basal ganglia, thalamus, midbrain, pons, cerebellar vermis and hemispheres, or upper medulla. Histopathologically, there was no degeneration of neuronal cell bodies in cerebellar or cervical dorsal root ganglia; however, almost total loss of myelinated fibers or variegated demyelination of myelinated fibers was observed in the anterior, lateral and posterior funiculus at both cervical segments of the spinal cord. The number of myelinated fibers was

  8. Proximal gastric motor activity in response to a liquid meal in type I diabetes mellitus with autonomic neuropathy

    NARCIS (Netherlands)

    Samsom, M.; Roelofs, J. M.; Akkermans, L. M.; van Berge Henegouwen, G. P.; Smout, A. J.

    1998-01-01

    Disordered gastric emptying occurs in 30-50% of patients with diabetes mellitus. Although the rate of gastric emptying is dependent on the integration of motor activity in different regions of the stomach, there is limited information about the function of the proximal stomach in diabetes mellitus.

  9. Penicillamin-induced neuropathy in rheumatoid arthritis

    DEFF Research Database (Denmark)

    Pedersen, P B; Hogenhaven, H

    1990-01-01

    A case of penicillamin-induced severe polyradiculopathy in rheumatoid arthritis is presented. The neuropathy was of demyelinating type, purely motor, proximal and clinically fully reversible when the drug ceased. In case of a progressive neuropathy, during penicillamin treatment, this adverse...

  10. Peripheral Neuropathy

    Science.gov (United States)

    ... Tooth disorders include extreme weakening and wasting of muscles in the lower legs and feet, gait abnormalities, loss of tendon reflexes, and numbness in the lower limbs. top How is peripheral neuropathy diagnosed? The symptoms ...

  11. Treatment of diabetic neuropathy in the lower limb

    African Journals Online (AJOL)

    The classic signs of motor neuropathy are a high medial arch, claw toes and metatarsal head prominence with fatty pad thinning. Symptoms of autonomic neuropathy in the diabetic foot usually include dry, cracked skin, nail changes, transient mottling and discoloration of the skin and cold feet. Confirmed clinical neuropathy ...

  12. A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy

    Directory of Open Access Journals (Sweden)

    Celia Zazo Seco

    2017-02-01

    Full Text Available A consanguineous family from Pakistan was ascertained to have a novel deafness-dystonia syndrome with motor regression, ichthyosis-like features and signs of sensory neuropathy. By applying a combined strategy of linkage analysis and whole-exome sequencing in the presented family, a homozygous nonsense mutation, c.4G>T (p.Glu2*, in FITM2 was identified. FITM2 and its paralog FITM1 constitute an evolutionary conserved protein family involved in partitioning of triglycerides into cellular lipid droplets. Despite the role of FITM2 in neutral lipid storage and metabolism, no indications for lipodystrophy were observed in the affected individuals. In order to obtain independent evidence for the involvement of FITM2 in the human pathology, downregulation of the single Fitm ortholog, CG10671, in Drosophila melanogaster was pursued using RNA interference. Characteristics of the syndrome, including progressive locomotor impairment, hearing loss and disturbed sensory functions, were recapitulated in Drosophila, which supports the causative nature of the FITM2 mutation. Mutation-based genetic counseling can now be provided to the family and insight is obtained into the potential impact of genetic variation in FITM2.

  13. Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations.

    Science.gov (United States)

    Echaniz-Laguna, Andoni; Geuens, Thomas; Petiot, Philippe; Péréon, Yann; Adriaenssens, Elias; Haidar, Mansour; Capponi, Simona; Maisonobe, Thierry; Fournier, Emmanuel; Dubourg, Odile; Degos, Bertrand; Salachas, François; Lenglet, Timothée; Eymard, Bruno; Delmont, Emilien; Pouget, Jean; Juntas Morales, Raul; Goizet, Cyril; Latour, Philippe; Timmerman, Vincent; Stojkovic, Tanya

    2017-05-01

    In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate the functional consequences of newly discovered variants. Among 510 unrelated patients with distal motor neuropathy, we identified mutations in HSPB1 (28 index patients/510; 5.5%) and HSPB8 (four index patients/510; 0.8%) genes. Patients have slowly progressive distal (100%) and proximal (13%) weakness in lower limbs (100%), mild lower limbs sensory involvement (31%), foot deformities (73%), progressive distal upper limb weakness (29%), mildly raised serum creatine kinase levels (100%), and central nervous system involvement (9%). We identified 12 HSPB1 and four HSPB8 mutations, including five and three not previously reported. Transmission was either dominant (78%), recessive (3%), or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser, Gly53Asp, and Gln128Arg) cause hyperphosphorylation of neurofilaments, whereas the C-terminal mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs and Ala61fs) create a premature stop codon leading to proteasomal degradation. Two mutations in HSPB8 (Lys141Met/Asn) exhibited increased binding to Bag3. We demonstrate that HSPB1 and HSPB8 mutations are a major cause of inherited motor axonal neuropathy. Mutations lead to diverse functional outcomes further demonstrating the pleotropic character of small heat shock proteins. © 2017 Wiley Periodicals, Inc.

  14. Rigid spine syndrome associated with sensory-motor axonal neuropathy resembling Charcot-Marie-Tooth disease is characteristic of Bcl-2-associated athanogene-3 gene mutations even without cardiac involvement.

    Science.gov (United States)

    Noury, Jean-Baptiste; Maisonobe, Thierry; Richard, Pascale; Delague, Valérie; Malfatti, Edoardo; Stojkovic, Tanya

    2017-02-22

    Bcl-2-associated athanogene-3 (BAG3) mutations have been described in rare cases of rapidly progressive myofibrillar myopathies. Symptoms begin in the first decade with axial involvement and contractures and are associated with cardiac and respiratory impairment in the second decade. Axonal neuropathy has been documented but usually not as a key clinical feature. We report a 24-year-old woman with severe rigid spine syndrome and sensory-motor neuropathy resembling Charcot-Marie-Tooth disease (CMT). Muscle MRI showed severe fat infiltration without any specific pattern. Deltoid muscle biopsy showed neurogenic changes and discrete myofibrillar abnormalities. Electrocardiogram and transthoracic echocardiography results were normal. Genetic analysis of a panel of 45 CMT genes showed no mutation. BAG3 gene screening identified the previously reported c.626C>T, pPro209Leu, mutation. This case indicates that rigid spine syndrome and sensory-motor axonal neuropathy are key clinical features of BAG3 mutations that should be considered even without cardiac involvement. Muscle Nerve, 2017. © 2017 Wiley Periodicals, Inc.

  15. Evaluation and Prevention of Diabetic Neuropathy

    Directory of Open Access Journals (Sweden)

    Pajouhi M

    2007-07-01

    Full Text Available Background: Diabetic neuropathy is an incapacitating disease that afflicts almost 50 percent of patients with diabetes. A late finding in type 1 diabetes, diabetic neuropathy can be an early finding in non insulin-dependent diabetes. Diabetic neuropathies are divided primarily into two groups, sensorimotor and autonomic. Patients may acquire only one type of diabetic neuropathy or may present with combinations of neuropathies, such as autonomic neuropathy or distal symmetric polyneuropathy, the latter of which the most common form. Motor deficits, orthostatic hypotension, silent cardiac ischemia, hyperhidrosis, vasomotor instability, gastroparesis, bladder dysfunction, and sexual dysfunction can also result from diabetic neuropathy. Strict control of blood sugar, combined with proper daily foot care, is essential to avoid the complications of this disorder. With the potential to afflict any part of the nervous system, diabetic neuropathy should be suspected in all patients with type 2 diabetes as well as patients who have had type 1 diabetes for over five years. Although some patients with diabetic neuropathy notice few symptoms, upon physical examination mild to moderately severe sensory loss may be noted by the physician. Idiopathic neuropathy has been known to precede the onset of type 2 diabetes.

  16. Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies

    DEFF Research Database (Denmark)

    La Morgia, C; Ross-Cisneros, F.N.; Sadun, A.A.

    2010-01-01

    Mitochondrial optic neuropathies, that is, Leber hereditary optic neuropathy and dominant optic atrophy, selectively affect retinal ganglion cells, causing visual loss with relatively preserved pupillary light reflex. The mammalian eye contains a light detection system based on a subset of retinal....... We studied the integrity of the retinohypothalamic tract in five patients with Leber hereditary optic neuropathy, in four with dominant optic atrophy and in nine controls by testing the light-induced suppression of nocturnal melatonin secretion. This response was maintained in optic neuropathy...... subjects as in controls, indicating that the retinohypothalamic tract is sufficiently preserved to drive light information detected by melanopsin retinal ganglion cells. We then investigated the histology of post-mortem eyes from two patients with Leber hereditary optic neuropathy and one case...

  17. Hereditary hyperbilirubinemias

    Directory of Open Access Journals (Sweden)

    Radlović Nedeljko

    2014-01-01

    Full Text Available Inherited disorders of bilirubin metabolism involve four autosomal recessive syndromes: Gilbert, Crigler- Najjar, Dubin-Johnson and Rotor, among which the first two are characterized by unconjugated and the second two by conjugated hyperbilirubinemia. Gilbert syndrome occurs in 2%-10% of general population, while others are rare. Except for Crigler-Najjar syndrome, hereditary hyperbilirubinemias belong to benign disorders and thus no treatment is required.

  18. Autonomic Neuropathy

    Science.gov (United States)

    ... home. Accessed April 30, 2015. Tesfaye S. Neuropathy in diabetes. Medicine. 2015;43:26. Accessed May 13, 2015. Coon E (expert opinion). Mayo Clinic, Rochester, Minn. May 14, 2015. June 06, 2015 Original article: http://www.mayoclinic.org/diseases-conditions/autonomic- ...

  19. Peripheral Neuropathy

    Science.gov (United States)

    ... exposure to toxins. One of the most common causes is diabetes mellitus. People with peripheral neuropathy generally describe the ... thyroid (hypothyroidism). In a number of cases, no cause can be identified ... include: Diabetes mellitus, especially if your sugar levels are poorly ...

  20. Autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J

    1983-01-01

    The diagnosis of autonomic neuropathy is often difficult to establish, since clinical symptoms generally appear late in the course of the disease, and may be non-specific. A number of recently developed quantifiable and reproducible autonomic nerve function tests are reviewed, with emphasis on th...

  1. Daspsone Induced Peripheral Neuropathy

    Directory of Open Access Journals (Sweden)

    P A Sarojini

    1988-01-01

    Full Text Available A 24 year old lady being treated with 300 mg of dapsone daily for dermatitits herpetiformis, developed weakness and wasting of muscles of feet with claw hand deformity and t drop, 2 months tater. Neurological examination and nerve conduction studies conformed the presence of a peripheral motor neuropathy. Dapsone was discontinued and the patient was treated with cotrimatoxazole, gluten-free diet and supportive therapy. This satisfactorily controlled the dermatological lesion without adversely affecting the resolution of her neuropthy. Symptomatic improvement reported by the patient was confirmed by EMG and nerve conduction studies.

  2. Chronic dysimmune neuropathies: Beyond chronic demyelinating polyradiculoneuropathy

    Directory of Open Access Journals (Sweden)

    Khadilkar Satish

    2011-01-01

    Full Text Available The spectrum of chronic dysimmune neuropathies has widened well beyond chronic demyelinating polyradiculoneuropathy (CIDP. Pure motor (multifocal motor neuropathy, sensorimotor with asymmetrical involvement (multifocal acquired demylinating sensory and motor neuropathy, exclusively distal sensory (distal acquired demyelinating sensory neuropathy and very proximal sensory (chronic immune sensory polyradiculopathy constitute the variants of CIDP. Correct diagnosis of these entities is of importance in terms of initiation of appropriate therapy as well as prognostication of these patients. The rates of detection of immune-mediated neuropathies with monoclonal cell proliferation (monoclonal gammopathy of unknown significance, multiple myeloma, etc. have been facilitated as better diagnostic tools such as serum immunofixation electrophoresis are being used more often. Immune neuropathies associated with malignancies and systemic vasculitic disorders are being defined further and treated early with better understanding of the disease processes. As this field of dysimmune neuropathies will evolve in the future, some of the curious aspects of the clinical presentations and response patterns to different immunosuppressants or immunomodulators will be further elucidated. This review also discusses representative case studies.

  3. Hereditary Cerebellar Ataxias: A Korean Perspective

    Directory of Open Access Journals (Sweden)

    Ji Sun Kim

    2015-05-01

    Full Text Available Hereditary ataxia is a heterogeneous disorder characterized by progressive ataxia combined with/without peripheral neuropathy, extrapyramidal symptoms, pyramidal symptoms, seizure, and multiple systematic involvements. More than 35 autosomal dominant cerebellar ataxias have been designated as spinocerebellar ataxia, and there are 55 recessive ataxias that have not been named systematically. Conducting genetic sequencing to confirm a diagnosis is difficult due to the large amount of subtypes with phenotypic overlap. The prevalence of hereditary ataxia can vary among countries, and estimations of prevalence and subtype frequencies are necessary for planning a diagnostic strategy in a specific population. This review covers the various hereditary ataxias reported in the Korean population with a focus on the prevalence and subtype frequencies as the clinical characteristics of the various subtypes.

  4. Axon Transport and Neuropathy: Relevant Perspectives on the Etiopathogenesis of Familial Dysautonomia

    OpenAIRE

    Tourtellotte, Warren G.

    2016-01-01

    Peripheral neuropathies are highly prevalent and are most often associated with chronic disease, side effects from chemotherapy, or toxic-metabolic abnormalities. Neuropathies are less commonly caused by genetic mutations, but studies of the normal function of mutated proteins have identified particular vulnerabilities that often implicate mitochondrial dynamics and axon transport mechanisms. Hereditary sensory and autonomic neuropathies are a group of phenotypically related diseases caused b...

  5. Hereditary angioedema

    DEFF Research Database (Denmark)

    Peterson, M P; Bygum, A

    2016-01-01

    We report a 64-year-old man who suffered from recurrent visible swelling attacks since the age of 20 as well as episodes with severe upper airway edema, resulting in 4 emergency tracheotomies. Eventually after 44 years he was diagnosed with hereditary angioedema (HAE) type II. The aims of this re...... of this report is to emphasize the importance of awareness concerning HAE, which does not respond to traditional anti-allergic therapy, and remind physicians to test for functional C1-INH deficiency....

  6. Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy.

    NARCIS (Netherlands)

    Collie, A.M.; Landsverk, M.L.; Ruzzo, E.; Mefford, H.C.; Buysse, K.; Adkins, J.R.; Knutzen, D.M.; Barnett, K.; Brown Jr., R.H.; Parry, G.J.; Yum, S.W.; Simpson, D.A.; Olney, R.K.; Chinnery, P.F.; Eichler, E.E.; Chance, P.F.; Hannibal, M.C.

    2010-01-01

    BACKGROUND: Genomic copy number variants have been shown to be responsible for multiple genetic diseases. Recently, a duplication in septin 9 (SEPT9) was shown to be causal for hereditary neuralgic amyotrophy (HNA), an episodic peripheral neuropathy with autosomal dominant inheritance. This

  7. Hereditary hemochromatosis

    Directory of Open Access Journals (Sweden)

    Stephen A. Geller

    2015-03-01

    Full Text Available Hereditary hemochromatosis (HH is the most commonly identified autosomal recessive genetic disorder in the white population, characterized by increased intestinal iron absorption and secondary abnormal accumulation in parenchymal organs, not infrequently accompanied by functional impairment. This entity is associated with mutations of the HFE gene (located on the short arm of chromosome 6 at location 6p22.2; closely linked to the HLA-A3 locus, which encodes the HFE protein, a membrane protein thought to regulate iron absorption by affecting the interaction between transferrin receptor and transferrin.

  8. Hereditary spherocytosis

    Directory of Open Access Journals (Sweden)

    Meenakshi Kalyan

    2014-01-01

    Full Text Available Hereditary spherocytosis (HS is a familial hemolytic disorder with marked heterogeneity of clinical features, ranging from an asymptomatic condition to a fulminant hemolytic anemia. In severe cases, the disorder may present in early childhood, but in some cases it may go unnoticed until later in adult life. We present a 32-year-old male who presented with anemia, jaundice, splenomegaly, and gallstones. Seven of his family members had similar illness in the past. The Mother died of similar illness at the age of 40. The Blood film showed spherocytosis and reticulocytosis. There was increased osmotic fragility and a negative direct coomb′s test. He was given folic acid supplements and was advised for splenectomy and cholecystectomy. This case is reported due to its rarity in Indian population.

  9. Distal acquired demyelinating symmetric (DADS) neuropathy associated with colorectal adenocarcinoma.

    Science.gov (United States)

    Ayyappan, Sujith; Day, Timothy; Kiers, Lynette

    2015-06-01

    Paraneoplastic neuropathies are well recognized as a remote effect of cancer, and subacute sensory neuronopathy is a recognized syndrome. Demyelinating neuropathies are relatively rare. Distal acquired demyelinating symmetric (DADS) neuropathy associated with lymphoproliferative disease has been reported previously. We present the association of DADS neuropathy with solid tumor. We report the clinical presentation, electrophysiology, and progress of DADS neuropathy in a patient later found to have colorectal adenocarcinoma. A patient presented with subacute onset of symmetric distal sensory and motor symptoms. Electrophysiology was typical of DADS neuropathy. Anti-MAG antibodies were initially positive at low titer, and indirect immunofluorescence analysis for anti-nuclear antibodies revealed autoantibodies to centromere nuclear protein-F (CENP-F). There was clinical and electrophysiologic resolution after tumor resection. This case describes the presentation of DADS neuropathy as a paraneoplastic syndrome in a patient later found to have colorectal adenocarcinoma. © 2014 Wiley Periodicals, Inc.

  10. Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy

    Science.gov (United States)

    Sung, Jia-Ying; Tani, Jowy; Chang, Tsui-San; Lin, Cindy Shin-Yi

    2017-01-01

    This study investigated sensory and motor nerve excitability properties to elucidate the development of diabetic neuropathy. A total of 109 type 2 diabetes patients were recruited, and 106 were analyzed. According to neuropathy severity, patients were categorized into G0, G1, and G2+3 groups using the total neuropathy score-reduced (TNSr). Patients in the G0 group were asymptomatic and had a TNSr score of 0. Sensory and motor nerve excitability data from diabetic patients were compared with data from 33 healthy controls. Clinical assessment, nerve conduction studies, and sensory and motor nerve excitability testing data were analyzed to determine axonal dysfunction in diabetic neuropathy. In the G0 group, sensory excitability testing revealed increased stimulus for the 50% sensory nerve action potential (Pdiabetic neuropathy and enable the early detection of sensory axonal abnormalities, which may provide a basis for neuroprotective therapeutic approaches. PMID:28182728

  11. Metabolic neuropathies and myopathies.

    Science.gov (United States)

    D'Amico, Adele; Bertini, Enrico

    2013-01-01

    Inborn errors of metabolism may impact on muscle and peripheral nerve. Abnormalities involve mitochondria and other subcellular organelles such as peroxisomes and lysosomes related to the turnover and recycling of cellular compartments. Treatable causes are β-oxidation defects producing progressive neuropathy; pyruvate dehydrogenase deficiency, porphyria, or vitamin B12 deficiency causing recurrent episodes of neuropathy or acute motor deficit mimicking Guillain-Barré syndrome. On the other hand, lysosomal (mucopolysaccharidosis, Gaucher and Fabry diseases), mitochondriopathic (mitochondrial or nuclear mutations or mDNA depletion), peroxisomal (adrenomyeloneuropathy, Refsum disease, sterol carrier protein-2 deficiency, cerebrotendinous xanthomatosis, α-methylacyl racemase deficiency) diseases are multisystemic disorders involving also the heart, liver, brain, retina, and kidney. Pathophysiology of most metabolic myopathies is related to the impairment of energy production or to abnormal production of reactive oxygen species (ROS). Main symptoms are exercise intolerance with myalgias, cramps and recurrent myoglobinuria or limb weakness associated with elevation of serum creatine kinase. Carnitine palmitoyl transferase deficiency, followed by acid maltase deficiency, and lipin deficiency, are the most common cause of isolated rhabdomyolysis. Metabolic myopathies are frequently associated to extra-neuromuscular disorders particularly involving the heart, liver, brain, retina, skin, and kidney. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Pathophysiology of immune-mediated demyelinating neuropathies--Part II: Neurology.

    Science.gov (United States)

    Franssen, Hessel; Straver, Dirk C G

    2014-01-01

    In the second part of this review we deal with the clinical aspects of immune-mediated demyelinating neuropathies. We describe the relationship between pathophysiology and symptoms and discuss the pathophysiology of specific disease entities, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, anti-myelin-associated glycoprotein neuropathy, and POEMS syndrome. Copyright © 2013 Wiley Periodicals, Inc.

  13. Is Pancreatic Cancer Hereditary?

    Science.gov (United States)

    ... Board Patient Education / Basics of Pancreatic Cancer Is pancreatic cancer hereditary? Cancer of the pancreas is a genetic ... found in cigarette smoke. The genetics of hereditary pancreatic cancer is a focus of research at Johns Hopkins. ...

  14. Treatment of diabetic neuropathy in the lower limb

    African Journals Online (AJOL)

    Muscular pain secondary to injury to the motor neurons can present as night cramps, spasm or a dull ache. Motor signs and symptoms include imbalance when walking and ankle weakness or even foot drop, usually asymmetrical at initial presentation. The classic signs of motor neuropathy are a high medial arch, claw toes.

  15. Chronic Inflammatory Demyelinating Polyneuropathy Manifesting as Neuropathy With Liability to Pressure Palsies: A Case Report.

    Science.gov (United States)

    Shah, Akshay; Rison, Richard A; Beydoun, Said R

    2015-12-01

    Chronic inflammatory demyelinating polyneuropathy (CIDP) is a progressive demyelinating neuropathy, which typically presents with proximal and distal neuropathic symptoms and is typically responsive to immunomodulatory therapies. Many variants have been subsequently described in the literature and have similarly shown to be responsive to immunotherapy. We present a case of a 43-year-old Middle Eastern/Arabic man presenting with symptoms of mixed sensorimotor neuropathy most evident at entrapment sites mimicking hereditary neuropathy with liability to pressure palsies. His electrodiagnostic study revealed features of acquired demyelinating neuropathy and a negative genetic workup. Alternative diagnosis of CIDP was considered in the context of symptomatic disease progression, negative genetic workup, and electrodiagnosis leading to initiation of immunotherapy with intravenous immunoglobulins. His neuropathy responded confirming our diagnosis of an inflammatory demyelinating polyneuropathy. We describe a previously unknown variant of CIDP with phenotypic characteristics of hereditary neuropathy with liability to pressure palsies and its potential for successful treatment with intravenous immunoglobulins. This case illustrates an unusual presentation of CIDP mimicking hereditary neuropathy with liability to pressure palsies.

  16. Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia.

    Science.gov (United States)

    Ylikallio, Emil; Kim, Doyoun; Isohanni, Pirjo; Auranen, Mari; Kim, Eunjoon; Lönnqvist, Tuula; Tyynismaa, Henna

    2015-10-01

    Variants in family 1 kinesin (KIF1A), which encodes a kinesin axonal motor protein, have been described to cause variable neurological manifestations. Recessive missense variants have led to spastic paraplegia, and recessive truncations to sensory and autonomic neuropathy. De novo missense variants cause developmental delay or intellectual disability, cerebellar atrophy and variable spasticity. We describe a family with father-to-son transmission of de novo variant in the KIF1A motor domain, in a phenotype of pure spastic paraplegia. Structural modeling of the predicted p.(Ser69Leu) amino acid change suggested that it impairs the stable binding of ATP to the KIF1A protein. Our study reports the first dominantly inherited KIF1A variant and expands the spectrum of phenotypes caused by heterozygous KIF1A motor domain variants to include pure spastic paraplegia. We conclude that KIF1A should be considered a candidate gene for hereditary paraplegias regardless of inheritance pattern.

  17. A novel missense variant (Gln220Arg) of GNB4 encoding guanine nucleotide-binding protein, subunit beta-4 in a Japanese family with autosomal dominant motor and sensory neuropathy.

    Science.gov (United States)

    Miura, Shiroh; Morikawa, Takuya; Fujioka, Ryuta; Noda, Kazuhito; Kosaka, Kengo; Taniwaki, Takayuki; Shibata, Hiroki

    2017-09-01

    Dominant intermediate Charcot-Marie-Tooth disease F (CMTDIF) is an autosomal dominant hereditary form of Charcot-Marie-Tooth disease (CMT) caused by variations in the guanine nucleotide-binding protein, subunit beta-4 gene (GNB4). We examined two Japanese familial cases with CMT. Case 1 was a 49-year-old male whose chief complaint was slowly progressive gait disturbance and limb dysesthesia that appeared at the age of 47. On neurological examination, he showed hyporeflexia or areflexia, distal limb muscle weakness, and distal sensory impairment with lower dominancy. Nerve conduction studies demonstrated demyelinating sensorimotor neuropathy with reduced action potentials in the lower limbs. Case 2 was an 80-year-old man, Case 1's father, who reported difficulty in riding a bicycle at the age of 76. On neurological examination, he showed areflexia in the upper and lower limbs. Distal sensory impairment in the lower limbs was also observed. Nerve conduction studies revealed mainly axonal involvement. Exome sequencing identified a novel heterozygous nonsynonymous variant (NM_021629.3:c.659T > C [p.Gln220Arg]) in GNB4 exon 8, which is known to be responsible for CMT. Sanger sequencing confirmed that both patients are heterozygous for the variation, which causes an amino acid substitution, Gln220Arg, in the highly conserved region of the WD40 domain of GNB4. The frequency of this variant in the Exome Aggregation Consortium Database was 0.000008247, and we confirmed its absence in 502 Japanese control subjects. We conclude that this novel GNB4 variant is causative for CMTDIF in these patients, who represent the first record of the disease in the Japanese population. Copyright © 2017. Published by Elsevier Masson SAS.

  18. [Diabetic neuropathy: do not only consider distal symmetrical neuropathy].

    Science.gov (United States)

    Doppler, K; Reiners, K

    2015-02-01

    Diabetic neuropathy is a common complication of diabetes mellitus. The length-dependent symmetrical sensorimotor type of neuropathy is the most prevalent form of diabetic neuropathy but other forms of diabetic neuropathy also need to be kept in mind. Their differential diagnosis is often more challenging but implicates specific forms of treatment other than improvement of metabolic control. This article gives an overview of the less frequent forms of diabetic neuropathy and discusses their impact, diagnostic and therapeutic implications. Autonomic diabetic neuropathy, diabetic small fiber neuropathy and less frequent forms of diabetic neuropathy, such as diabetic radiculoplexopathy, diabetic neuropathy of cranial nerves, therapy-induced neuropathy and alternative causes of peripheral neuropathy in patients with diabetes are described. Diagnosis of less frequent subtypes of diabetic neuropathy and differentiation towards alternative causes of peripheral neuropathy are often difficult in daily medical routine. Diagnostic clues are helpful in identifying rarer forms of diabetic neuropathy, thus enabling more specific treatment.

  19. Fifteen-day acupuncture treatment relieves diabetic peripheral neuropathy.

    Science.gov (United States)

    Tong, Yanqing; Guo, Hongyang; Han, Bing

    2010-06-01

    Our study aimed to investigate the effects of acupuncture on diabetic peripheral neuropathy. We compared 42 cases treated with acupuncture with 21 cases exposed to sham acupuncture and observed the effects on nerve conduction velocity and a variety of subjective symptoms associated with diabetic peripheral neuropathy. Three of the six measures of motor nerves, and two measures of sensory function, demonstrated significant improvement (p day treatment period in the acupuncture group, while no motor or sensory function significantly improved in the sham acupuncture group. There were also significant differences in vibration perception threshold between the groups (p neuropathy. Copyright 2010 Korean Pharmacopuncture Institute. Published by .. All rights reserved.

  20. Muscular atrophy in diabetic neuropathy

    DEFF Research Database (Denmark)

    Andersen, H; Gadeberg, P C; Brock, B

    1997-01-01

    Diabetic patients with polyneuropathy develop motor dysfunction. To establish whether motor dysfunction is associated with muscular atrophy the ankle dorsal and plantar flexors of the non-dominant leg were evaluated with magnetic resonance imaging in 8 patients with symptomatic neuropathy, in 8 non......-neuropathic patients and in 16 individually matched control subjects. In the neuropathic patients the muscle strength of the ankle dorsal and plantar flexors was reduced by 41 % as compared to the non-neuropathic patients (p ... confirmed that the atrophy predominated distally. We conclude that muscular atrophy underlies motor weakness at the ankle in diabetic patients with polyneuropathy and that the atrophy is most pronounced in distal muscles of the lower leg indicating that a length dependent neuropathic process explains...

  1. Protein misfolding and clearance in demyelinating peripheral neuropathies

    Science.gov (United States)

    Lee, Samuel M.

    2012-01-01

    Peripheral neuropathies such as Charcot-Marie-Tooth disease (CMT) are a group of neurological disorders that affect the peripheral nervous system. Although demyelinating CMT is the most prevalent hereditary peripheral neuropathy, there are currently no effective treatments for patients suffering from this disease. Recent studies by our group and others have provided a link between protein misfolding and demyelinating CMT and indicate that impairment of the proteasome and aggresome-autophagy pathways may contribute to CMT pathogenesis. These studies suggest that targeting protein quality control systems involved in cytoprotection against CMT-associated misfolded proteins could have therapeutic benefits for treating demyelinating CMT. PMID:22482025

  2. Mitochondrial abnormalities in patients with LHON-like optic neuropathies.

    Science.gov (United States)

    Abu-Amero, Khaled K; Bosley, Thomas M

    2006-10-01

    To investigate certain biochemical and molecular characteristics of mitochondria in patients with Leber hereditary optic neuropathy (LHON)-like optic neuropathies. Patients who had LHON-like optic neuropathies in both eyes were selected from neuro-ophthalmology clinics. Evaluation included clinical examination, neuroimaging, and assessment of several mitochondrial parameters in the blood, including sequencing the entire mitochondrial (mt)DNA coding region, measuring relative mtDNA content, studying mitochondrial respiratory function in some patients, and sequencing the OPA1 and OPA3 genes. Thirty-five patients (21 men and 14 women; average age at onset 19.0 +/- 8.7 years) met inclusion and exclusion criteria for LHON-like optic neuropathies with median visual acuity approximately 20/200. Other hereditary retinopathies and optic neuropathies were unlikely because of inclusion and exclusion criteria, because ERGs were normal, and because no patient had pathogenic sequence changes in the OPA1 or OPA3 genes. Compared with control subjects, these patients had more potentially pathogenic nonsynonymous mtDNA changes, greater relative mtDNA content (P LHON mutations; however, even the 29 patients without primary LHON mutations had significant evidence of mitochondrial abnormalities. Mitochondrial haplogroup distribution was similar in patients and control subjects. Primary LHON mutations are less common in patients with LHON-like optic neuropathy selected from a clinical setting than in patients with LHON from multigenerational families. The results suggest that mitochondrial dysfunction plays a role in this type of optic neuropathy whether or not primary LHON mutations are present. This information has implications for diagnostic testing and for future investigations into mechanisms of disease.

  3. [Hereditary ovarian cancer].

    Science.gov (United States)

    Zikán, M; Foretová, L; Cibula, D; Kotlas, J; Pohlreich, P

    2006-05-01

    This article reviews the topic of hereditary ovarian cancer, describes persons at risk of hereditary disposition to cancer and gives instructions for genetic counselling and molecular analysis, including contacts to specialized centres in the Czech Republic. Review. Institute of Biochemistry and Experimental Oncology, Charles University in Prague. Hereditary ovarian cancer occurs in three autosomal dominant syndromes: appropriate hereditary ovarian cancer (HOC), hereditary breast and ovarian cancer (HBOC) and hereditary non-poliposis colorectal cancer (HNPCC). Physician in practice or specialist at the clinic should focus interest on patients form families with frequent occurrence of breast and/or ovarian cancer, patients with early onset disease or tumour duplicity (breast and ovarian cancer). Hereditary disposition to ovarian (and breast) cancer could be assessed by molecular genetic analysis of two main susceptibility genes BRCA1 and BRCA2, or other genes in families with diverse tumours. Molecular genetic analysis should be in any cases indicated by experienced clinical genetic. In the Czech Republic, the consensus of genetic and clinical care of risk patients was published and specialized centres for families with hereditary predisposition were settled in Prague and Brno. Persons with hereditary susceptibility to cancer constitute noted group where painstaking dispensarisation and preventive care may prevent malignancy or detect it in the early stage.

  4. MR imaging of trigeminal neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Si Yeon; Yoon, Pyeong Ho; Chung, Jin Il; Lee, Seung Ik; Kim, Dong Ik [Yonsei Univ. College of Medicine, Seoul (Korea, Republic of)

    2001-03-01

    The trigeminal nerve is the largest of the cranial nerves and has both sensory and motor functions. It can be divided into proximal (brainstem, preganglionic, gasserian ganglion, and cavernous sinus) and distal (extracranial opthalmic, maxillary, and mandibular) segments. Patients with trigeminal neuropathy present with a wide variety of symptoms, and lesions producing those symptoms may occur anywhere along the protracted course of the trigeminal nerve, from its distal facial branches to its nuclear columns in the brainstem. The purpose of this article is to illustrate the normal anatomy of the trigeminal nerve and associated various pathologic conditions. These are arranged anatomically according to their site of interaction with it.

  5. Neuronal involvement in cisplatin neuropathy

    DEFF Research Database (Denmark)

    Krarup-Hansen, A; Helweg-Larsen, Susanne Elisabeth; Schmalbruch, H

    2007-01-01

    Although it is well known that cisplatin causes a sensory neuropathy, the primary site of involvement is not established. The clinical symptoms localized in a stocking-glove distribution may be explained by a length dependent neuronopathy or by a distal axonopathy. To study whether the whole neuron...... of large dorsal root ganglion cells. Motor conduction studies, autonomic function and warm and cold temperature sensation remained unchanged at all doses of cisplatin treatment. The results of these studies are consistent with degeneration of large sensory neurons whereas there was no evidence of distal...

  6. Avaliação das perdas sensório-motoras do pé e tornozelo decorrentes da neuropatia diabética Assessment of motor sensory losses in the foot and ankle due to diabetic neuropathy

    Directory of Open Access Journals (Sweden)

    ICN Sacco

    2007-02-01

    Full Text Available OBJETIVOS: Identificar déficits sensório-motores de pés de pacientes diabéticos neuropatas e comparar os déficits do grupo neuropata com um grupo de sujeitos saudáveis. MÉTODO: 49 diabéticos neuropatas (GD e 22 controles foram submetidos a um protocolo de três estágios: (1 entrevista por meio de questionário, que caracterizou a neuropatia e sintomas, (2 avaliação da função muscular, amplitude de movimentos e testes funcionais dos pés e tornozelos, (3 avaliação da sensibilidade tátil e térmica. Os grupos foram comparados por meio dos testes Qui-quadrado, Mann-Withney e Teste T (pOBJECTIVE: To identify motor sensory deficits in the feet of neuropathic diabetic patients and compare their deficits with a group of healthy subjects. METHOD: 49 neuropathic diabetics (group NG and 22 controls (group CG underwent a three-stage protocol: (1 an interview using a questionnaire to characterize the neuropathy and symptoms; (2 assessment of muscle function and range of motion, and functional tests on the feet and ankles; (3 assessment of tactile and thermal sensitivity. The groups were compared using the chi-squared, Mann-Whitney and Student t tests (p<0.05. RESULTS: NG presented significant losses of tactile and thermal sensitivity in comparison with CG, especially in the heels (49.0% of NG and 97.3% of CG. Muscle function was decreased in NG, with predominance of loss of grade 5. The muscles most affected were the interossei (23.4%, extensor hallucis (42.5% and triceps surae (43.2%, while all muscle function was preserved in CG. All ranges of motion in NG were reduced in comparison with CG. The functional tests on the ankles in NG presented a decrease of around 50%. CONCLUSION: There were significant differences between the groups with regard to sensitivity, muscle function, range of motion and functional losses. These differences can be attributed to the diabetic neuropathy.

  7. Genetics Home Reference: hereditary angioedema

    Science.gov (United States)

    ... named? Additional Information & Resources MedlinePlus (2 links) Encyclopedia: Hereditary angioedema Health Topic: Vascular Diseases Genetic and Rare Diseases Information Center (1 link) Hereditary ...

  8. Coexistence of Factor VII Deficiency and Hereditary Spastic Paraplegia in Two Siblings

    Directory of Open Access Journals (Sweden)

    Hortensia De la Corte-Rodriguez

    2016-01-01

    Full Text Available We present the case of two patients aged 12 years and 7 years who were referred to our hospital for factor VII deficiency inherited in an autosomal recessive pattern, who had suffered from previous multiple joint haemarthroses. They presented with fine motor symptoms and difficulty in walking. During physical examination we observed neurological symptoms (general hypotonia, muscular hypotrophy, exaggerated tendon reflexes, pes cavus, and spastic gait. Given that the symptoms were not justified by the deficiency of coagulation factor VII and on suspicion of hereditary spastic paraplegia (HSP, tests were carried out. Findings from the tests confirmed the diagnosis of HSP (axonal degeneration of the central motor pathway and pyramidal tracts, further complicated by mixed neuropathy. This disease was also inherited in an autosomal recessive pattern with no direct genetic association with factor VII deficiency. Neurological symptoms had gone unnoticed due to a history of multiple joint haemarthrosis; musculoskeletal examination led to a satisfactory differential diagnosis. Haematological prophylaxis was commenced with rFVIIa at 30 mcg/kg, three days per week. A rehabilitation programme was prescribed so that the patient could remain independent for as long as possible, based on orthosis, physiotherapy, and occupational therapy. Response to treatment is currently satisfactory and no new bleeding has presented. As far as we are aware, the coexistence of these two diseases (factor VII deficiency and HSP has not been previously reported in the literature.

  9. Optic and auditory pathway dysfunction in demyelinating neuropathies.

    Science.gov (United States)

    Knopp, M; Leese, R J; Martin-Lamb, D; Rajabally, Y A

    2014-07-01

    The involvement of optic and auditory pathways has rarely been studied in demyelinating polyneuropathies. We here aimed to study this further in a cohort of patients with acquired and gentic demyelinating neuropathy. We studied eight patients with hereditary neuropathy with liability to pressure palsies (HNPP), six with Charcot-Marie-Tooth disease type 1A (CMT1A), ten with chronic inflammatory demyelinating polyneuropathy (CIDP) and seven with antimyelin-associated glycoprotein (MAG) neuropathy using visual evoked potentials and brainstem auditory evoked potentials. Optic pathway dysfunction was detected in 6/7 anti-MAG neuropathy patients, about half of those with CIDP and HNPP, but only in 1/6 patients with CMT1A. Peripheral auditory nerve dysfunction appeared common in all groups except HNPP. Brainstem involvement was exceptional in all groups. We conclude optic nerve involvement may be frequent in all demyelinating polyneuropathies, particularly anti-MAG neuropathy, except in CMT1A. Peripheral auditory nerves may be spared in HNPP possibly due to absence of local compression. Evidence for central brainstem pathology appeared infrequent in all four studied neuropathies. This study suggests that acquired and genetic demyelinating polyneuropathies may be associated with optic and auditory nerve involvement, which may contribute to neurological disability, and require greater awareness. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. HEREDITARY BREAST CANCER

    Directory of Open Access Journals (Sweden)

    E. M. Bit-Sava

    2013-01-01

    Full Text Available Hereditary breast cancer occurs in 5–20 % of cases and it is associated with inherited mutations in particular genes, such as BRCA1 и BRCA2 in most cases. The CHEK2, PTEN, TP53, ATM, RAD51, BLM, PALB2, Nbs genes are associated with low and median risks ofdeveloping breast cancer. Molecular genetic studies identify germinal mutations underlying hereditary breast cancer. In most cases hereditary breast cancer refers to triple-negative phenotype, which is the most aggressive type of breast cancer, that does not express the genes for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2. The review presents the diagnostic and treatment methods of hereditary breast cancer. Clinical-morphological aspects allow the new diagnostic and treatment methods of hereditary breast cancer to be identified. Poly (ADP-ribose polymerase (PARP inhibitors demonstrate the potential for effective treatment of BRCA-associated breast cancer.

  11. Diabetic neuropathy: Part 2

    National Research Council Canada - National Science Library

    Gupta, Anu; Gupta, Yashdeep

    2014-01-01

    To conclude, effective management of hyperglycaemia, symptom control, and prevention of foot ulcers and infection through screening and surveillance remain mainstays of diabetic neuropathy management...

  12. Multifocal sensory demyelinating neuropathy: Report of a case.

    Science.gov (United States)

    Oh, Shin J

    2017-10-01

    Multifocal sensory demyelinating neuropathy has not been adequately reported in the literature. A 42-year-old man with numbness of the left hand for 3 years and of the right hand for 6 months had a pure multifocal sensory neuropathy involving both hands, most prominently affecting 2-point discrimination, number writing, and object recognition of the left hand. Near-nerve needle sensory and mixed nerve conduction studies were performed on the left ulnar nerve. Studies of the left ulnar nerve documented a demyelinating neuropathy characterized by temporal dispersion and marked decrease in the amplitudes of the sensory and mixed compound nerve potentials in the above-elbow-axilla segment. With intravenous immunoglobulin treatment, there was improvement in his neuropathic condition. In this study I describe a case of multifocal sensory demyelinating neuropathy as a counterpart of multifocal motor neuropathy. Muscle Nerve 56: 825-828, 2017. © 2016 Wiley Periodicals, Inc.

  13. Knockdown of Pnpla6 protein results in motor neuron defects in zebrafish

    Directory of Open Access Journals (Sweden)

    Yang Song

    2013-03-01

    Mutations in patatin-like phospholipase domain containing 6 (PNPLA6, also known as neuropathy target esterase (NTE or SPG39, cause hereditary spastic paraplegia (HSP. Although studies on animal models, including mice and Drosophila, have extended our understanding of PNPLA6, its roles in neural development and in HSP are not clearly understood. Here, we describe the generation of a vertebrate model of PNPLA6 insufficiency using morpholino oligonucleotide knockdown in zebrafish (Danio rerio. Pnpla6 knockdown resulted in developmental abnormalities and motor neuron defects, including axon truncation and branching. The phenotypes in pnpla6 knockdown morphants were rescued by the introduction of wild-type, but not mutant, human PNPLA6 mRNA. Our results also revealed the involvement of BMP signaling in pnpla6 knockdown phenotypes. Taken together, these results demonstrate an important role of PNPLA6 in motor neuron development and implicate overexpression of BMP signaling as a possible mechanism underlying the developmental defects in pnpla6 morphants.

  14. Propylthiouracil and peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Valentina Van Boekel

    1992-06-01

    Full Text Available Peripheral neuropathy is a rare manifestation in hyperthyroidism. We describe the neurological manifestations of a 38 year old female with Graves' disease who developed peripheral neuropathy in the course of her treatment with propylthiouracil. After the drug was tapered off, the neurological signs disappeared. Therefore, we call attention for a possible toxic effect on peripheral nervous system caused by this drug.

  15. Nuclear matrix proteins and hereditary diseases.

    Science.gov (United States)

    Sjakste, N; Sjakste, T

    2005-03-01

    The review summarizes literature data on alterations of structure or expression of different nuclear matrix proteins in hereditary syndromes. From the point of view of involvement of nuclear matrix proteins in etiology and pathogenesis of the disease hereditary pathologies can be classified in pathologies with pathogenesis associated with defects of nuclear matrix proteins and pathologies associated to changes of the nuclear matrix protein spectrum. The first group includes laminopathies, hereditary diseases with abnormal nuclear-matrix associated proteins and triplet extension diseases associated with accumulation of abnormal proteins in the nuclear matrix. Laminopathies are hereditary diseases coupled to structural defects of the nuclear lamina. These diseases include Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy (DCM) with conduction system disease, familial partial lipodystrophy (FPLD), autosomal recessive axonal neuropathy (Charcot-Marie-Tooth disorder type 2, CMT2), mandibuloacral dysplasia (MAD), Hutchison Gilford Progeria syndrome (HGS), Greenberg Skeletal Dysplasia, and Pelger-Huet anomaly (PHA). Most of them are due to mutations in the lamin A/C gene, one - to mutations in emerin gene, some are associated with mutations in Lamin B receptor gene. In Werner's, Bloom's, Cockayne's syndromes, Fanconi anemia, multiple carboxylase deficiency mutations in nuclear matrix protein or enzyme gene lead to deficient DNA repair, abnormal regulation of cell growth and differentiation or other specific metabolic functions. Proteins with a long polyglutamic tract synthesized in the cells of patients with dentato-rubral and pallido-luysian atrophy, myotonic dystrophy and Huntington disease interfere with transcription on the nuclear matrix. Down's syndrome is a representative of the group of diseases with altered nuclear matrix protein spectrum.

  16. Pupillometric evaluation of the melanopsin containing retinal ganglion cells in mitochondrial and non-mitochondrial optic neuropathies

    DEFF Research Database (Denmark)

    Ba-Ali, Shakoor; Lund-Andersen, Henrik

    2017-01-01

    of pupillary light reflex is primarily driven by the ipRGCs. Optic neuropathies i.e. Leber hereditary optic neuropathy (LHON), autosomal dominant optic atrophy (ADOA), nonarteritic anterior ischemic optic neuropathy (NAION), glaucoma, optic neuritis and idiopathic intracranial hypertension (IIH) are among...... the diseases, which have been subject to pupillometric studies. The ipRGCs are differentially affected in these various optic neuropathies. In mitochondrial optic neuropathies, the ipRGCs are protected against degeneration, whereas in glaucoma, NAION, optic neuritis and IIH the ipRGCs are damaged. Here, we...... will review the results of pupillometric, histopathological and animal studies evaluating the ipRGCs in mitochondrial and non-mitochondrial optic neuropathies....

  17. Genetic and phenotypic characterization of complex hereditary spastic paraplegia.

    Science.gov (United States)

    Kara, Eleanna; Tucci, Arianna; Manzoni, Claudia; Lynch, David S; Elpidorou, Marilena; Bettencourt, Conceicao; Chelban, Viorica; Manole, Andreea; Hamed, Sherifa A; Haridy, Nourelhoda A; Federoff, Monica; Preza, Elisavet; Hughes, Deborah; Pittman, Alan; Jaunmuktane, Zane; Brandner, Sebastian; Xiromerisiou, Georgia; Wiethoff, Sarah; Schottlaender, Lucia; Proukakis, Christos; Morris, Huw; Warner, Tom; Bhatia, Kailash P; Korlipara, L V Prasad; Singleton, Andrew B; Hardy, John; Wood, Nicholas W; Lewis, Patrick A; Houlden, Henry

    2016-07-01

    generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35) (4/97) and two in ZFYVE26/SPG15 Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson's disease-associated gene ATP13A2, neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

  18. Genetic and phenotypic characterization of complex hereditary spastic paraplegia

    Science.gov (United States)

    Kara, Eleanna; Tucci, Arianna; Manzoni, Claudia; Lynch, David S.; Elpidorou, Marilena; Bettencourt, Conceicao; Chelban, Viorica; Manole, Andreea; Hamed, Sherifa A.; Haridy, Nourelhoda A.; Federoff, Monica; Preza, Elisavet; Hughes, Deborah; Pittman, Alan; Jaunmuktane, Zane; Brandner, Sebastian; Xiromerisiou, Georgia; Wiethoff, Sarah; Schottlaender, Lucia; Proukakis, Christos; Morris, Huw; Warner, Tom; Bhatia, Kailash P.; Korlipara, L.V. Prasad; Singleton, Andrew B.; Hardy, John; Wood, Nicholas W.; Lewis, Patrick A.

    2016-01-01

    generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35) (4/97) and two in ZFYVE26/SPG15. Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson’s disease-associated gene ATP13A2, neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes. PMID:27217339

  19. ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia

    OpenAIRE

    Cooper, Helen M.; Yang, Yang; Ylikallio, Emil; Khairullin, Rafil; Woldegebriel, Rosa; Lin, Kai-Lan; Euro, Liliya; Palin, Eino; Wolf, Alexander; Trokovic, Ras; Isohanni, Pirjo; Kaakkola, Seppo; Auranen, Mari; Lonnqvist, Tuula; Wanrooij, Sjoerd

    2017-01-01

    Abstract De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G?>?A (p.G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral...

  20. Hereditary Neuropathy with Liability to Pressure Palsies: A Clinical ...

    African Journals Online (AJOL)

    Sample from a 16th individual, who was not examined, was insufficient. Conclusion This study is the first report of the existence of HNPP in South Africa. Cases are probably being missed. The correct diagnosis is important, as with appropriate measures and patient education, disability can be significantly reduced. Résumé

  1. [Past, present, and future in Leber's hereditary optic neuropathy].

    Science.gov (United States)

    Oguchi, Y

    2001-12-01

    Leber's disease is a disease of optic atrophy first reported by Theodor Leber in 1871. Since then, 130 years have passed. Recently, several new findings about the pathology, causes, and heredity of this disease have been made. In 1988 Wallace and others reported a new mutation of 11778 base pairs of mtDNA of patients with Leber's disease. Since then, the study of this disease has progressed remarkably. In this review clinical studies on Leber's disease which were carried out in our department from 1990 are summarized. 1. Genetic diagnosis and clinics Two hundred and twenty-four cases were examined, including patients at our hospital, for the 8 years between 1990 and 1998. Among them, 72 cases were diagnosed as Leber's disease. There were 3 cases (4%) of 3460 mutations, 63 cases(83%) of 11778 mutations, and 6 cases(8%) of 14484 mutations as primary mutations. The reasons for performing the genetic diagnosis were mostly the need for a definite diagnosis of Leber's disease and research on the genesis of optic nerve atrophy of unknown origin. Concerning the secondary mutations, it was confirmed that these mutations were polymorphic as seen in European and American patients. There is a problem of heteroplasmy about the mtDNA mutation. We developed a simple and exact method to evaluate heteroplasmy by using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). In a study of peripheral blood samples in one family, Leber's disease does not appear under conditions of less than 60% mtDNA mutation. As for the three kinds of mutation in Leber's disease, cases of recovery of a visual acuity of 0.3 and above were only 7% in 11778 mutations, but 38% in 3460 mutations and 50% in 14484 mutations. It is assumed that visual prognosis depends on the kind of mutation. 2. Characteristics of visual evoked potential(VEP) In pattern VEP in the acute stage, latency was not delayed very much, but the amplitude was low. On the other hand, in the acute stage of optic neuritis, the latency was very much delayed and the amplitude was diminished. Therefore, I deduced that not only demyelination of the optic nerve fibers but also papilla-macula bundle defects may play an important role. In flash VEP, only the amplitude was low, but latency was normal. 3. Image analysis of the optic nerve In high resolution T2-weighted fast spin-echo magnetic resonance imaging(MRI), the image of the optic nerve can be clearly demonstrated within a short operation time. In MRI in the acute stage of Leber's disease, the image of the optic nerve appeared almost normal. But in the course of time, patients with Leber's disease showed markedly high signals in the optic nerve on the T2-weighted fast spin-echo MRI, and in the atrophic stage the image of the optic nerve showed thinning. The results in this study support the hypothesis that a primary lesion in Leber's disease may be intraocular. 4. Possibility of therapy at the present time The effectiveness of using idebenone combined with vitamin B2, vitamin C, and isopropyl unoprostone(Rescula) for recovery of the circulation of the optic nerve head for patients in the acute stage was compared with untreated patients. In patients with visual acuity of 0.3 and more, there was no statistical difference between the two groups. The recovery interval up to 0.3 was significantly shorter in the treated group than in the untreated group. I suggest that this kind of treatment may aid spontaneous recovery. Among 15 cases of Leber's disease which occurred in the patients teens, at least one eye in 8 cases(53%) recovered to 0.3 or more. Among the 8 recovered cases, 5 cases were from the treated group. On the other hand, 6 cases were treated and 5 cases recovered visual acuity. It is said that the patients developing the disease at younger ages have a tendency toward visual recovery. Pharmacological treatment can aid recovery. 5. Visual function after the recovery of visual acuity The recovery of visual acuity in Leber's disease has the characteristics of fenestrated central scotoma. The visual acuity can be recovered by the appearance of a small part of sensitive area inside the absolute central scotoma. This phenomenon coincides with the results of VEP which does not recover in spite of recovery of vision. Good visual acuity or bad visual acuity depends not only on the recovery of the total area of the central part but on the existence of an area with good sensitivity. In the results of a Humphrey visual field analyzer(10-2) obtained from 8 recovering patients, the part nasal to the fovea was more sensitive than the temporal area. In the early stage of visual recovery, scanning laser ophthalmoscope(SLO) microperimetry can detect this sensitive area, and with the enlargement of this sensitive area, the Humphrey visual field analyzer(10-2) can also detect this recovery area. 6. Strategy for gene therapy We have succeeded in cloning a human retina-specific amine oxidase gene which was found specifically in retinal ganglion cells. By using this promoter, we are now developing a vector specific to the ganglion cells. The fact that there is spontaneous recovery shows the possibility that some papillamacular bundle may exist. In Leber's disease, retinal ganglion cells may die from the mechanism of apoptosis. Therefore it may be possible to treat this disease by transferring the apoptosis block gene to ganglion cells for protection, and to protect the cells from death by apoptosis.

  2. Genetics Home Reference: hereditary sensory and autonomic neuropathy type IE

    Science.gov (United States)

    ... caused by impaired function of nerve cells called sensory neurons, which transmit information about sensations such as pain, ... resulting in abnormalities in the maintenance of the neurons that make up the nervous system. However, it is not ... DNMT1 Related Information ...

  3. Genetics Home Reference: hereditary sensory and autonomic neuropathy type II

    Science.gov (United States)

    ... condition that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, ... in the cells of the nervous system, including sensory neurons. The mutations involved in HSAN2A result in an ...

  4. Genetics Home Reference: hereditary sensory and autonomic neuropathy type V

    Science.gov (United States)

    ... condition that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, ... development and survival of nerve cells (neurons), including sensory neurons. The NGFβ protein functions by attaching (binding) to ...

  5. Antiretroviral therapy-induced Leber's hereditary optic neuropathy

    African Journals Online (AJOL)

    2014-06-01

    Jun 1, 2014 ... The rest of his neurological examination was normal, and standard haematological, biochemical and CSF examination tests were normal. His CD4+ count was 615 cells/µl and viral load was 27 copies/ml. MRI of the brain and orbits was normal, as was his chest radiograph. The VEP P100 wave amplitudes.

  6. Learning about Hereditary Hemochromatosis

    Science.gov (United States)

    Skip to main content Learning About Hereditary Hemochromatosis Enter Search Term(s): Español Research Funding An Overview Bioinformatics Current Grants Education and Training Funding Extramural Research ...

  7. Hereditary fructose intolerance

    Science.gov (United States)

    Fructosemia; Fructose intolerance; Fructose aldolase B-deficiency; Fructose-1, 6-bisphosphate aldolase deficiency ... substances build up in the liver. Hereditary fructose intolerance is inherited, which means it can be passed ...

  8. Treatment of inflammatory and paraproteinemic neuropathies.

    Science.gov (United States)

    Monaco, Salvatore; Turri, Emanuela; Zanusso, Gianluigi; Maistrello, Barbara

    2004-06-01

    Acquired demyelinating and inflammatory neuropathies encompass a number of acute and chronic autoimmune conditions characterized by variable degrees of clinical involvement. These disorders, including Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), and paraprotein-associated neuropathy, have an overall annual incidence of 2-4/100,000 worldwide and are potentially treatable. Over the last few years, several investigations have helped clarify the pathogenesis of immune neuropathies and the definition of molecular targets involved in these diseases, thus providing firmer grounds for treatment with classical immunosuppressive drugs and new biological agents. In GBS and related variants, which are characterized by cellular inflammation and alterations of the blood-nerve barrier, randomized clinical trials show that plasma exchange (PE) and intravenous immunoglobulin (IVIg) are equally effective as disease-modifying treatments, although IVIg has been adopted as the favourite treatment in most centres. In CIDP, controlled clinical trials have established the efficacy of oral prednisone, PE and IVIg, with intermittent IVIg treatment or corticosteroids being usually preferred. Adding azathioprine can help keep lower the required dose of prednisone, while other immunosuppressive agents, such as cyclophosphamide and cyclosporin A may have side effects, limiting their use to selected cases. Currently, the efficacy of interferon beta and alfa is under evaluation. Controlled trials support the view that IVIg is the treatment of choice in MMN. Patients resistant to IVIg administration may benefit of treatments which deplete B cells, such as cyclophosphamide and rituximab. Demyelinating neuropathies associated with circulating paraproteins are clinically heterogeneous, depending on the reactivity and type of the monoclonal (M) protein. In many cases, neuropathies associated with IgM M proteins are

  9. [Hereditary kidney diseases in children].

    Science.gov (United States)

    Zhang, Yan-qin; Ding, Jie; Wang, Fang; Zhang, Hong-wen

    2013-04-18

    About 10 to 15 percent of kidney diseases are inherited or related to genetic factors. While, hereditary kidney diseases have no specific clinical manifestations and react poorly to the therapy, as a result, about 30 percent of hospitalized children with chronic renal failure is due to hereditary kidney diseases in our country. Hereditary kidney diseases are related to many genes. Molecular genetic analysis plays an important role in the diagnosis and prenatal diagnosis of hereditary kidney diseases. Our group have made a series of research in hereditary kidney diseases for nearly 30 years. Here we review the research work and the main results in hereditary kidney diseases of our group.

  10. Correlation of Michigan neuropathy screening instrument, United Kingdom screening test and electrodiagnosis for early detection of diabetic peripheral neuropathy.

    Science.gov (United States)

    Fateh, Hamid R; Madani, Seyed Pezhman; Heshmat, Ramin; Larijani, Bagher

    2015-01-01

    Almost half of Diabetic Peripheral Neuropathies (DPNs) are symptom-free. Methods including questionnaires and electrodiagnosis (EDx) can be fruitful for easy reach to early diagnosis, correct treatments of diabetic neuropathy, and so decline of complications for instance diabetic foot ulcer and prevention of high costs. The goal of our study was to compare effectiveness of the Michigan neuropathy screening instrument (MNSI), United Kingdom screening test (UKST) and electrophysiological evaluation in confirming diabetic peripheral neuropathy. One hundred twenty five known diabetes mellitus male and female subjects older than 18 with or without symptoms of neuropathy comprised in this research. All of them were interviewed in terms of demographic data, lipid profile, HbA1C, duration of disease, and history of retinopathy, so examined by Michigan neuropathy screening instrument (MNSI), United Kingdom screening test (UKST), and nerve conduction studies (NCS). The collected data were analyzed by SPSS software 18. One hundred twenty five diabetic patients (70 female, 55 male) were recruited in this study with a mean age of 58.7 ± 10.2, and mean duration of diabetes was 10.17 ± 6.9 years. The mean neuropathy score of MNSI and UKST were 2.3 (1.7) and 4.16 (2.9), respectively. Each instrument detected the peripheral neuropathy in 78 (69 %) and 91 (73 %) of patients, respectively. There was a significant relationship between number of neuropathies and mean of diabetes duration and development of retinopathy in both questionnaire evaluations and NCS. By nerve conduction study, neuropathy was detected in 121 (97 %) diabetic patients were reported in order 15 (12 %) mononeuropathy (as 33 % sensory and 67 % motor neuropathy) and 106 (85 %) polyneuropathy (as 31 % motor and 69 % sensorimotor neuropathy). As regards NCS is an objective, simple, and non-invasive tool and also can determine level of damage and regeneration in peripheral nerves, this study

  11. Detection of antibodies in neuropathy patients by synthetic GM1 mimics

    NARCIS (Netherlands)

    Pukin, A.; Jacobs, B.C.; Tio-Gillen, A.P.; Gilbert, M.; Endtz, H.P.; Belkum, van A.; Visser, G.M.; Zuilhof, H.

    2011-01-01

    Antibodies to the ganglioside GM1 are associated with various forms of acute and chronic immune-mediated neuropathy, including Guillain–Barré syndrome (GBS) and multifocal motor neuropathy. In diagnostics and research, these antibodies are usually detected by GM1 preparations derived from bovine

  12. Painful Traumatic Trigeminal Neuropathy.

    Science.gov (United States)

    Rafael, Benoliel; Sorin, Teich; Eli, Eliav

    2016-08-01

    This article discusses neuropathic pain of traumatic origin affecting the trigeminal nerve. This syndrome has been termed painful traumatic trigeminal neuropathy by the International Headache Society and replaces atypical odontalgia, deafferentation pain, traumatic neuropathy, and phantom toothache. The discussion emphasizes the diagnosis and the early and late management of injuries to the trigeminal nerve and subsequent painful conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Hereditary cancer syndromes.

    Science.gov (United States)

    Rahner, Nils; Steinke, Verena

    2008-10-01

    Persons carrying mutations for hereditary cancer syndromes are at high risk for the development of tumors at an early age, as well as the synchronous or metachronous development of multiple tumors of the corresponding tumor spectrum. The genetic causes of many hereditary cancer syndromes have already been identified. About 5% of all cancers are part of a hereditary cancer syndrome. Selective literature review, including evidence-based guidelines and recommendations. Clinical criteria are currently available according to which many hereditary cancer syndromes can be diagnosed or suspected and which point the way to further molecular genetic analysis. A physician can easily determine whether these criteria are met by directed questioning about the patient's personal and family medical history. The identification of the causative germ line mutation in the family allows confirmation of the diagnosis in the affected individual and opens up the option of predictive testing in healthy relatives. Mutation carriers for hereditary cancer syndromes need long-term medical surveillance in a specialized center. It is important that these persons should be identified in the primary care setting and then referred for genetic counseling if molecular genetic testing is to be performed in a targeted, rational manner.

  14. [A amyotrophic lateral sclerosis (ALS) 4 family misdiagnosed as hereditary spastic paraplegia-a case report].

    Science.gov (United States)

    Taniguchi, Takaki; Hokezu, Youichi; Okada, Takashi; Ishibashi, Masato; Hashiguchi, Akihiro; Matsuura, Eiji; Takashima, Hiroshi

    2017-11-25

    We report a 44 years old man with slowly progressive muscular atrophy of the extremities for over 30 years. He experienced difficulty in walking in his 10's and was diagnosed as hereditary spastic paraplegia (HSP) in his 20's. And then, muscle atrophy of the extremities slowly progressed especially in his distal muscles. Sensory axonal neuropathy was detected with sural nerve biopsy. His father and uncle have been diagnosed as HSP in their early days. His father noticed weakness of his leg in his 20's. He lost motor function of the leg in his 60's. In addition, marked disturbance of thermal sensation, vibration, and sense of position were found by physical examination. Our genetic study detected senataxin (SETX) gene mutation (c.8C>T,p.T3I) in the blood of those two patients, and they had been identified as family cases of amyotrophic lateral sclerosis (ALS) 4. As clinical symptoms of ALS4 would be similar to those of HSP at the onset, we suggest considering ALS4 in seeing patients with HSP without gene diagnosis.

  15. Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10.

    Science.gov (United States)

    Goizet, Cyril; Boukhris, Amir; Mundwiller, Emeline; Tallaksen, Chantal; Forlani, Sylvie; Toutain, Annick; Carriere, Nathalie; Paquis, Véronique; Depienne, Christel; Durr, Alexandra; Stevanin, Giovanni; Brice, Alexis

    2009-02-01

    Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower extremities. Only a few different mutations in the SPG10 gene, KIF5A, have been described in pure dominant forms of the disease. We sequenced the motor domain of KIF5A in a large panel of 205 European HSP patients with either pure or complicated forms of the disease. We identified eight different heterozygous missense mutations, seven novels, in eight different families of French origin. Residue R280 was a mutational hot spot. Interestingly, the patients in 7/8 families had a complex phenotype, with peripheral neuropathy, severe upper limb amyotrophy (Silver syndrome-like), mental impairment, parkinsonism, deafness and/or retinitis pigmentosa as variably associated features. We report the largest series of SPG10 families described so far, which extends both the mutational spectrum of the disease and its phenotype, which now includes complicated forms of HSP. SPG10 mutations were found in 10% of our complicated forms of HSP, suggesting that mutations in KIF5A represent the major cause of complicated AD-HSP in France. (c) 2008 Wiley-Liss, Inc.

  16. Longitudinal Patterns of Thalidomide Neuropathy in Children and Adolescents.

    Science.gov (United States)

    Liew, Wendy K M; Pacak, Christina A; Visyak, Nicole; Darras, Basil T; Bousvaros, Athos; Kang, Peter B

    2016-11-01

    To characterize the longitudinal clinical and electrophysiological patterns of thalidomide neuropathy in children and adolescents. Retrospective analysis of clinical records at a tertiary care children's hospital, including serial electrophysiological studies. Sixteen patients aged 6-24 years received thalidomide to treat Crohn's disease from 2002 to 2012. Nine subjects had electrophysiological evidence of sensorimotor axonal polyneuropathy, 8 of whom had sensory and/or motor symptoms. The patients with polyneuropathy received thalidomide for 5 weeks to 52 months, with cumulative doses ranging from 1.4 to 207.7 g. All subjects with cumulative doses greater than 60 g developed polyneuropathy, and 4 of the 5 subjects who received thalidomide for more than 20 months developed polyneuropathy. The 7 subjects who had normal neurophysiological studies received therapy for 1 week to 25 months, with cumulative doses ranging from 0.7 to 47 g. In contrast to some previous reports, several patients had sensorimotor polyneuropathies, rather than pure sensory neuropathies. In patients with neuropathy who received therapy for more than 24 months and had 3 or more electromyography studies, the severity of the neuropathy plateaued. Factors in addition to the total dose may contribute to the risk profile for thalidomide neuropathy, including pharmacogenetic susceptibilities. The severity of the neuropathy does not worsen relentlessly. Children, adolescents, and young adults receiving thalidomide should undergo regular neurophysiological studies to monitor for neuropathy. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Glycoconjugates as target antigens in peripheral neuropathies

    Directory of Open Access Journals (Sweden)

    Ljubica Suturkova

    2014-12-01

    Full Text Available Identification and characterization of antigens present at the human peripheral nerve is a great challenge in the field of neuroimmunology. The latest investigations are focused on the understanding of the biology of glycoconjugates present at the peripheral nerve, and their immunological reactivity. Increased titers of antibodies that recognize carbohydrate determinants of glycoconjugates (glycolipids and glycoproteins are associated with distinct neuropathic syndromes. There is considerable cross-reactivity among anti-ganglioside antibodies, resulting from shared oligosaccharide epitopes, possibly explaining the overlap in syndromes observed in many affected patients. Sera from patients with neuropathies (GBS, chronic inflammatory demielynating polyneuropathy - CIDP, multifocal motor neuropathy - MMN, cross-react with glycoproteins isolated from human peripheral nerve and from Campylobacter jejuni O:19. The frequency of occurrence of antibodies against these glycoproteins is different, depending of the type of neuropathy. Identification of the cross-reactive glycoproteins and possible additional auto antigens could be useful in laboratory evaluation of peripheral neuropathies and help to develop a more effective therapeutic approach.

  18. ALS and MMN mimics in patients with BSCL2 mutations: the expanding clinical spectrum of SPG17 hereditary spastic paraplegia.

    Science.gov (United States)

    Musacchio, Thomas; Zaum, Ann-Kathrin; Üçeyler, Nurcan; Sommer, Claudia; Pfeifroth, Nora; Reiners, Karlheinz; Kunstmann, Erdmute; Volkmann, Jens; Rost, Simone; Klebe, Stephan

    2017-01-01

    Silver syndrome/SPG17 is a motor manifestation of mutations in the BSCL2 gene and usually presents as a complicated form of hereditary spastic paraplegia (HSP). We present clinical data, follow-up, and genetic results of seven patients with Silver syndrome/SPG17 including a family with a variable intrafamilial phenotype ranging from subclinical signs to a severe and rapidly progressing amyotrophic lateral sclerosis (ALS)-like phenotype. For molecular diagnosis of the family, we used the TruSight Exome sequencing panel consisting of 2761 genes. We filtered for variants common to affected family members and for exclusive variants in the ALS-like index patient to find possible modifier mutations. We found that de novo mutations and/or incomplete penetrance in BSCL2 has been taken into account for Silver syndrome/SPG17 and confirm the large phenotypical heterogeneity of BSCL2 mutations. Our findings broaden the reported spectrum of the disease to an ALS-like and multifocal motor neuropathy phenotype and underline the need for further research for genetic modifiers due to the striking interindividual and intrafamilial variability.

  19. Hereditary gastric cancer.

    Science.gov (United States)

    Oliveira, Carla; Seruca, Raquel; Carneiro, Fátima

    2009-01-01

    Gastric cancer is a heterogeneous and highly prevalent disease, being the fourth most common cancer and the second leading cause of cancer associated death worldwide. Most cases are sporadic and familial clustering is observed in about 10% of the cases. Hereditary gastric cancer accounts for a very low percentage of cases (1-3%) and a single hereditary syndrome - Hereditary Diffuse Gastric Cancer (HDGC) - has been characterised. Among families that fulfil the clinical criteria for HDGC, about 40% carry CDH1 germline mutations, the genetic cause of the others being unknown. The management options for CDH1 asymptomatic germline carriers are intensive endoscopic surveillance and prophylactic gastrectomy. In this chapter we review the pathophysiology and clinicopathological features of HDGC and discuss issues related with genetic testing and management of family members.

  20. [Hereditary systemic autoinflammatory diseases].

    Science.gov (United States)

    Aróstegui, Juan I

    2011-01-01

    Systemic autoinflammatory diseases encompass different rare clinical entities characterized by recurrent acute inflammatory episodes secondary to a dysregulated inflammatory process. Since their first clinical descriptions, the Mendelian hereditary nature of some of them became evident, with their genetic and molecular basis being recently elucidated. There are disease-causing mutations in genes encoding for different proteins involved in the innate immune response and inflammation. Herein, we will introduce the reader to an updated review of the main clinical, physiopathological and therapeutic features of the different hereditary systemic autoinflammatory diseases. Copyright © 2010 Elsevier España, S.L. All rights reserved.

  1. Peripheral neuropathies in childhood: a neuropathological approach Neuropatias periféricas na infância: uma abordagem neuropatológica

    Directory of Open Access Journals (Sweden)

    Leila Chimelli

    1996-09-01

    Full Text Available Peripheral neuropathies affect children more often than the young and middle age adults, but less frequently than the elderly. They differ from those in the adults because of the high incidence of hereditary neuropathies, including those associated with metabolic and degenerative disorders of the central nervous system; the low incidence of toxic neuropathies and those associated with systemic disorders; and a lower incidence of chronic acquired polineuropathies. Nerve biopsies are indicated if the diagnosis has not been made with clinical and electrophysiologic studies and other methods, and should only be performed in laboratories with appropriate techniques for the study of the nerve. It is important to know the normal development of the nerve, the thickness of the myelin sheath and the distribution of small and large fibers, according to the age. The main morphological aspects of the most frequent neuropathies in children - acquired (inflammatory, demyelinating and hereditary (sensory-motor, sensory-autonomic, ataxic, and those associated with metabolic and degenerative disorders, are reviewed.As neuropatias periféricas afetam as crianças mais frequentemente do que os adultos jovens e de meia idade, mas menos frequentemente do que os mais velhos. Diferem das dos adultos pela alta incidência de neuropatias hereditárias, incluindo as associadas a doenças metabólicas e degenerativas do sistema nervoso central; pela baixa incidência de neuropatias tóxicas e associadas a doenças sistêmicas; e pela menor incidência de polineuropatias crônicas adquiridas. As biópsias de nervo são indicadas se o diagnóstico não for feito com estudos clínicos, eletrofisiológicos e outros métodos de investigação, e só devem ser realizadas em laboratórios que dispõem de técnicas apropriadas para estudo do nervo. É importante conhecer o desenvolvimento do nervo periférico, a espessura da mielina e a distribuição das fibras quanto ao calibre

  2. Lithium attenuates peripheral neuropathy induced by paclitaxel in rats.

    Science.gov (United States)

    Pourmohammadi, Nasir; Alimoradi, Houman; Mehr, Shahram Ejtemaei; Hassanzadeh, Gholamreza; Hadian, Mohammad Reza; Sharifzadeh, Mohammad; Bakhtiarian, Azam; Dehpour, Ahmad Reza

    2012-03-01

    As a cancer chemotherapeutic agent, paclitaxel (Taxol® ) causes dose-related peripheral neuropathy in human beings. The mechanisms underlying this toxicity are currently unknown, and there are no validated treatments for its prevention or control. To assess whether lithium as a pre-treatment and at subtherapeutic dose could prevent the peripheral neuropathy produced by it, rats were treated with paclitaxel (2 mg/kg i.p. every other day for a total of 16 times) and/or lithium chloride (300 mg/l) via water supply. General toxicity and body-weight were measured regularly during the experiment. To evaluate the sensory and motor neuropathy hot-plate, open-field test and nerve conduction velocity were used. In rats treated with only paclitaxel, there was behavioural, electrophysiological and histological evidence of a mixed sensorimotor neuropathy after 16 injections. Lithium robustly reduced the rate of mortality and general toxicity. Paclitaxel-induced sensorimotor neuropathy was significantly improved as indicated by changes in hotplate latency, total distance moved and a significant increase in sciatic, sural and tail sensory or motor nerve conduction velocity. The same results were observed in histopathological examinations; however, dorsal root ganglion neurons did not significantly change in the paclitaxel-treated groups. These results suggest that lithium, at subtherapeutic doses, can prevent both motor and sensory components of paclitaxel neuropathy in rats. Thus, lithium at these doses, as an inexpensive and relatively safe salt, may be useful clinically in preventing the neuropathy induced by paclitaxel treatment. © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.

  3. Genetics Home Reference: infantile-onset ascending hereditary spastic paralysis

    Science.gov (United States)

    ... characterized by progressive muscle stiffness (spasticity) and eventual paralysis of the lower limbs (paraplegia). The spasticity and paraplegia result from degeneration (atrophy) of motor neurons , which are specialized nerve cells in the brain and spinal cord that control muscle movement. Hereditary ...

  4. Managing hereditary ovarian cancer

    NARCIS (Netherlands)

    Mourits, M. J.; de Bock, G. H.

    2009-01-01

    In this review we present an overview of recent developments in the management of hereditary ovarian cancer. Until recently, intensive screening of the ovaries was recommended to mutation carriers and their first-degree female relatives. However, since screening is not effective in detecting

  5. Hereditary periodic fever syndromes

    NARCIS (Netherlands)

    McDermott, MF; Frenkel, J

    Hereditary periodic fever syndromes are defined by recurrent attacks of generalised inflammation for which no infectious or auto-immune cause can be identified. For most of these disorders, the molecular basis has recently been elucidated. This has opened the prospect of novel therapeutic

  6. Hereditary Angioedema in Childhood

    DEFF Research Database (Denmark)

    Kjaer, Line; Bygum, Anette

    2012-01-01

    Hereditary angioedema (HAE) is a rare inherited disease that is often difficult to diagnose. We report a case of a 9-year-old boy with a spontaneous mutation causing HAE, diagnosed after a life-threatening episode of angioedema of the head and upper respiratory tract after a 5-year history of r...

  7. Ultrasound differentiation of axonal and demyelinating neuropathies.

    Science.gov (United States)

    Grimm, Alexander; Heiling, Bianka; Schumacher, Ulrike; Witte, Otto W; Axer, Hubertus

    2014-12-01

    Ultrasound can be used to visualize peripheral nerve abnormality. Our objective in this study was to prove whether nerve ultrasound can differentiate between axonal and demyelinating polyneuropathies (PNPs). Systematic ultrasound measurements of peripheral nerves were performed in 53 patients (25 with demyelinating, 20 with axonal, 8 with mixed neuropathy) and 8 healthy controls. Nerve conduction studies of corresponding nerves were undertaken. Analysis of variance revealed significant differences between the groups with regard to motor conduction velocity, compound muscle action potential amplitude, and cross-sectional area (CSA) of different nerves at different locations. Receiver operating characteristic curve analysis revealed CSA measurements to be well suited for detection of demyelinating neuropathies, and boundary values of peripheral nerve CSA could be defined. Systematic ultrasound CSA measurement in different nerves helped detect demyelination, which is an additional cue in the etiological diagnosis of PNP, along with nerve conduction studies and nerve biopsy. © 2014 Wiley Periodicals, Inc.

  8. Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy.

    Directory of Open Access Journals (Sweden)

    Jia-Ying Sung

    Full Text Available This study investigated sensory and motor nerve excitability properties to elucidate the development of diabetic neuropathy. A total of 109 type 2 diabetes patients were recruited, and 106 were analyzed. According to neuropathy severity, patients were categorized into G0, G1, and G2+3 groups using the total neuropathy score-reduced (TNSr. Patients in the G0 group were asymptomatic and had a TNSr score of 0. Sensory and motor nerve excitability data from diabetic patients were compared with data from 33 healthy controls. Clinical assessment, nerve conduction studies, and sensory and motor nerve excitability testing data were analyzed to determine axonal dysfunction in diabetic neuropathy. In the G0 group, sensory excitability testing revealed increased stimulus for the 50% sensory nerve action potential (P<0.05, shortened strength-duration time constant (P<0.01, increased superexcitability (P<0.01, decreased subexcitability (P<0.05, decreased accommodation to depolarizing current (P<0.01, and a trend of decreased accommodation to hyperpolarizing current in threshold electrotonus. All the changes progressed into G1 (TNSr 1-8 and G2+3 (TNSr 9-24 groups. In contrast, motor excitability only had significantly increased stimulus for the 50% compound motor nerve action potential (P<0.01 in the G0 group. This study revealed that the development of axonal dysfunction in sensory axons occurred prior to and in a different fashion from motor axons. Additionally, sensory nerve excitability tests can detect axonal dysfunction even in asymptomatic patients. These insights further our understanding of diabetic neuropathy and enable the early detection of sensory axonal abnormalities, which may provide a basis for neuroprotective therapeutic approaches.

  9. Hip joint torques in type II diabetes with and without neuropathy

    Directory of Open Access Journals (Sweden)

    Laleh Abadi, MS (PT

    2017-12-01

    Full Text Available Background: Patients with diabetes and peripheral neuropathy demonstrate significantly reduced peak torques at the peripheral joints. Objectives: The aim of this study was to assess isometric and concentric peak torques of the hip joint in people with type II diabetes with and without peripheral neuropathy in comparison with healthy participants. Methods: 27 patients with type II diabetes including 15 patients without peripheral neuropathy, 12 patients with diabetes and peripheral neuropathy and 15 healthy people participated. Isometric and concentric peak torques of hip flexion, extension, adduction and abduction of the non-dominant leg were measured by motorized dynamometer. Results: Peak and average peak concentric torques of the hip extension and abduction in patients with diabetes and peripheral neuropathy were lower than those patients with diabetes and control group. Angle of extension peak torque was significantly greater in patients with diabetes and peripheral neuropathy compared with other groups. Angle of flexion peak torque was lower in the patients with diabetes and peripheral neuropathy. Conclusions: Torque related parameters in patients with type II diabetes with or without peripheral neuropathy, are different from healthy subjects. As a result, patients with diabetes especially with peripheral neuropathy are more susceptible of injury and disability in lower limbs. Keywords: type II diabetes, hip, joint, torques, peripheral neuropathy

  10. Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy

    NARCIS (Netherlands)

    Gerber, S.; Ding, M.G.; Gerard, X.; Zwicker, K.; Zanlonghi, X.; Rio, M. del; Serre, V.; Hanein, S.; Munnich, A.; Rotig, A.; Bianchi, L.; Amati-Bonneau, P.; Elpeleg, O.; Kaplan, J.; Brandt, U.; Rozet, J.M.

    2017-01-01

    BACKGROUND: Non-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains

  11. Another cause of occupational entrapment neuropathy: la main du cuisinier (the chef's hand).

    Science.gov (United States)

    Krishnan, Arun V; Fulham, Michael J; Kiernan, Matthew C

    2009-04-01

    Recent studies have raised the possibility of a predisposition to mononeuropathies in a number of professions including musicians, cleaners, and industrial workers. There are, however, no previous reports of increased rates of mononeuropathies in the culinary arts. The authors report three cases of mononeuropathies occurring in professional chefs that presented over a 3-month period in the same outpatient clinic, with a case each of distal ulnar neuropathy, distal median motor neuropathy (thenar motor syndrome) and posterior interosseous neuropathy. There was no history of direct hand trauma in any of the patients. In all three patients, the injuries occurred exclusively in the dominant hand, further strengthening the argument for an occupational link.

  12. Role of nitrosative and oxidative stress in neuropathy in patients with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Marwan S Al-Nimer

    2012-01-01

    Full Text Available Objectives : Evidences of oxidative and/or nitrosative stress in type 2 diabetes mellitus were demonstrated in experimental and human studies. This study is aimed to assess the serum peroxynitrite and oxidized lipoproteins in patients with type 2 diabetes mellitus presented with clinical and laboratory evidences of peripheral neuropathy. Materials and Methods : Eighty four patients with type 2 diabetes mellitus (51 of them had neuropathy and 31 apparent healthy subjects were studied in the unit of neurophysiology at the University Hospital of Medical College, Al-Nahrin University in Baghdad, Iraq. Neuropathy total symptom score (NTSS, neuropathy impairment score in the lower leg (NIS-LL, and nerve conduction velocity of sensory (ulnar and sural and motor (ulnar and common peroneal nerves were used to assess the neuropathy. Fasting venous blood was obtained from each participant for the determination of serum glucose and oxidized lipoproteins. Results: The electrophysiology study revealed significant decrease in conduction velocity of ulnar (sensory and motor components, sural, and common peroneal nerves in diabetic neuropathy compared to diabetics without neuropathy and healthy subjects. Significant high level of serum peroxynitrite was found in diabetic patients with or without neuropathy compared with non-diabetics. The changes in serum-oxidized lipoproteins in patients with diabetics with or without neuropathy were non-significantly differed from healthy subjects. Neither nitrosative stress nor oxidative stress indices correlated with the variables that are related to the neuropathy. Conclusion: It concludes that evidence of nitrosative and to less extent the oxidative stress is associated with neuropathy in type 2 diabetes mellitus and their indices not correlated with variables related to neuropathy.

  13. [Peripheral neuropathies after bariatric surgery].

    Science.gov (United States)

    Philippi, N; Vinzio, S; Collongues, N; Vix, M; Boehm, N; Tranchant, C; Echaniz-Laguna, A

    2011-01-01

    Peripheral neuropathies sometimes complicate bariatric surgery. We report the detailed clinical, electrophysiological, biological and histological characteristics of five patients who developed peripheral neuropathy after bariatric surgery. Three patients presented with small fiber neuropathy, one presented with axonal polyneuropathy, and one with demyelinating polyradiculoneuropathy. All patients had in common prominent neuropathic pain, massive weight loss, and multiple nutritional deficiencies. The pathophysiology of postbariatric surgery polyneuropathies is complex and involves nutritional, infectious and dysimmune mechanisms. The spectrum of peripheral neuropathies complicating bariatric surgery is wide, and includes pure small fiber neuropathy, axonal polyneuropathy, and demyelinating polyradiculoneuropathy. Treatment is mainly preventive, but sometimes surgical revision is needed. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  14. Catecholamines and diabetic autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J

    1995-01-01

    In diabetic patients with autonomic neuropathy plasma noradrenaline concentration, used as an index of sympathetic nervous activity, is low. This decrease is, however, only found in patients with a long duration of diabetes with clinically severe autonomic neuropathy. This apparent insensitivity...... of plasma catecholamine measurements is not due to changes in the clearance of catecholamines in diabetic autonomic neuropathy. The physiological responses to infused adrenaline and to noradrenaline are enhanced, for noradrenaline mainly cardiovascular responses. Adrenoceptors (alpha and beta adrenoceptors......) are not altered in circulating blood cells in diabetic autonomic neuropathy. Thus, a generalized up-regulation of adrenoceptors does not occur in diabetic autonomic neuropathy....

  15. Small molecule suppressors of Drosophila kinesin deficiency rescue motor axon development in a zebrafish model of spinal muscular atrophy.

    Directory of Open Access Journals (Sweden)

    Andrew Gassman

    Full Text Available Proximal spinal muscular atrophy (SMA is the most common inherited motor neuropathy and the leading hereditary cause of infant mortality. Currently there is no effective treatment for the disease, reflecting a need for pharmacologic interventions that restore performance of dysfunctional motor neurons or suppress the consequences of their dysfunction. In a series of assays relevant to motor neuron biology, we explored the activities of a collection of tetrahydroindoles that were reported to alter the metabolism of amyloid precursor protein (APP. In Drosophila larvae the compounds suppressed aberrant larval locomotion due to mutations in the Khc and Klc genes, which respectively encode the heavy and light chains of kinesin-1. A representative compound of this class also suppressed the appearance of axonal swellings (alternatively termed axonal spheroids or neuritic beads in the segmental nerves of the kinesin-deficient Drosophila larvae. Given the importance of kinesin-dependent transport for extension and maintenance of axons and their growth cones, three members of the class were tested for neurotrophic effects on isolated rat spinal motor neurons. Each compound stimulated neurite outgrowth. In addition, consistent with SMA being an axonopathy of motor neurons, the three axonotrophic compounds rescued motor axon development in a zebrafish model of SMA. The results introduce a collection of small molecules as pharmacologic suppressors of SMA-associated phenotypes and nominate specific members of the collection for development as candidate SMA therapeutics. More generally, the results reinforce the perception of SMA as an axonopathy and suggest novel approaches to treating the disease.

  16. Testing for autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J

    1984-01-01

    Autonomic neuropathy is a common complication in long-term diabetes, about 30% of the patients showing measurable signs of autonomic dysfunction after 10 years duration of disease. The diagnosis is often difficult to establish because clinical symptoms generally occur late in the course of the di...

  17. Hereditary Renal Diseases.

    Science.gov (United States)

    Mehta, Lakshmi; Jim, Belinda

    2017-07-01

    Hereditary kidney disease comprises approximately 10% of adults and nearly all children who require renal replacement therapy. Technologic advances have improved our ability to perform genetic diagnosis and enhanced our understanding of renal and syndromic diseases. In this article, we review the genetics of renal diseases, including common monogenic diseases such as polycystic kidney disease, Alport syndrome, and Fabry disease, as well as complex disorders such as congenital anomalies of the kidney and urinary tract. We provide the nephrologist with a general strategy to approach hereditary disorders, which includes a discussion of commonly used genetic tests, a guide to genetic counseling, and reproductive options such as prenatal diagnosis or pre-implantation genetic diagnosis for at-risk couples. Finally, we review pregnancy outcomes in certain renal diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Hereditary breast cancer

    DEFF Research Database (Denmark)

    Larsen, Martin J; Thomassen, Mads; Gerdes, Anne-Marie

    2014-01-01

    Pathogenic mutations in BRCA1 or BRCA2 are only detected in 25% of families with a strong history of breast cancer, though hereditary factors are expected to be involved in the remaining families with no recognized mutation. Molecular characterization is expected to provide new insight...... into the tumor biology to guide the search of new high-risk alleles and provide better classification of the growing number of BRCA1/2 variants of unknown significance (VUS). In this review, we provide an overview of hereditary breast cancer, its genetic background, and clinical implications, before focusing...... on the pathologically and molecular features associated with the disease. Recent transcriptome and genome profiling studies of tumor series from BRCA1/2 mutation carriers as well as familial non-BRCA1/2 will be discussed. Special attention is paid to its association with molecular breast cancer subtypes as well...

  19. ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia.

    Science.gov (United States)

    Cooper, Helen M; Yang, Yang; Ylikallio, Emil; Khairullin, Rafil; Woldegebriel, Rosa; Lin, Kai-Lan; Euro, Liliya; Palin, Eino; Wolf, Alexander; Trokovic, Ras; Isohanni, Pirjo; Kaakkola, Seppo; Auranen, Mari; Lönnqvist, Tuula; Wanrooij, Sjoerd; Tyynismaa, Henna

    2017-04-15

    De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G > A (p.G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral palsy, both with disease onset in childhood. HSP is a clinically and genetically heterogeneous disorder of the upper motor neurons. Symptoms beginning in early childhood may resemble spastic cerebral palsy. The function of ATAD3A, a mitochondrial inner membrane AAA ATPase, is yet undefined. AAA ATPases form hexameric rings, which are catalytically dependent on the co-operation of the subunits. The dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity. We further show that overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass. Similarly, we observed altered dynamics of the mitochondrial network and increased lysosomes in patient fibroblasts and neurons derived through differentiation of patient-specific induced pluripotent stem cells. These alterations were verified in patient fibroblasts to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including HSP, with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity. © The Author 2017. Published by Oxford University Press.

  20. HFE-Associated Hereditary Haemochromatosis

    OpenAIRE

    Eijkelkamp, Emmeke J; Yapp, Thomas R; Powell, Lawrie W

    2000-01-01

    Hereditary hemochromatosis is a common inherited disorder of the iron metabolism. Screening studies indicate that it has a prevalence of one in 200 to 400, depending on the population studied, and a carrier rate of about one in seven to one in 10. Feder et al identified the hereditary hemochromatosis gene (HFE) in 1996 and two candidate mutations; the C282Y mutation has been shown to be responsible for the majority of the hereditary hemochromatosis cases worldwide. The gene discovery has led ...

  1. Genetics Home Reference: hereditary hyperekplexia

    Science.gov (United States)

    ... Neuromuscular Disorders Health Topic: Sudden Infant Death Syndrome Genetic and Rare Diseases Information Center (1 link) Hereditary hyperekplexia Additional NIH Resources (1 link) National Institute ...

  2. Genetics Home Reference: hereditary fructose intolerance

    Science.gov (United States)

    ... Home Health Conditions Hereditary fructose intolerance Hereditary fructose intolerance Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description Hereditary fructose intolerance is a condition that affects a person's ability ...

  3. Genetics Home Reference: hereditary diffuse gastric cancer

    Science.gov (United States)

    ... Health Conditions Hereditary diffuse gastric cancer Hereditary diffuse gastric cancer Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description Hereditary diffuse gastric cancer (HDGC) is an inherited disorder that greatly increases ...

  4. Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy.

    Science.gov (United States)

    Kagiava, Alexia; Sargiannidou, Irene; Theophilidis, George; Karaiskos, Christos; Richter, Jan; Bashiardes, Stavros; Schiza, Natasa; Nearchou, Marianna; Christodoulou, Christina; Scherer, Steven S; Kleopa, Kleopas A

    2016-04-26

    Inherited demyelinating peripheral neuropathies are progressive incurable diseases without effective treatment. To develop a gene therapy approach targeting myelinating Schwann cells that can be translatable, we delivered a lentiviral vector using a single lumbar intrathecal injection and a myelin-specific promoter. The human gene of interest, GJB1, which is mutated in X-linked Charcot-Marie-Tooth Disease (CMT1X), was delivered intrathecally into adult Gjb1-null mice, a genetically authentic model of CMT1X that develops a demyelinating peripheral neuropathy. We obtained widespread, stable, and cell-specific expression of connexin32 in up to 50% of Schwann cells in multiple lumbar spinal roots and peripheral nerves. Behavioral and electrophysiological analysis revealed significantly improved motor performance, quadriceps muscle contractility, and sciatic nerve conduction velocities. Furthermore, treated mice exhibited reduced numbers of demyelinated and remyelinated fibers and fewer inflammatory cells in lumbar motor roots, as well as in the femoral motor and sciatic nerves. This study demonstrates that a single intrathecal lentiviral gene delivery can lead to Schwann cell-specific expression in spinal roots extending to multiple peripheral nerves. This clinically relevant approach improves the phenotype of an inherited neuropathy mouse model and provides proof of principle for treating inherited demyelinating neuropathies.

  5. Content validity of symptom-based measures for diabetic, chemotherapy, and HIV peripheral neuropathy.

    Science.gov (United States)

    Gewandter, Jennifer S; Burke, Laurie; Cavaletti, Guido; Dworkin, Robert H; Gibbons, Christopher; Gover, Tony D; Herrmann, David N; Mcarthur, Justin C; McDermott, Michael P; Rappaport, Bob A; Reeve, Bryce B; Russell, James W; Smith, A Gordon; Smith, Shannon M; Turk, Dennis C; Vinik, Aaron I; Freeman, Roy

    2017-03-01

    No treatments for axonal peripheral neuropathy are approved by the United States Food and Drug Administration (FDA). Although patient- and clinician-reported outcomes are central to evaluating neuropathy symptoms, they can be difficult to assess accurately. The inability to identify efficacious treatments for peripheral neuropathies could be due to invalid or inadequate outcome measures. This systematic review examined the content validity of symptom-based measures of diabetic peripheral neuropathy, HIV neuropathy, and chemotherapy-induced peripheral neuropathy. Use of all FDA-recommended methods to establish content validity was only reported for 2 of 18 measures. Multiple sensory and motor symptoms were included in measures for all 3 conditions; these included numbness, tingling, pain, allodynia, difficulty walking, and cramping. Autonomic symptoms were less frequently included. Given significant overlap in symptoms between neuropathy etiologies, a measure with content validity for multiple neuropathies with supplemental disease-specific modules could be of great value in the development of disease-modifying treatments for peripheral neuropathies. Muscle Nerve 55: 366-372, 2017. © 2016 Wiley Periodicals, Inc.

  6. Restless leg syndrome in different types of demyelinating neuropathies: a single-center pilot study.

    Science.gov (United States)

    Luigetti, Marco; Del Grande, Alessandra; Testani, Elisa; Bisogni, Giulia; Losurdo, Anna; Giannantoni, Nadia Mariagrazia; Mazza, Salvatore; Sabatelli, Mario; Della Marca, Giacomo

    2013-09-15

    to determine the prevalence of restless legs syndrome (RLS) in a cohort of patients with demyelinating neuropathies. Patients were retrospectively recruited from our cohort of different forms of demyelinating neuropathies, including chronic inflammatory demyelinating neuropathy (CIDP), Charcot-Marie-Tooth 1A (CMT1A), and hereditary neuropathy with liability to pressure palsies (HNPP) referred to our Department of Neurology in a 10-year period. The validated 4-item RLS questionnaire was used for diagnosis of RLS. All patients with RLS who fulfilled criteria underwent a suggested immobilization test to confirm the diagnosis. A group of outpatients referred to the sleep disorders unit and data from published literature were used as controls. Prevalence of RLS in demyelinating neuropathy group was higher than prevalence observed in control population (p = 0.0142) or in the literature data (p = 0.0007). In particular, in comparison with both control population and literature data, prevalence of RLS was higher in CIDP group (p = 0.0266 and p = 0.0063, respectively) and in CMT1A group (p = 0.0312 and p = 0.0105, respectively), but not in HNPP (p = 1.000 and p = 0.9320, respectively). our study confirms a high prevalence of RLS in inflammatory neuropathies as CIDP and, among inherited neuropathies, in CMT1A but not in HNPP. Considering that this is only a small cohort from a single-center retrospective experience, the link between RLS and neuropathy remains uncertain, and larger multicenter studies are probably needed to clarify the real meaning of the association between RLS and neuropathy.

  7. Canine hereditary ataxia.

    Science.gov (United States)

    Urkasemsin, Ganokon; Olby, Natasha J

    2014-11-01

    The hereditary ataxias are a group of neurodegenerative diseases that cause a progressive (or episodic) cerebellar ataxia. A large number of different disorders have been described in different breeds of purebred dog, and in some instances, more than one disorder occurs in a single breed, creating a confusing clinical picture. The mutations associated with these disorders are being described at a rapid rate, potentially changing our ability to prevent, diagnose, and treat affected dogs. A breed-related neurodegenerative process should be suspected in any pure bred dog with slowly progressive, symmetric signs of ataxia. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Hereditary angioedema in women

    Directory of Open Access Journals (Sweden)

    Bouillet Laurence

    2010-07-01

    Full Text Available Abstract Women with hereditary angioedema (HAE are more likely to be symptomatic that men. Hormonal factors (puberty, contraception, pregnancy,.... play a significant role in the precipitation or worsening of the condition in women. So, combined contraceptive pills are not indicated and progestogen pill must be preferred. During pregnancy, attack rate can increase (38-48% of women. C1Inhibitor concentrate and tranexamic acid can be used during pregnancy. Attenuated androgens for long term prophylaxis are effective but side effects appear more often in female patients. These side effects are dose dependant and can be attenuated by titrating the dose down the lowest effective level.

  9. HFE-associated hereditary hemochromatosis

    NARCIS (Netherlands)

    Eijkelkamp, EJ; Yapp, TR; Powell, LW

    Hereditary hemochromatosis is a common inherited disorder of the iron metabolism Screening studies indicate that it has a prevalence of one in 200 to 400, depending on the population studied, and a carrier rate of about one in seven to one in 10. Feder et al identified the hereditary hemochromatosis

  10. EAMJ Oct Hereditary.indd

    African Journals Online (AJOL)

    HEREDITARY GINGIVAL FIBROMATOSIS: REPORT OF FAMILY CASE SERIES. E. G. WAGAIYU, R. N. NG'ANG'A and A. M. KEMOLI. SUMMARY. Hereditary gingival hyperplasia (HGF) is a rare condition characterised by hyperplastic, dense fibrous connective tissue with acanthotic gingival epithelium. A family presented.

  11. Drug-induced peripheral neuropathy

    DEFF Research Database (Denmark)

    Vilholm, Ole Jakob; Christensen, Alex Alban; Zedan, Ahmed

    2014-01-01

    Peripheral neuropathy can be caused by medication, and various descriptions have been applied for this condition. In this MiniReview, the term 'drug-induced peripheral neuropathy' (DIPN) is used with the suggested definition: Damage to nerves of the peripheral nervous system caused by a chemical...... substance used in the treatment, cure, prevention or diagnosis of a disease. Optic neuropathy is included in this definition. A distinction between DIPN and other aetiologies of peripheral neuropathy is often quite difficult and thus, the aim of this MiniReview is to discuss the major agents associated...

  12. [Regional anaesthesia for labor adn delivery in a parturient with neuropathy with liability to pressure palsy (tomaculous neuropathy)].

    Science.gov (United States)

    Berdai, S; Benhamou, D

    2004-10-01

    Tomaculous neuropathy (or hereditary neuropathy with liability to pressure palsy [HNLPP]) is a rare and hereditary disease which incidence has probably been underestimated. It is characterised by demyelination resulting in numbness and weakness after nerve pressure, injury or stretch. Despite a well-documented genetic pathophysiologic mechanism, implications for anaesthesia in patients with HNLPP are only speculative and the use of regional anaesthesia is debatable. We report here the case of a patient with HNLPP who was followed during two consecutive pregnancies in the same hospital and for whom an expert of the SOS-RA hotline service was consulted before each delivery. For the first delivery, epidural analgesia was performed for labour pain control but a caesarean section was necessary because of failure to progress (0.0625% bupivacaine with 0.2 microg/ml sufentanil for labour then 2% lidocaine with adrenaline for surgery). Two years later, the patient was again seen for a preanaesthetic visit because elective Caesarean section was planned. Spinal anaesthesia using hyperbaric bupivacaine and sufentanil was used. Both deliveries were uneventful and there were no neurologic complaints in the postpartum periods.

  13. A Review of Mitochondrial Optic Neuropathies: From Inherited to Acquired Forms.

    Science.gov (United States)

    Pilz, Yasmine L; Bass, Sherry J; Sherman, Jerome

    In recent years, the term mitochondrial optic neuropathy (MON) has increasingly been used within the literature to describe a group of optic neuropathies that exhibit mitochondrial dysfunction in retinal ganglion cells (RGCs). Interestingly, MONs include genetic aetiologies, such as Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA), as well as acquired aetiologies resulting from drugs, nutritional deficiencies, and mixed aetiologies. Regardless of an inherited or acquired cause, patients exhibit the same clinical manifestations with selective loss of the RGCs due to mitochondrial dysfunction. Various novel therapies are being explored to reverse or limit damage to the RGCs. Here we review the pathophysiology, clinical manifestations, differential diagnosis, current treatment, and promising therapeutic targets of MON. Published by Elsevier España, S.L.U.

  14. Immunotherapy-responsive allodynia due to distal acquired demyelinating symmetric (DADS) neuropathy.

    Science.gov (United States)

    Liewluck, Teerin; Engelstad, Janean K; Mauermann, Michelle L

    2016-11-01

    Distal acquired demyelinating symmetric (DADS) neuropathy is a distal variant of chronic inflammatory demyelinating polyradiculoneuropathy. It is characterized by chronic distal symmetric sensory or sensorimotor deficits. Sensory ataxia is a common clinical presentation. Nerve conduction studies typically show markedly prolonged distal motor latencies. We report 2 patients with chronic progressive generalized pain and fatigue, with normal neurological examinations except for allodynia. Nerve conduction studies were typical of DADS neuropathy. Monoclonal protein studies were negative. Cerebrospinal fluid protein levels were elevated. Sural nerve biopsies revealed segmental demyelination and remyelination. One biopsy had marked endoneurial and epineurial lymphocytic infiltration. Immunomodulatory therapy alleviated the pain and fatigue and markedly improved distal motor latencies in both patients. DADS neuropathy can present with pain and a normal neurological examination apart from allodynia. Nerve conduction studies are necessary for diagnosis. These patients respond to immunotherapy better than typical DADS neuropathy patients with sensory ataxia. Muscle Nerve 54: 973-977, 2016. © 2016 Wiley Periodicals, Inc.

  15. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice.

    Science.gov (United States)

    Trammell, Samuel A J; Weidemann, Benjamin J; Chadda, Ankita; Yorek, Matthew S; Holmes, Amey; Coppey, Lawrence J; Obrosov, Alexander; Kardon, Randy H; Yorek, Mark A; Brenner, Charles

    2016-05-27

    Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies.

  16. Hereditary pancreatitis for the endoscopist

    Science.gov (United States)

    Patel, Milan R.; Eppolito, Amanda L.

    2013-01-01

    Hereditary pancreatitis shares a majority of clinical and morphologic features with chronic alcoholic pancreatitis, but may present at an earlier age. The term hereditary pancreatitis has primarily been associated with mutations in the serine protease 1 gene (PRSS1) which encodes for cationic trypsinogen. PRSS1 mutations account for approximately 68–81% of hereditary pancreatitis. Mutations in other genes, primarily serine protease inhibitor Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) are also associated with hereditary pancreatitis. While chronic alcoholic pancreatitis may develop in the fourth or fifth decades, patients with hereditary pancreatitis may develop symptoms in the first or second decades of life. Hereditary pancreatitis is diagnosed either by detecting a causative gene mutation or by the presence of chronic pancreatitis in two first-degree or three second-degree relatives, in two or more generations, without precipitating factors and with a negative workup for known causes. Patients with hereditary pancreatitis may have recurrent acute pancreatitis and may develop pancreatic exocrine and endocrine insufficiency. Hereditary pancreatitis may involve premature trypsinogen activation or decreased control of trypsin. Recurrent inflammation can lead to acute pancreatitis and subsequently to chronic pancreatitis with parenchymal calcification. There is a markedly increased risk of pancreatic carcinoma compared with the general population. Patients are often referred for evaluation of pancreatitis, biliary or pancreatic ductal dilatation, jaundice, biliary obstruction, pancreatic duct stone or stricture, pancreatic pseudocysts, and for evaluation for malignancy. Medical treatment includes pancreatic enzyme supplementation, nutritional supplementation, diabetes management, and palliation of pain. Patients should avoid tobacco use and alcohol exposure. Hereditary pancreatitis is reviewed and recommendations for

  17. Prevalence and predictors of peripheral neuropathy in non-diabetic children with chronic kidney disease.

    Science.gov (United States)

    Yoganathan, Sangeetha; Bagga, Arvind; Gulati, Sheffali; Toteja, G S; Hari, Pankaj; Sinha, Aditi; Pandey, Ravindra Mohan; Irshad, Mohammad

    2017-11-29

    The aim of this study was to determine the prevalence and predictors of peripheral neuropathy in non-diabetic children with chronic kidney disease (CKD). Fifty-one consecutive normally nourished children, aged 3-18 years, with CKD stage IV and V of non-diabetic etiology were enrolled from May to December 2012. Nerve conduction studies were performed in fifty children. Blood samples were analyzed for the biochemical parameters, trace elements and micronutrients. The prevalence of peripheral neuropathy in our cohort was 52% (95% CI 37.65, 66.34). The majority (80.8%) had axonal neuropathy while 11.5% had demyelinating neuropathy. Isolated motor neuropathy was identified in 92.3% and sensorimotor neuropathy in 7.6%. The significant risk factors associated with peripheral neuropathy were older age, low serum copper and dialysis therapy. Electrodiagnostic studies should be performed in children with CKD to assess for peripheral neuropathy with the aim of optimizing medical care. This article is protected by copyright. All rights reserved. © 2017 Wiley Periodicals, Inc.

  18. Comparing treatment options for chronic inflammatory neuropathies and choosing the right treatment plan.

    Science.gov (United States)

    Nobile-Orazio, Eduardo; Gallia, Francesca; Terenghi, Fabrizia; Bianco, Mariangela

    2017-08-01

    Chronic inflammatory neuropathies are disorders caused by an immune response to peripheral nerve. They include chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN) and neuropathy associated with anti-MAG IgM monoclonal gammopathy and other less frequent neuropathies. Several immune therapies have been proven to be effective in these neuropathies even if the best therapeutic option is still unsettled. Areas covered: The authors reviewed the literature to compare the efficacy and safety of currently used immune therapies in these neuropathies. The authors also analyzed the effect of other immune suppressive agents and of biological agents including rituximab, eculizumab, natalizumab, alemtuzumab and fingolimod that were found effective in other autoimmune diseases. Expert commentary: Despite the reported efficacy of a number of new immune therapies in some patients with immune mediated neuropathies, their efficacy has not been so far confirmed in randomized controlled studies. High-dose intravenous immunoglobulin (IVIg) (and subcutaneous immunoglobulin [SCIg] for maintenance treatment), steroids and plasma exchange remain the only therapy of proven efficacy in CIDP, IVIg in MMN and, with certain limits, rituximab and, occasionally plasma exchange in neuropathy associated with anti-MAG antibodies. New biological agents are also on the horizon but their efficacy needs to be proved in controlled studies.

  19. Delayed radiation neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Nagashima, T.; Miyamoto, K.; Beppu, H.; Hirose, K.; Yamada, K. (Tokyo Metropolitan Neurological Hospital (Japan))

    1981-07-01

    A case of cervical plexus neuropathy was reported in association with chronic radio-dermatitis, myxedema with thyroid adenoma and epiglottic tumor. A 38-year-old man has noticed muscle weakness and wasting of the right shoulder girdle since age 33. A detailed history taking revealed a previous irradiation to the neck because of the cervical lymphadenopathy at age 10 (X-ray 3,000 rads), keroid skin change at age 19, obesity and edema since 26, and hoarseness at 34. Laryngoscopic examination revealed a tumor on the right vocal cord, diagnosed as benign papilloma by histological study. In addition, there were chronic radio-dermatitis around the neck, primary hypothyroidism with a benign functioning adenoma on the right lobe of the thyroid, the right phrenic nerve palsy and the right recurrent nerve palsy. All these lesions were considered to be the late sequellae of radiation to the neck in childhood. Other neurological signs were weakness and amyotrophy of the right shoulder girdle with patchy sensory loss, and areflexia of the right arm. Gross power was fairly well preserved in the right hand. EMG showed neurogenic changes in the tested muscles, suggesting a peripheral nerve lesion. Nerve conduction velocities were normal. No abnormal findings were revealed by myelography and spinal CT. The neurological findings of the patient were compatible with the diagnosis of middle cervical plexus palsy apparently due to late radiation effect. In the literature eight cases of post-radiation neuropathy with a long latency have been reported. The present case with the longest latency after the radiation should be included in the series of the reported cases of ''delayed radiation neuropathy.'' (author).

  20. [Hereditary and familial colorectal cancer].

    Science.gov (United States)

    Balaguer, Francesc

    2014-09-01

    Up to 5% of all colorectal cancer cases are caused by a known hereditary syndrome. These hereditary types often need a higher degree of clinical suspicion to be diagnosed and require specific and specialized management. In addition, diagnosing hereditary colorectal cancer has significant consequences not only for the patient, for whom there are effective preventative measures, but also for their families, who could be carriers of the condition. The most significant advances in the field of colorectal cancer have come from the diagnosis and characterization of these syndromes. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  1. Hereditary neuromuscular diseases

    Energy Technology Data Exchange (ETDEWEB)

    Oezsarlak, O. E-mail: ozkan.ozsarlak@uza.be; Schepens, E.; Parizel, P.M.; Goethem, J.W. van; Vanhoenacker, F.; Schepper, A.M. de; Martin, J.J

    2001-12-01

    This article presents the actual classification of neuromuscular diseases based on present expansion of our knowledge and understanding due to genetic developments. It summarizes the genetic and clinical presentations of each disorder together with CT findings, which we studied in a large group of patients with neuromuscular diseases. The muscular dystrophies as the largest and most common group of hereditary muscle diseases will be highlighted by giving detailed information about the role of CT and MRI in the differential diagnosis. The radiological features of neuromuscular diseases are atrophy, hypertrophy, pseudohypertrophy and fatty infiltration of muscles on a selective basis. Although the patterns and distribution of involvement are characteristic in some of the diseases, the definition of the type of disease based on CT scan only is not always possible.

  2. Hereditary colorectal cancer diagnostics

    DEFF Research Database (Denmark)

    Klarskov, Louise; Holck, Susanne; Bernstein, Inge

    2012-01-01

    BackgroundThe hereditary non-polyposis colorectal cancer (HNPCC) subset of tumours can broadly be divided into tumours caused by an underlying mismatch-repair gene mutation, referred to as Lynch syndrome, and those that develop in families with similar patterns of heredity but without disease......-predisposing germline mismatch repair mutations, referred to as familial colorectal cancer type X (FCCTX). Recognition of HNPCC-associated colorectal cancers is central since surveillance programmes effectively reduce morbidity and mortality. The characteristic morphological features linked to Lynch syndrome can aid...... in the identification of this subset, whereas the possibility to use morphological features as an indicator of FCCTX is uncertain.Objective and methodsTo perform a detailed morphological evaluation of HNPCC-associated colorectal cancers and demonstrate significant differences between tumours associated with FCCTX...

  3. Hereditary Fructose Intolerance

    Directory of Open Access Journals (Sweden)

    N.V. Nagornaya

    2014-06-01

    Full Text Available Hereditary fructose intolerance, the prevalence of which is 1 : 20,000 population, is diagnosed much less frequently than is found in child and adult populations. Presented pathology is caused by a deficiency in ferment aldolase B and block of fructose transformation in the gastrointestinal tract with the accumulation of unprocessed fructose in the intestine, manifesting by characteristic symptom and numerous biochemical changes in the body. The disease is asymptomatic until a person begins to use fructose, sucrose or sorbitol. This article describes the fructose metabolism, genetic aspects of the discussing disease, the diversity of its clinical manifestations. The authors presented modern diagnostic criteria and international approaches to diet therapy.

  4. Does Peripheral Neuropathy Associate with Cranial Nerves Neuropathy in Type 2 diabetes Patients?

    Directory of Open Access Journals (Sweden)

    Walaa Fadhil Jalal

    2017-02-01

    Full Text Available Diabetic peripheral neuropathy (DPN is the most common complication of type 2 diabetes mellitus. Cranial neuropathies is usually presenting as mononeuropathies coexist with DPN either presented clinically or in subclinical form. The aim of this study is to detect cranial neuropathy in diabetic patients. Eighty three patients with type 2 diabetes mellitus (T2DM with an age range of 30-69 years were included in the study. The study also involved normal healthy persons whose age and gender are harmonized with that of our patients that were deliberated as control group (60 persons. Diabetic patients with DPN had significant difference in age, highly significant difference in the duration of the disease and highly significance difference in BMI had poor glycemic control reflected by high FBS and HbA1c, while lipid profile picture showed insignificant difference when compared with diabetic patients without DPN. Nerve conduction study (sensory and motor showed a significant difference regarding latency, amplitude, and conduction velocity between diabetic patients with DPN and those without DPN. The results of blink reflex showed highly significant difference between diabetic patients and controls.

  5. Neuroprotective effects of octreotide on diabetic neuropathy in rats.

    Science.gov (United States)

    Solmaz, Volkan; Çınar, Bilge Piri; Yiğittürk, Gürkan; Özlece, Hatice Köse; Avni Eroglu, Hüseyin; Tekatas, Aslan; Erbaş, Oytun; Taşkıran, Dilek

    2017-05-01

    The purpose of the present study is to investigate the possible healing effects of octreotide (OCT) on motor performance, electrophysiological and histopathological findings of diabetic neuropathy in a rat model of diabetes mellitus (DM). To induce diabetes, rats were administered a single dose (60mg/kg) of streptozotocin (STZ). Diabetic rats were treated either with saline (1ml/kg/day, n=7) or OCT (0.1mg/kg/day, n=7) for four weeks. Seven rats served as control group and received no treatment. At the end of the study, electromyography (EMG), gross motor function (inclined plate test), general histology and the perineural thickness of sciatic nerve were evaluated. At the end of study, weight loss was significantly lower in OCT treated rats than that of saline treated ones (pneuropathy, which promisingly support the use of OCT as a neuroprotective agent in patients with diabetic neuropathy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Hereditary iron and copper deposition

    DEFF Research Database (Denmark)

    Aaseth, Jan; Flaten, Trond Peder; Andersen, Ole

    2007-01-01

    Hereditary deposition of iron (primary haemochromatosis) or copper (Wilson's disease) are autosomal recessive metabolic disease characterized by progressive liver pathology and subsequent involvement of various other organs. The prevalence of primary haemochromatosis is approximately 0.5%, about...

  7. Postural characteristics of diabetic neuropathy.

    Science.gov (United States)

    Oppenheim, U; Kohen-Raz, R; Alex, D; Kohen-Raz, A; Azarya, M

    1999-02-01

    To explore the posturographic correlates of diabetic neuropathy by comparing the performances of three groups of diabetic patients (severe, moderate, and absent neuropathy) with those of normal subjects and four clinical control groups. Using the Interactive Balance System (Tetrax, Ramat Gan, Israel), based on the assessment of the interaction of vertical pressure fluctuations on four independent platforms, one for each heel and toe part, respectively, posturographic examinations were given to 28 diabetic patients (8 with severe, 12 with moderate, and 8 with no peripheral neuropathy), 30 normal control subjects, and a clinical control group of 52 patients (14 with stage II Parkinson's disease, 13 with brain damage, 7 with whiplash, and 19 with peripheral vestibular pathology). The following posturographic parameters were evaluated; 1) general stability; 2) Fourier analysis showing patterns of sway intensity within eight frequency bands between 0.1 and 3 Hz; 3) weight distribution; 4) synchronization of sway; and 5) performance patterns for eight positions, requiring closure of eyes and standing on an elastic surface, as well as left, right, back, and downward head turns. For positions with closed eyes, diabetic patients with severe and moderate neuropathy were significantly less stable than normal subjects and diabetic patients without neuropathy, but diabetic patients with severe and moderate neuropathy turned out to be as equally unstable as clinical control subjects. However, for sway intensity within the band of 0.5 to 1.00 Hz on positions with lateral head turn with occluded vision, neuropathic diabetic patients performed significantly worse than did both normal and clinical control subjects. The same posturographic parameter also differed significantly between normal subjects and diabetic patients without neuropathy. As reported in previous studies, general instability in diabetic neuropathy is not a sufficiently characteristic correlate of the syndrome. On

  8. Role of A3 adenosine receptor in diabetic neuropathy.

    Science.gov (United States)

    Yan, Heng; Zhang, Enshui; Feng, Chang; Zhao, Xin

    2016-10-01

    Neuropathy is the most common diabetic complication. Although the A1 and A2A adenosine receptors are important pharmacological targets in alleviating diabetic neuropathy, the role of the A3 adenosine receptor remains unknown. Because the A3 adenosine receptor regulates pain induced by chronic constriction injury or chemotherapy, its stimulation might also attenuate diabetic neuropathy. This study examines the effects of systemic treatment with the A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide (IB-MECA) on diabetic neuropathy and explores the putative mechanisms underlying its pharmacological effects. We show that IB-MECA alleviated mechanical hyperalgesia and thermal hypoalgesia in mice 2 weeks but not 4 weeks after streptozocin (STZ) treatment. Furthermore, IB-MECA prevented the reduction in sciatic motor nerve conduction velocity and sensory nerve conduction velocity in diabetic mice 2 weeks but not 4 weeks after STZ treatment. Similarly, IB-MECA inhibited the activation of nuclear factor-κB and decreased the generation of tumor necrosis factor-α in the spinal cord of mice 2 weeks but not 4 weeks after STZ treatment. These phenomena were associated with reduction of A3 adenosine receptor expression in the spinal cord after long-term diabetes. Our results suggest that the A3 adenosine receptor plays a critical role in regulating diabetic neuropathy and that reduction in A3 adenosine receptor expression/function might contribute to the progression of diabetic neuropathy. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  9. Restoration of optic neuropathy

    Directory of Open Access Journals (Sweden)

    You SW

    2017-03-01

    Full Text Available Si-Wei You,1 Ming-Mei Wu,2 Fang Kuang,2 Kin-Sang Cho,3 Kwok-Fai So4,5 1Department of Ophthalmology, Xijing Hospital, 2Institute of Neurosciences, The Fourth Military Medical University, Xi’an, China; 3Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; 4GHM Institute of CNS Regeneration, Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, 5Department of Ophthalmology, The State Key laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China Abstract: Optic neuropathy refers to disorders involving the optic nerve (ON. Any damage to ON or ON-deriving neurons, the retinal ganglion cells (RGCs, may lead to the breakdown of the optical signal transmission from the eye to the brain, thus resulting in a partial or complete vision loss. The causes of optic neuropathy include trauma, ischemia, inflammation, compression, infiltration, and mitochondrial damages. ON injuries include primary and secondary injuries. During these injury phases, various factors orchestrate injured axons to die back and become unable to regenerate, and these factors could be divided into two categories: extrinsic and intrinsic. Extrinsic inhibitory factors refer to the environmental conditions that influence the regeneration of injured axons. The presence of myelin inhibitors and glial scar, lack of neurotrophic factors, and inflammation mediated by injury are regarded as these extrinsic factors. Extrinsic factors need to trigger the intracellular signals to exert inhibitory effect. Proper regulation of these intracellular signals has been shown to be beneficial to ON regeneration. Intrinsic factors of RGCs are the pivotal reasons that inhibit ON regeneration and are closely linked with extrinsic factors. Intracellular cyclic adenosine monophosphate (cAMP and calcium levels affect axon guidance and growth cone response to guidance molecules

  10. Pseudoperipheral palsy: a case of subcortical infarction imitating peripheral neuropathy.

    Science.gov (United States)

    Jusufovic, Mirza; Lygren, Astrid; Aamodt, Anne Hege; Nedregaard, Bård; Kerty, Emilia

    2015-08-25

    Vascular damage in the central hand knob area can mimic peripheral motor nerve deficits. We describe the case of a woman presenting with apparent peripheral neuropathy. Brain magnetic resonance imaging and computed tomography angiography revealed an infarct in the precentral hand knob area, with significant stenosis in the right proximal middle cerebral artery trunk. Subsequent 3-Tesla magnetic resonance imaging of the brain suggested cerebral angiitis. The patient experienced improved hand function following combined glucocorticoid and cyclophosphamide treatment. Vascular damage in the hand knob area should be considered when evaluating peripheral motor nerve deficits in the presence of normal nerve conduction velocities. The diagnosis of cerebral angiitis remains a major challenge for clinicians.

  11. Mitochondrial optic neuropathies – Disease mechanisms and therapeutic strategies

    Science.gov (United States)

    Yu-Wai-Man, Patrick; Griffiths, Philip G.; Chinnery, Patrick F.

    2011-01-01

    Leber hereditary optic neuropathy (LHON) and autosomal-dominant optic atrophy (DOA) are the two most common inherited optic neuropathies in the general population. Both disorders share striking pathological similarities, marked by the selective loss of retinal ganglion cells (RGCs) and the early involvement of the papillomacular bundle. Three mitochondrial DNA (mtDNA) point mutations; m.3460G>A, m.11778G>A, and m.14484T>C account for over 90% of LHON cases, and in DOA, the majority of affected families harbour mutations in the OPA1 gene, which codes for a mitochondrial inner membrane protein. Optic nerve degeneration in LHON and DOA is therefore due to disturbed mitochondrial function and a predominantly complex I respiratory chain defect has been identified using both in vitro and in vivo biochemical assays. However, the trigger for RGC loss is much more complex than a simple bioenergetic crisis and other important disease mechanisms have emerged relating to mitochondrial network dynamics, mtDNA maintenance, axonal transport, and the involvement of the cytoskeleton in maintaining a differential mitochondrial gradient at sites such as the lamina cribosa. The downstream consequences of these mitochondrial disturbances are likely to be influenced by the local cellular milieu. The vulnerability of RGCs in LHON and DOA could derive not only from tissue-specific, genetically-determined biological factors, but also from an increased susceptibility to exogenous influences such as light exposure, smoking, and pharmacological agents with putative mitochondrial toxic effects. Our concept of inherited mitochondrial optic neuropathies has evolved over the past decade, with the observation that patients with LHON and DOA can manifest a much broader phenotypic spectrum than pure optic nerve involvement. Interestingly, these phenotypes are sometimes clinically indistinguishable from other neurodegenerative disorders such as Charcot-Marie-Tooth disease, hereditary spastic

  12. Hereditary Renal Cancer Syndromes

    Science.gov (United States)

    Haas, Naomi B.

    2013-01-01

    Inherited susceptibility to kidney cancer is a fascinating and complex topic. Our knowledge about types of genetic syndromes associated with an increased risk of disease is continually expanding. Currently, there are 10 syndromes associated with an increased risk of all types of renal cancer, which are reviewed herein. Clear cell renal cancer is associated with von Hippel Lindau disease, chromosome 3 translocations, PTEN hamartomatous syndrome and mutations in BAP1, as well as several of the genes encoding the proteins comprising the succinate dehydrogenase complex (SDHB/C/D). Type 1 papillary renal cancers arise in conjunction with germline mutations in MET and type 2 as part of Hereditary Leiomyomatosis and Renal Cell Cancer (FH mutations). Chromophone and oncocytic renal cancers are predominantly associated with Birt Hogg Dubé syndrome. Angiomyolipomas are commonly and their malignant counterpart epitheliod angiomyolipomas rarely are found in patients with Tuberous Sclerosis Complex. The targeted therapeutic options for the renal cancer associated with these diseases are just starting to expand, and are an area of active clinical research. PMID:24359990

  13. A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathies.

    Directory of Open Access Journals (Sweden)

    Jocelyn Plassais

    2016-12-01

    Full Text Available Human Hereditary Sensory Autonomic Neuropathies (HSANs are characterized by insensitivity to pain, sometimes combined with self-mutilation. Strikingly, several sporting dog breeds are particularly affected by such neuropathies. Clinical signs appear in young puppies and consist of acral analgesia, with or without sudden intense licking, biting and severe self-mutilation of the feet, whereas proprioception, motor abilities and spinal reflexes remain intact. Through a Genome Wide Association Study (GWAS with 24 affected and 30 unaffected sporting dogs using the Canine HD 170K SNP array (Illumina, we identified a 1.8 Mb homozygous locus on canine chromosome 4 (adj. p-val = 2.5x10-6. Targeted high-throughput sequencing of this locus in 4 affected and 4 unaffected dogs identified 478 variants. Only one variant perfectly segregated with the expected recessive inheritance in 300 sporting dogs of known clinical status, while it was never present in 900 unaffected dogs from 130 other breeds. This variant, located 90 kb upstream of the GDNF gene, a highly relevant neurotrophic factor candidate gene, lies in a long intergenic non-coding RNAs (lincRNA, GDNF-AS. Using human comparative genomic analysis, we observed that the canine variant maps onto an enhancer element. Quantitative RT-PCR of dorsal root ganglia RNAs of affected dogs showed a significant decrease of both GDNF mRNA and GDNF-AS expression levels (respectively 60% and 80%, as compared to unaffected dogs. We thus performed gel shift assays (EMSA that reveal that the canine variant significantly alters the binding of regulatory elements. Altogether, these results allowed the identification in dogs of GDNF as a relevant candidate for human HSAN and insensitivity to pain, but also shed light on the regulation of GDNF transcription. Finally, such results allow proposing these sporting dog breeds as natural models for clinical trials with a double benefit for human and veterinary medicine.

  14. ANTIOXIDANT STATUS IN DIABETIC NEUROPATHY

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    Giriraja Vrushabaiah Kanakapura

    2017-09-01

    Full Text Available BACKGROUND Diabetic neuropathy, retinopathy and nephropathy are the chronic complications of diabetes mellitus. Neuropathy, retinopathy and nephropathy are microvascular complication of diabetes mellitus. Antioxidant status is reduced in DM-induced retinopathy and nephropathy. Present study is undertaken to evaluate the degree of oxidative stress in diabetic neuropathy patients. The aim of the study is to study on oxidative stress as measured by lipid peroxidation marker, malondialdehyde and antienzyme status in type II DM patients with neuropathy and compared them with a controlled nondiabetic group. MATERIALS AND METHODS The study included 100 subjects from Sapthagiri Medical College, Bangalore, from January 1, 2015, to December 31, 2015, of age group 50 to 70 yrs. out of which 50 patients were non-insulin-dependent DM with neuropathy and rest 50 age and sex matched apparently healthy individuals (control group. Antioxidant status was assessed by measuring superoxide dismutase (SOD, glutathione peroxidase (GPx, glutathione reductase (GR, Catalase and Reduced Glutathione (GSH. RESULTS It showed a significant increase p<0.001 in FBS, PPBS, TC, TG, LDL, VLDL, CAT, MDA, while HDL, GSH, GPX, GR and SOD were found to be decreased significantly (p 0.001. CONCLUSION MDA was significantly elevated in diabetic group, whereas antioxidant enzymes superoxide dismutase, glutathione peroxidase, glutathione reductase and reduced glutathione were significantly decreased, which might be helpful in risk assessment of various complications of DM. The data suggests that alteration in antioxidant status and MDA may help to predict the risk of diabetic neuropathy.

  15. Burden of Chemotherapy-Induced Neuropathy in School ged children

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    Artan Shkoza

    2015-11-01

    Full Text Available Chemotherapy-induced peripheral neuropathy (CIPN is the most common neurological complication in cancer treatment and probably the most common toxic neuropathy in our environment. The aim of the study was to assess the incidence and discomfort caused by neuropathic symptoms in children treated for hematologic cancers. The study included all children admitted to the pediatric oncology service at the University Hospital Center “Mother Teresa”, Tirana, by the year 2011 – 2013 divided in three diagnosis groups: acute lymphoblastic leukemia, Hodgkin and non-Hodgkin’s lymphoma, or other solid tumors. In a prospective cohort setting, data were collected by standard questionnaire for symptoms and signs of neurological damage, according to The Pediatric - Modified Total Neuropathy Scale (Ped - mTNS, as well as clinical evaluation of pin sensibility, vibration sensibility, muscle strength and deep tendon reflexes (DTR. The results obtained from Ped-mTNS, showed the high incidence of sensory and motor symptoms as well as functional deficits in balance and manual dexterity in children treated with anticancer drugs. Ped-mTNS scores, as the first measure designed to assess CIPN in school-aged children, are significantly higher for children undergoing neurotoxic chemotherapy. Even though the neuropathy in these children was relatively mild, it was associated with functional deficits in balance and manual dexterity, suggesting clinical importance. An important limiting factor of this study is the exclusion of children younger than 5 years old, whom discomfort is evident but not properly evaluated.

  16. Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment.

    Science.gov (United States)

    Mo, Michelle; Erdelyi, Ildiko; Szigeti-Buck, Klara; Benbow, Jennifer H; Ehrlich, Barbara E

    2012-11-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect that occurs in many patients undergoing chemotherapy. It is often irreversible and frequently leads to early termination of treatment. In this study, we have identified two compounds, lithium and ibudilast, that when administered as a single prophylactic injection prior to paclitaxel treatment, prevent the development of CIPN in mice at the sensory-motor and cellular level. The prevention of neuropathy was not observed in paclitaxel-treated mice that were only prophylactically treated with a vehicle injection. The coadministration of lithium with paclitaxel also allows for administration of higher doses of paclitaxel (survival increases by 60%), protects against paclitaxel-induced cardiac abnormalities, and, notably, does not interfere with the antitumor effects of paclitaxel. Moreover, we have determined a mechanism by which CIPN develops and have discovered that lithium and ibudilast inhibit development of peripheral neuropathy by disrupting the interaction between paclitaxel, neuronal calcium sensor 1 (NCS-1), and the inositol 1,4,5-trisphosphate receptor (InsP3R) to prevent treatment-induced decreases in intracellular calcium signaling. This study shows that lithium and ibudilast are candidate therapeutics for the prevention of paclitaxel-induced neuropathy and could enable patients to tolerate more aggressive treatment regimens.

  17. [Ataxias and hereditary spastic paraplegias].

    Science.gov (United States)

    Schüle, R; Schöls, L

    2017-07-01

    Hereditary ataxias and spastic paraplegias are genetic disorders with age-dependent nearly complete penetrance. The mostly monogenetic etiology allows one to establish the diagnosis, study pathogenesis and to develop new causative therapeutic approaches for these diseases. Both the causative genes as well as the clinical presentation overlap considerably between hereditary ataxias and spastic paraplegias. This strongly argues towards a united classification for these two groups of diseases. Next generation sequencing technologies have greatly expanded the number of genes known to be causative for hereditary ataxias and spastic paraplegias and allow simultaneous time- and cost-effective diagnostic testing of > 200 genes. However, repeat expansions and large genomic deletions must be considered separately. Here, we suggest a pragmatic algorithm for genetic testing in hereditary ataxias and spastic paraplegias that we have developed in our specialized outpatient clinics. Detailed phenotyping remains crucial to interpret the multitude of genetic variants discovered by high throughput sequencing techniques. Despite recent technical advances, a substantial proportion of ataxia and spastic paraplegia families are still without a molecular diagnosis. Beside new and so far undetected ataxia and spasticity genes, unusual mutation types including noncoding variants and polygenic inheritance patterns may contribute. Because of these clinical, genetic, and technological challenges, patients with hereditary ataxias and spastic paraplegias should be referred to specialized centers offering research and clinical studies. This will also help to recruit representative patient cohorts for upcoming interventional trials.

  18. Hereditary pancreatitis: current perspectives

    Directory of Open Access Journals (Sweden)

    Raphael KL

    2016-07-01

    Full Text Available Kara L Raphael, Field F Willingham Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Abstract: Hereditary pancreatitis (HP is a rare cause of acute, recurrent acute, and chronic pancreatitis. It may present similarly to other causes of acute and chronic pancreatitis, and often there has been a protracted evaluation prior to the diagnosis of HP. Since it was first described in 1952, multiple genetic defects that affect the action of digestive enzymes in the pancreas have been implicated. The most common mutations involve the PRSS1, CFTR, SPINK1, and CTRC genes. New mutations in these genes and previously unrecognized mutations in other genes are being discovered due to the increasing use of next-generation genomic sequencing. While the inheritance pathways of these genetic mutations may be variable and complex, sometimes involving coinheritance of other mutations, the clinical presentation of patients tends to be similar. Interactions with environmental triggers often play a role. Patients tend to present at an early age (prior to the second decade of life and have a significantly increased risk for the development of pancreatic adenocarcinoma. Patients with HP may develop sequelae of chronic pancreatitis such as strictures and fluid collections as well as exocrine and endocrine insufficiency. Management of patients with HP involves avoidance of environmental triggers, surveillance for pancreatic adenocarcinoma, medical therapy for endocrine and exocrine insufficiency, pain management, and endoscopic or surgical treatment for complications. Care for affected patients should be individualized, with an emphasis on early diagnosis and multidisciplinary involvement to develop a comprehensive treatment strategy. Keywords: pancreatic cancer, chronic pancreatitis, idiopathic pancreatitis, pancreatitis, familial pancreatitis, genetic mutations

  19. New genetic causes for complex hereditary spastic paraplegia.

    Science.gov (United States)

    Souza, Paulo Victor Sgobbi de; Bortholin, Thiago; Dias, Renan Braido; Chieia, Marco Antônio Troccoli; Burlin, Stênio; Naylor, Fernando George Monteiro; Pinto, Wladimir Bocca Vieira de Rezende; Oliveira, Acary Souza Bulle

    2017-08-15

    Hereditary Spastic Paraplegia (HSP) represents a complex and heterogeneous group of rare neurodegenerative disorders that share a common clinical feature of weakness and lower limb spasticity that can occur alone or in combination with a constellation of other neurological or systemic signs and symptoms. Although the core clinical feature of weakness and lower limb spasticity is virtually universal, the genetic heterogeneity is almost uncountable with more than 70 genetic forms described so far. We performed review of medical records from twenty-one patients from seventeen Brazilian families with complex phenotype of HSP. All cases have previously negative mutations in SPG11/KIAA1840 and SPG7 gene and were evaluated by whole-exome sequencing. An extensive description of systemic and neurological signs has been described. Whole-exome sequencing was unremarkable in eight patients and established a definite genetic diagnosis in thirteen patients of twelve non-related families. Mutations were found in genes previously implicated in other neurodegenerative disorders such as Amyotrophic Lateral Sclerosis, Hereditary Neuropathy, Spastic Ataxias, Neurodegeneration with Brain Iron Accumulation, Glycogen Metabolism, Congenital Lipodystrophy and aminoacyl-tRNA synthetases disorders. We report thirteen new genetically-proven cases of complex HSP, expanding the clinical spectrum of presentations of HSP, providing new pathophysiological mechanisms and disclosing new potential therapeutic targets. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Comparison of two chemotherapy-induced peripheral neuropathy measurement approaches in children.

    Science.gov (United States)

    Gilchrist, L S; Marais, L; Tanner, L

    2014-02-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment in children; however, measurement of CIPN has been hampered by limitations in available tools, which may impact prevalence estimates. The purpose of this study was to assess the relative ability of the Common Terminology Criteria (CTCAE) rating process to detect sensory and motor neuropathy as compared to administration of the pediatric modified Total Neuropathy Score (peds-mTNS). The ped-mTNS was administered to 60 children/adolescents ages 5-18 undergoing treatment for acute lymphocytic leukemia, lymphoma, or non-CNS solid tumors. CTCAE v3.0 scores for the same time point were abstracted from the medical record by a separate trained rater. Comparisons were made between scores using descriptive statistics, correlations, and specificity and sensitivity calculations. The median ped-mTNS score was 9 (32 possible), while the median sensory and motor CTCAE ratings were 0 and 2, respectively (4 and 5 possible, respectively). There was no correlation between ped-mTNS and combined sensory and motor CTCAE scores. The only ped-mTNS item with significant correlation to CTCAE scoring was strength testing. Medical record abstraction of CTCAE scores failed to identify sensory neuropathy in 40 % and significant motor neuropathy (manual muscle test grade 3 or worse) in 15 % of subjects. Prospective measures of CIPN using the ped-mTNS identified a far greater proportion of subjects with peripheral neurotoxicity as compared to CTCAE v3.0 sensory and motor neuropathy ratings, and thus we recommend the use of a specific measure of CIPN such as the ped-mTNS.

  1. [Association between neuropathy and peripheral vascular insufficiency in patients with diabetes mellitus type 2].

    Science.gov (United States)

    Millán-Guerrero, Rebeca O; Vásquez, Clemente; Isaís-Millán, Sara; Trujillo-Hernández, Benjamín; Caballero-Hoyos, Ramiro

    2011-01-01

    Diabetes mellitus (DM) can present complications of neuropathy and peripheral arterial disease with high risk for developing foot ulcers and consequent amputations. To identify the association between peripheral vascular disease, and neuropathy in type 2 Diabetes mellitus patients from the Hospital General de Zona No. 1 IMSS in Colima, Mexico. Cross-sectional study of 80 patients with diabetes mellitus evaluated by means of the Edinburgh Claudication Questionnaire, Michigan Neuropathy Screening Instrument, ankle-arm index, Motor Nerve Conduction Velocity and H-reflex. 51 women and 29 men were studied. Mean age was 53.9 +/- 9.6 years, mean diabetes mellitus progression was 8 +/- 6.6 years and mean glucose level was 283 +/- 110 mg/mL. Neuropathy presented in 65 patients (81.2%). Ankle/arm index revealed 19% of patients presented with moderate peripheral vascular insufficiency. Motor Nerve Conduction Velocity was abnormal in 40% of patients and H-reflex was absent in 70%. Grade 2 motor-sensitive polyneuropathy was found in 70-80% of patients and moderate peripheral vascular insufficiency in 19%. It can thus be inferred that the complication of diabetic neuropathy appears before that of peripheral vessel damage.

  2. Novel EXOSC3 mutation causes complicated hereditary spastic paraplegia.

    Science.gov (United States)

    Halevy, Ayelet; Lerer, Israela; Cohen, Rony; Kornreich, Liora; Shuper, Avinoam; Gamliel, Moria; Zimerman, Bat-El; Korabi, Isam; Meiner, Vardiella; Straussberg, Rachel; Lossos, Alexander

    2014-11-01

    We describe two pairs of siblings from a consanguineous family manifesting autosomal recessive hereditary spastic paraplegia caused by a novel mutation in the EXOSC3 gene, previously reported in pontocerebellar hypoplasia type 1. Clinical findings included delayed motor milestones, early-onset spastic paraplegia, variable cognitive disability, and cerebellar signs. Cerebral imaging demonstrated enlarged cisterna magna and mild hypoplasia and atrophy of the lower vermis with a normal pons. Genetic analysis using homozygosity mapping followed by whole exome sequencing identified homozygous c.571G>T; p.G191C mutation in the EXOSC3 gene. We suggest that EXOSC3 mutations may present not only as pontocerebellar hypoplasia type 1, but also as a complicated form of hereditary spastic paraplegia without pontine hypoplasia or atrophy.

  3. Risk factors for motor neuron diseases : genes, environment and lifestyle

    NARCIS (Netherlands)

    Sutedja, N.A.

    2010-01-01

    The main focus of this thesis is to identify susceptibility factors in diseases affecting the motor neuron: both motor neuron disease (MND), in which primarily the cell body is affected, and multifocal motor neuropathy (MMN), in which primarily the axon is affected, are covered. Due to its

  4. Pathology of hereditary breast cancer

    OpenAIRE

    van der Groep, Petra; van der Wall, Elsken; van Diest, Paul J.

    2011-01-01

    Background Hereditary breast cancer runs in families where several members in different generations are affected. Most of these breast cancers are caused by mutations in the high penetrance genes BRCA1 and BRCA2 accounting for about 5% of all breast cancers. Other genes that include CHEK2, PTEN, TP53, ATM, STK11/LKB1, CDH1, NBS1, RAD50, BRIP1 and PALB2 have been described to be high or moderate penetrance breast cancer susceptibility genes, all contributing to the hereditary breast cancer spe...

  5. [Small fiber neuropathy].

    Science.gov (United States)

    Langlois, V; Bedat Millet, A-L; Lebesnerais, M; Miranda, S; Marguet, F; Benhamou, Y; Marcorelles, P; Lévesque, H

    2017-04-11

    Small fiber neuropathy (SFN) is still unknown. Characterised by neuropathic pain, it typically begins by burning feet, but could take many other expression. SFN affects the thinly myelinated Aδ and unmyelinated C-fibers, by an inherited or acquired mechanism, which could lead to paresthesia, thermoalgic disorder or autonomic dysfunction. Recent studies suggest the preponderant role of ion channels such as Nav1.7. Furthermore, erythromelalgia or burning mouth syndrome are now recognized as real SFN. Various aetiologies of SFN are described. It could be isolated or associated with diabetes, impaired glucose metabolism, vitamin deficiency, alcohol, auto-immune disease, sarcoidosis etc. Several mutations have recently been identified, like Nav1.7 channel leading to channelopathies. Diagnostic management is based primarily on clinical examination and demonstration of small fiber dysfunction. Laser evoked potentials, Sudoscan®, cutaneous biopsy are the main test, but had a difficult access. Treatment is based on multidisciplinary management, combining symptomatic treatment, psychological management and treatment of an associated etiology. Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  6. Neuropathy under chemotherapy.

    Science.gov (United States)

    Beinert, T; Masuhr, F; Mwela, E; Schweigert, M; Flath, B; Harder, H; Binder, D; Oehm, C; Behse, F; Possinger, K

    2000-10-30

    Neuropathy is a dose-limiting side effect for a number of effective chemotherapeutic agents. A better understanding of effective mechanisms will lead to novel treatment strategies that will protect neurons without decreasing therapeutic efficacy. The assessment of the efficacy and neurotoxicity of various chemotherapeutic agents is vital, for a determination of the maximum allowable dose. The introduction of chemotherapy in the 50s and 60s of the twentieth century has resulted in the development of curative therapeutic interventions for patients with several types of solid tumours and hemopoietic neoplasms. The important obstacles encountered in the use of chemotherapy have been the toxicity to the normal tissue. During the past 8 years there has come about a new level of understanding of the mechanisms through which chemotherapeutic agents work. This has opened the door to new paradigms of treatment in which molecular, genetic, and biologic therapy can be used together to increase the sensitivity of abnormal cells to treatment, and to protect the normal tissues of the body from therapy-induced side effects. The implementation of new strategies could change the way therapy is delivered over the next few years and improve the outcome especially in patients with neoplasms that are currently resistant to conventional dose therapy.

  7. Hypothyroidism: Can It Cause Peripheral Neuropathy?

    Science.gov (United States)

    Hypothyroidism: Can it cause peripheral neuropathy? Can hypothyroidism cause peripheral neuropathy and, if so, how is it treated? Answers from Todd B. Nippoldt, M.D. Hypothyroidism — a condition in which your ...

  8. Autophagy as an Emerging Common Pathomechanism in Inherited Peripheral Neuropathies

    Directory of Open Access Journals (Sweden)

    Mansour Haidar

    2017-05-01

    Full Text Available The inherited peripheral neuropathies (IPNs comprise a growing list of genetically heterogeneous diseases. With mutations in more than 80 genes being reported to cause IPNs, a wide spectrum of functional consequences is expected to follow this genotypic diversity. Hence, the search for a common pathomechanism among the different phenotypes has become the holy grail of functional research into IPNs. During the last decade, studies on several affected genes have shown a direct and/or indirect correlation with autophagy. Autophagy, a cellular homeostatic process, is required for the removal of cell aggregates, long-lived proteins and dead organelles from the cell in double-membraned vesicles destined for the lysosomes. As an evolutionarily highly conserved process, autophagy is essential for the survival and proper functioning of the cell. Recently, neuronal cells have been shown to be particularly vulnerable to disruption of the autophagic pathway. Furthermore, autophagy has been shown to be affected in various common neurodegenerative diseases of both the central and the peripheral nervous system including Alzheimer’s, Parkinson’s, and Huntington’s diseases. In this review we provide an overview of the genes involved in hereditary neuropathies which are linked to autophagy and we propose the disruption of the autophagic flux as an emerging common pathomechanism. We also shed light on the different steps of the autophagy pathway linked to these genes. Finally, we review the concept of autophagy being a therapeutic target in IPNs, and the possibilities and challenges of this pathway-specific targeting.

  9. An update on electrophysiological studies in neuropathy

    DEFF Research Database (Denmark)

    Krarup, Christian

    2003-01-01

    The review concentrates on the use of clinical neurophysiology in peripheral nerve disorders covered in the present issue. It is pertinent to distinguish different types of involvement of fibers in diabetic neuropathy, including the involvement of small and large fibers, to outline the diagnostic...... criteria of inflammatory neuropathies, and to describe the spectrum of peripheral nerve pathophysiology in inherited neuropathies. Painful neuropathies represent a particular challenge to clinical neurophysiology since it is mainly small fibers, which are difficult to study, that are affected....

  10. Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy.

    Science.gov (United States)

    Klebe, Stephan; Depienne, Christel; Gerber, Sylvie; Challe, Georges; Anheim, Mathieu; Charles, Perrine; Fedirko, Estelle; Lejeune, Elodie; Cottineau, Julien; Brusco, Alfredo; Dollfus, Hélène; Chinnery, Patrick F; Mancini, Cecilia; Ferrer, Xavier; Sole, Guilhem; Destée, Alain; Mayer, Jean-Michel; Fontaine, Bertrand; de Seze, Jérôme; Clanet, Michel; Ollagnon, Elisabeth; Busson, Philippe; Cazeneuve, Cécile; Stevanin, Giovanni; Kaplan, Josseline; Rozet, Jean-Michel; Brice, Alexis; Durr, Alexandra

    2012-10-01

    Mutations in the spastic paraplegia 7 (SPG7) gene encoding paraplegin are responsible for autosomal recessive hereditary spasticity. We screened 135 unrelated index cases, selected in five different settings: SPG7-positive patients detected during SPG31 analysis using SPG31/SPG7 multiplex ligation-dependent probe amplification (n = 7); previously reported ambiguous SPG7 cases (n = 5); patients carefully selected on the basis of their phenotype (spasticity of the lower limbs with cerebellar signs and/or cerebellar atrophy on magnetic resonance imaging/computer tomography scan and/or optic neuropathy and without other signs) (n = 24); patients with hereditary spastic paraparesis referred consecutively from attending neurologists and the national reference centre in a diagnostic setting (n = 98); and the index case of a four-generation family with autosomal dominant optic neuropathy but no spasticity linked to the SPG7 locus. We identified two SPG7 mutations in 23/134 spastic patients, 21% of the patients selected according to phenotype but only 8% of those referred directly. Our results confirm the pathogenicity of Ala510Val, which was the most frequent mutation in our series (65%) and segregated at the homozygous state with spastic paraparesis in a large family with autosomal recessive inheritance. All SPG7-positive patients tested had optic neuropathy or abnormalities revealed by optical coherence tomography, indicating that abnormalities in optical coherence tomography could be a clinical biomarker for SPG7 testing. In addition, the presence of late-onset very slowly progressive spastic gait (median age 39 years, range 18-52 years) associated with cerebellar ataxia (39%) or cerebellar atrophy (47%) constitute, with abnormal optical coherence tomography, key features pointing towards SPG7-testing. Interestingly, three relatives of patients with heterozygote SPG7 mutations had cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower

  11. Cutaneous reflexes from the foot during gait in hereditary spastic paraparesis

    NARCIS (Netherlands)

    Duysens, J; Baken, B C M; Burgers, L; Plat, F M; den Otter, A R; Kremer, H P H

    2004-01-01

    OBJECTIVE: It is known that P2 cutaneous reflexes from the foot show phase-dependent modulation during gait. The role of the motor cortex and the cortico-spinal tract in these reflexes and their modulation is unknown. Patients with hereditary spastic paraparesis (HSP) have a lesion in the

  12. Immunophenotyping of hereditary breast cancer

    NARCIS (Netherlands)

    van der Groep, P.|info:eu-repo/dai/nl/304810789

    2009-01-01

    Hereditary breast cancer runs in families where several family members in different generations are affected. Most of these breast cancers are caused by mutations in the high penetrance genes BRCA1 and BRCA2 which account for about 5% of all breast cancers. However, mutations in BRCA1 and BRCA2 may

  13. Drug therapy for hereditary cancers

    Directory of Open Access Journals (Sweden)

    Imyanitov Evgeny N

    2011-08-01

    Full Text Available Abstract Tumors arising in patients with hereditary cancer syndromes may have distinct drug sensitivity as compared to their sporadic counterparts. Breast and ovarian neoplasms from BRCA1 or BRCA2 mutation carriers are characterized by deficient homologous recombination (HR of DNA, that makes them particularly sensitive to platinum compounds or inhibitors of poly (ADP-ribose polymerase (PARP. Outstandingly durable complete responses to high dose chemotherapy have been observed in several cases of BRCA-related metastatic breast cancer (BC. Multiple lines of evidence indicate that women with BRCA1-related BC may derive less benefit from taxane-based treatment than other categories of BC patients. There is virtually no reports directly assessing drug response in hereditary colorectal cancer (CRC patients; studies involving non-selected (i.e., both sporadic and hereditary CRC with high-level microsatellite instability (MSI-H suggest therapeutic advantage of irinotecan. Celecoxib has been approved for the treatment of familial adenomatous polyposis (FAP. Hereditary medullary thyroid cancers (MTC have been shown to be highly responsive to a multitargeted tyrosine kinase inhibitor vandetanib, which exerts specific activity towards mutated RET receptor. Given the rapidly improving accessibility of DNA analysis, it is foreseen that the potential predictive value of cancer-associated germ-line mutations will be increasingly considered in the future studies.

  14. Genetics Home Reference: hereditary hemochromatosis

    Science.gov (United States)

    ... several genes, including HAMP , HFE , HFE2 , SLC40A1 , and TFR2 , can cause hereditary hemochromatosis . Type 1 hemochromatosis results ... the HFE2 or HAMP gene. Mutations in the TFR2 gene cause type 3 hemochromatosis, and mutations in ...

  15. Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathy.

    Science.gov (United States)

    Sullivan, Jeremy M; Zimanyi, Christina M; Aisenberg, William; Bears, Breanne; Chen, Dong-Hui; Day, John W; Bird, Thomas D; Siskind, Carly E; Gaudet, Rachelle; Sumner, Charlotte J

    2015-12-01

    To characterize 2 novel TRPV4 mutations in 2 unrelated families exhibiting the Charcot-Marie-Tooth disease type 2C (CMT2C) phenotype. Direct CMT gene testing was performed on 2 unrelated families with CMT2C. A 4-fold symmetric tetramer model of human TRPV4 was generated to map the locations of novel TRPV4 mutations in these families relative to previously identified disease-causing mutations (neuropathy, skeletal dysplasia, and osteoarthropathy). Effects of the mutations on TRPV4 expression, localization, and channel activity were determined by immunocytochemical, immunoblotting, Ca(2+) imaging, and cytotoxicity assays. Previous studies suggest that neuropathy-causing mutations occur primarily at arginine residues on the convex face of the TRPV4 ankyrin repeat domain (ARD). Further highlighting the key role of this domain in TRPV4-mediated hereditary neuropathy, we report 2 novel heterozygous missense mutations in the TRPV4-ARD convex face (p.Arg237Gly and p.Arg237Leu). Generation of a model of the TRPV4 homotetramer revealed that while ARD residues mutated in neuropathy (including Arg237) are likely accessible for intermolecular interactions, skeletal dysplasia-causing TRPV4 mutations occur at sites suggesting disruption of intramolecular and/or intersubunit interactions. Like previously described neuropathy-causing mutations, the p.Arg237Gly and p.Arg237Leu substitutions do not alter TRPV4 subcellular localization in transfected cells but cause elevations of cytosolic Ca(2+) levels and marked cytotoxicity. These findings expand the number of ARD residues mutated in TRPV4-mediated neuropathy, providing further evidence of the central importance of this domain to TRPV4 function in peripheral nerve.

  16. Novel pathomechanisms in inflammatory neuropathies.

    Science.gov (United States)

    Schafflick, David; Kieseier, Bernd C; Wiendl, Heinz; Meyer Zu Horste, Gerd

    2017-11-28

    Inflammatory neuropathies are rare autoimmune-mediated disorders affecting the peripheral nervous system. Considerable progress has recently been made in understanding pathomechanisms of these disorders which will be essential for developing novel diagnostic and therapeutic strategies in the future. Here, we summarize our current understanding of antigenic targets and the relevance of new immunological concepts for inflammatory neuropathies. In addition, we provide an overview of available animal models of acute and chronic variants and how new diagnostic tools such as magnetic resonance imaging and novel therapeutic candidates will benefit patients with inflammatory neuropathies in the future. This review thus illustrates the gap between pre-clinical and clinical findings and aims to outline future directions of development.

  17. Peripheral neuropathy in Tangier disease.

    Science.gov (United States)

    Pollock, M; Nukada, H; Frith, R W; Simcock, J P; Allpress, S

    1983-12-01

    Peripheral nerve morphometry was assessed in four patients with Tangier disease. Three patients with a relapsing and remitting multiple mononeuropathy had prominent peripheral nerve demyelination and remyelination with affected internodes clustered along particular nerve fibres. Putative lipid vacuoles were almost exclusively confined in this multifocal neuropathy syndrome to Remak cells. By contrast a fourth patient with a slowly progressive syringomyelia-like neuropathy had advanced peripheral nerve degeneration and a more global distribution of lipid vacuoles within peripheral nerve. A review of Tangier disease in the literature indicated the possibility of additional peripheral nerve syndromes. The clinical heterogeneity raises the possibility of different metabolic errors in Tangier disease or a common metabolic error subject to genetic influences. The results of this study indicate that normal serum cholesterol levels do not exclude a diagnosis of Tangier disease. It is therefore advisable to determine both high density lipoproteins and serum cholesterol levels in patients with undiagnosed multifocal neuropathy or syringomyelia-like syndromes.

  18. Genetics of Hereditary Angioedema Revisited.

    Science.gov (United States)

    Germenis, Anastasios E; Speletas, Matthaios

    2016-10-01

    Contemporary genetic research has provided evidences that angioedema represents a diverse family of disorders related to kinin metabolism, with a much greater genetic complexity than was initially considered. Convincing data have also recently been published indicating that the clinical heterogeneity of hereditary angioedema due to C1 inhibitor deficiency (classified as C1-INH-HAE) could be attributed at least in part, either to the type of SERPING1 mutations or to mutations in genes encoding for enzymes involved in the metabolism and function of bradykinin. Alterations detected in at least one more gene (F12) are nowadays considered responsible for 25 % of cases of hereditary angioedema with normal C1-INH (type III hereditary angioedema (HAE), nlC1-INH-HAE). Interesting data derived from genetic approaches of non-hereditary angioedemas indicate that other immune pathways might be implicated in the pathogenesis of HAE. More than 125 years after the recognition of the hereditary nature of HAE by Osler, the heterogeneity of clinical expressions, the genetics of this disorder, and the genotype-phenotype relationships, still presents a challenge that will be discussed in this review. Large scale, in-depth genetic studies are expected not only to answer these emerging questions but also to further elucidate many of the unmet aspects of angioedema pathogenesis. Uncovering genetic biomarkers affecting the severity of the disease and/or the effectiveness of the various treatment modalities might lead to the prevention of attacks and the optimization of C1-INH-HAE management that is expected to provide a valuable benefit to the sufferers of angioedema.

  19. Sulfatide levels correlate with severity of neuropathy in metachromatic leukodystrophy

    DEFF Research Database (Denmark)

    Dali, Christine I; Barton, Norman W; Farah, Mohamed H

    2015-01-01

    OBJECTIVE: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder due to deficient activity of arylsulfatase A (ASA) that causes accumulation of sulfatide and lysosulfatide. The disorder is associated with demyelination and axonal loss in the central and periphera...... involvement by the disease process. The magnitude of the biochemical disturbance produces a continuously graded spectrum of impairments in neurophysiological function and sural nerve histopathology.......) the clinical deficit in gross motor function (GMFM-88), (2) median and peroneal nerve motor and median and sural nerve sensory conduction studies (NCS), (3) median and tibial nerve somatosensory evoked potentials (SSEPs), (4) sural nerve histopathology, and (5) brain MR spectroscopy. RESULTS: Eleven patients...... had a sensory-motor demyelinating neuropathy on electrophysiological testing, whereas two patients had normal studies. Sural nerve and CSF (lyso)sulfatide levels strongly correlated with abnormalities in electrophysiological parameters and large myelinated fiber loss in the sural nerve, but there were...

  20. Does Endurance Training Compensate for Neurotrophin Deficiency Following Diabetic Neuropathy?

    Science.gov (United States)

    Eslami, Rasoul; Gharakhanlou, Reza; Kazemi, Abdolreza; Dakhili, Amir Bahador; Sorkhkamanzadeh, Ghazaleh; Sheikhy, Ayob

    2016-10-01

    A lack of neurotrophic support is believed to contribute to the development of diabetic neuropathy. On the other hand, neurotrophins have consistently been shown to increase in the central and peripheral nervous system following exercise, but the effects of exercise intervention on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in diabetic neuropathy are not understood. This experimental study was designed and carried out at the Tarbiat Modares university (TMU) in Tehran, Iran, to investigate the hypothesis that increased activity as endurance training can help to increase the endogenous expression of neurotrophins in diabetic rats. This was an experimental study with 2 × 2 factorial plans performed at TMU in Iran. Sampling was accidental and 28 adult male Wistar rats in the body mass range of 326.3 ± 8.4 g comprised the sample, with each rat randomly assigned to four groups: diabetic control (DC), diabetic training (DT), healthy control (HC), and healthy training (HT). To induce diabetic neuropathy, after 12 hours of food deprivation, an intraperitoneal injection of streptozotocin (STZ) solution (45 mg/Kg) method was used. Two weeks after STZ injection, the endurance training protocol was performed for 6 weeks; 24 hours after the last training session, the rats were sacrificed. Real-time PCR was used for BDNF and NGF expression. The data indicate that diabetes decreases BDNF and NGF expression in sensory (92%, P = 0.01; 90%, P = 0.038, respectively) and motor (93%, P = 0.05; 60%, P = 0.029, respectively) roots. However, NGF mRNA levels in the DT group were significantly higher than in the HC group ((7.1-fold), P = 0.01; (2.2-fold), P = 0.001, respectively, for sensory and motor roots), but this was not shown for BDNF. In addition, endurance training can increase NGF expression in healthy rats ((7.4-fold), P = 0.01; (3.8-fold), P = 0.001, respectively, for sensory and motor roots). This study shows that BDNF and NGF expression decreases in