Talectomy for Equinovarus Deformity in Family Members with Hereditary Motor and Sensory Neuropathy Type I

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Hristo Georgiev

2014-01-01

Full Text Available The treatment of severe rigid neurogenic clubfoot deformities still remains a challenging problem in modern paediatric orthopaedics. In those cases, in spite of being a palliative procedure, talectomy has been advocated for the correction of the deformity thus providing a stable plantigrade foot which allows pain-free walking with standard footwear. Herein, we present the results after talectomy in two patients (brother and sister affected by a hereditary motor and sensory neuropathy type I, with rigid severe pes equinovarus deformities.

Genetics Home Reference: hereditary sensory neuropathy type IA

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... sensory neuropathy type IA Hereditary sensory neuropathy type IA Printable PDF Open All Close All Enable Javascript ... expand/collapse boxes. Description Hereditary sensory neuropathy type IA is a condition characterized by nerve abnormalities in ...

Inherited focal, episodic neuropathies: hereditary neuropathy with liability to pressure palsies and hereditary neuralgic amyotrophy.

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Chance, Phillip F

2006-01-01

Hereditary neuropathy with liability to pressure palsies (HNPP; also called tomaculous neuropathy) is an autosomal-dominant disorder that produces a painless episodic, recurrent, focal demyelinating neuropathy. HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal tunnel syndrome, and other entrapment neuropathies may be frequent manifestations of HNPP. Motor and sensory nerve conduction velocities may be reduced in clinically affected patients, as well as in asymptomatic gene carriers. The histopathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or "sausage-like" formations. Mild overlap of clinical features with Charcot-Marie-Tooth (CMT) disease type 1 (CMT1) may lead patients with HNPP to be misdiagnosed as having CMT1. HNPP and CMT1 are both demyelinating neuropathies, however, their clinical, pathological, and electrophysiological features are quite distinct. HNPP is most frequently associated with a 1.4-Mb pair deletion on chromosome 17p12. A duplication of the identical region leads to CMT1A. Both HNPP and CMT1A result from a dosage effect of the PMP22 gene, which is contained within the deleted/duplicated region. This is reflected in reduced mRNA and protein levels in sural nerve biopsy samples from HNPP patients. Treatment for HNPP consists of preventative and symptom-easing measures. Hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) is an autosomal-dominant disorder causing episodes of paralysis and muscle weakness initiated by severe pain. Individuals with HNA may suffer repeated episodes of intense pain, paralysis, and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attack(s). Episodes are often

Hereditary motor neuropathies and motor neuron diseases: which is which.

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Hanemann, Clemens O; Ludolph, Albert C

2002-12-01

When Charcot first defined amyotrophic lateral sclerosis (ALS) he used the clinical and neuropathological pattern of vulnerability as a guideline. Similarly other motor neuron diseases such as the spinal muscular atrophies (SMA) and the motor neuropathies (MN) were grouped following clinical criteria. However, ever since the etiology of these diseases has started to be disclosed by genetics, we have learnt that the limits of the syndromes are not as well defined as our forefathers thought. A mutation leading to ALS can also be associated with the clinical picture of spinal muscular atrophy; even more unexpected is the overlap of the so-called motor neuropathies with the clinical syndrome of slowly progressive ALS or that primary lateral sclerosis (PLS) can be caused by the same gene as that responsible for some cases of ALS. In this review we summarise recent work showing that there is a considerable overlap between CMT, MN, SMA, ALS and PLS. Insights into these phenotypes should lead to study of the variants of motor neuron disease and possibly to a reclassification. This comprehensive review should help to improve understanding of the pathogenesis of motor neuron degeneration and finally may aid the research for urgently needed new treatment strategies, perhaps with validity for the entire group of motor neuron diseases.

Alanyl-tRNA synthetase mutation in a family with dominant distal hereditary motor neuropathy

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Zhao, Z.; Hashiguchi, A.; Sakiyama, Y.; Okamoto, Y.; Tokunaga, S.; Zhu, L.; Shen, H.; Takashima, H.

2012-01-01

Objective: To identify a new genetic cause of distal hereditary motor neuropathy (dHMN), which is also known as a variant of Charcot-Marie-Tooth disease (CMT), in a Chinese family. Methods: We investigated a Chinese family with dHMN clinically, electrophysiologically, and genetically. We screened for the mutations of 28 CMT or related pathogenic genes using an originally designed microarray resequencing DNA chip. Results: Investigation of the family history revealed an autosomal dominant transmission pattern. The clinical features of the family included mild weakness and wasting of the distal muscles of the lower limb and foot deformity, without clinical sensory involvement. Electrophysiologic studies revealed motor neuropathy. MRI of the lower limbs showed accentuated fatty infiltration of the gastrocnemius and vastus lateralis muscles. All 4 affected family members had a heterozygous missense mutation c.2677G>A (p.D893N) of alanyl-tRNA synthetase (AARS), which was not found in the 4 unaffected members and control subjects. Conclusion: An AARS mutation caused dHMN in a Chinese family. AARS mutations result in not only a CMT phenotype but also a dHMN phenotype. PMID:22573628

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

Hereditary sensory neuropathy type I.

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Auer-Grumbach, Michaela

2008-03-18

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

[Review of the recent literature on hereditary neuropathies].

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Birouk, N

2014-12-01

The recent literature included interesting reports on the pathogenic mechanisms of hereditary neuropathies. The axonal traffic and its abnormalities in some forms of Charcot-Marie-Tooth (CMT) disease were particularly reviewed by Bucci et al. Many genes related to CMT disease code for proteins that are involved directly or not in intracellular traffic. KIF1B controls vesicle motility on microtubules. MTMR2, MTMR13 and FIG4 regulate the metabolism of phosphoinositide at the level of endosomes. The HSPs are involved in the proteasomal degradation. GDAP1 and MFN2 regulate the mitochondrial fission and fusion respectively and the mitochondial transport within the axon. Pareyson et al. reported a review on peripheral neuropathies in mitochondrial disorders. They used the term of "mitochondrial CMT" for the forms of CMT with abnormal mitochondrial dynamic or structure. Among the new entities, we can draw the attention to a proximal form of hereditary motor and sensory neuropathy with autosomal dominant inheritance, which is characterized by motor deficit with cramps and fasciculations predominating in proximal muscles. Distal sensory deficit can be present. The gene TFG on chromosome 3 has been recently identified to be responsible for this form. Another rare form of axonal autosomal recessive neuropathy due to HNT1 gene mutation is characterized by the presence of hands myotonia that appears later than neuropathy but constitute an interesting clinical hallmark to orientate the diagnosis of this form. In terms of differential diagnosis, CMT4J due to FIG4 mutation can present with a rapidly progressive and asymmetric weakness that resembles CIDP. Bouhy et al. made an interesting review on the therapeutic trials, animal models and the future therapeutic strategies to be developed in CMT disease. Copyright © 2014. Published by Elsevier Masson SAS.

Manual dexterity in hereditary motor and sensory neuropathy type 1a: severity of limitations and feasibility and reliability of two assessment instruments

NARCIS (Netherlands)

Videler, Annemieke J.; Beelen, Anita; van Schaik, Ivo N.; de Visser, Marianne; Nollet, Frans

2008-01-01

OBJECTIVE: To assess the prevalence and significance of impaired manual dexterity in hereditary motor and sensory neuropathy type 1a (HMSN 1a), with the Sollerman hand function and the Functional Dexterity test, and compare the reliability and agreement of the tests. DESIGN: Descriptive

Novel association of achalasia with hereditary sensory and motor neuropathy with sensorineural deafness.

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Asthana, A K; Lubel, J S; Kohn, G P

2016-08-01

Achalasia is a primary esophageal motility disorder. Unlike diffuse esophageal spasm, it has not previously been described in association with hereditary sensory and motor neuropathy (HSMN). An 18-year-old-male with HSMN with sensorineural deafness presented with a 2-day history of dysphagia to solids and liquids. Achalasia was diagnosed after extensive investigations, and his symptoms resolved with endoscopic and definitive surgical management. His monozygotic twin brother had also been diagnosed with HSMN and suffered from chronic dysphagia, which was also subsequently diagnosed with achalasia. This is the first case to illustrate an association between HSMN with sensorineural deafness and achalasia. © 2013 Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.

Genetic linkage of hereditary motor and sensory neuropathy type I (Charcot-Marie-Tooth disease) to markers of chromosomes 1 and 17

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Defesche, J. C.; Hoogendijk, J. E.; de Visser, M.; de Visser, O.; Bolhuis, P. A.

1990-01-01

Hereditary motor and sensory neuropathy type 1 (HMSN I) is an autosomal dominant disorder genetically localized on chromosome 1 in a few families and on chromosome 17 in other families. We analyzed linkage between 6 markers of chromosome 1, 2 markers of chromosome 17, and the HMSN I locus using

HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum.

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Gess, Burkhard; Auer-Grumbach, Michaela; Schirmacher, Anja; Strom, Tim; Zitzelsberger, Manuela; Rudnik-Schöneborn, Sabine; Röhr, Dominik; Halfter, Hartmut; Young, Peter; Senderek, Jan

2014-11-04

To determine the nature and frequency of HSJ1 mutations in patients with hereditary motor and hereditary motor and sensory neuropathies. Patients were screened for mutations by genome-wide or targeted linkage and homozygosity studies, whole-exome sequencing, and Sanger sequencing. RNA and protein studies of skin fibroblasts were used for functional characterization. We describe 2 additional mutations in the HSJ1 gene in a cohort of 90 patients with autosomal recessive distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2 (CMT2). One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A, which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression. Another family, presenting with a CMT2 phenotype, carried the homozygous missense mutation c.14A>G (p.Tyr5Cys). This mutation was classified as likely disease-related by several automatic algorithms for prediction of possible impact of an amino acid substitution on the structure and function of proteins. Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population. Taken together, in our cohort of 90 probands, we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2. We provide clinical and functional information on an HSJ1 splice-site mutation and report the detailed phenotype of 2 patients with CMT2, broadening the phenotypic spectrum of HSJ1-related neuropathies. © 2014 American Academy of Neurology.

Sensory and motor neuropathy in a Border Collie.

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Harkin, Kenneth R; Cash, Walter C; Shelton, G Diane

2005-10-15

A 5-month-old female Border Collie was evaluated because of progressive hind limb ataxia. The predominant clinical findings suggested a sensory neuropathy. Sensory nerve conduction velocity was absent in the tibial, common peroneal, and radial nerves and was decreased in the ulnar nerve; motor nerve conduction velocity was decreased in the tibial, common peroneal, and ulnar nerves. Histologic examination of nerve biopsy specimens revealed considerable nerve fiber depletion; some tissue sections had myelin ovoids, foamy macrophages, and axonal degeneration in remaining fibers. Marked depletion of most myelinated fibers within the peroneal nerve (a mixed sensory and motor nerve) supported the electrodiagnostic findings indicative of sensorimotor neuropathy. Progressive deterioration in motor function occurred over the following 19 months until the dog was euthanatized. A hereditary link was not established, but a littermate was similarly affected. The hereditary characteristic of this disease requires further investigation.

Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies.

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Salter, Claire G; Beijer, Danique; Hardy, Holly; Barwick, Katy E S; Bower, Matthew; Mademan, Ines; De Jonghe, Peter; Deconinck, Tine; Russell, Mark A; McEntagart, Meriel M; Chioza, Barry A; Blakely, Randy D; Chilton, John K; De Bleecker, Jan; Baets, Jonathan; Baple, Emma L; Walk, David; Crosby, Andrew H

2018-04-01

To identify the genetic cause of disease in 2 previously unreported families with forms of distal hereditary motor neuropathies (dHMNs). The first family comprises individuals affected by dHMN type V, which lacks the cardinal clinical feature of vocal cord paralysis characteristic of dHMN-VII observed in the second family. Next-generation sequencing was performed on the proband of each family. Variants were annotated and filtered, initially focusing on genes associated with neuropathy. Candidate variants were further investigated and confirmed by dideoxy sequence analysis and cosegregation studies. Thorough patient phenotyping was completed, comprising clinical history, examination, and neurologic investigation. dHMNs are a heterogeneous group of peripheral motor neuron disorders characterized by length-dependent neuropathy and progressive distal limb muscle weakness and wasting. We previously reported a dominant-negative frameshift mutation located in the concluding exon of the SLC5A7 gene encoding the choline transporter (CHT), leading to protein truncation, as the likely cause of dominantly-inherited dHMN-VII in an extended UK family. In this study, our genetic studies identified distinct heterozygous frameshift mutations located in the last coding exon of SLC5A7 , predicted to result in the truncation of the CHT C-terminus, as the likely cause of the condition in each family. This study corroborates C-terminal CHT truncation as a cause of autosomal dominant dHMN, confirming upper limb predominating over lower limb involvement, and broadening the clinical spectrum arising from CHT malfunction.

[History of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P)].

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Takashima, Hiroshi

2013-01-01

We established a new disease autosomal dominant hereditary motor and sensory neuropathy with proximal dominant involvement (HMSNP) in 1997, in Okinawa, Japan. This disease is characterized by proximal dominant neurogenic atrophy with fasciculations, painful muscle cramp, obvious sensory nerve involvement, areflexia, high incidence of elevated creatine kinase levels, hyperlipidemia and hyperglycemia. (MIM %604484). HMSNP is so called or HMSNO (HMSN OKINAWA type),. These clinical features resembled those of Kennedy-Alter-Sung syndrome. Most HMSNP patients have severe muscle atrophy and finally the tracheostomy and artificial ventilation are required. Therefore, we initially thought to classify HMSNP into a subtype of motor neuron disease (MND) like familial amyotrophic lateral sclerosis (FALS) or spinal muscular atrophy (SMA). However, the general consensus for MND was no sensory involvement. Therefore, as the disease showed severe sensory involvement, we categorized HMSNP in subtype of HMSN at that time. We also reported the pathology of HMSNP, showing severely decreased anterior horn cells, decreased posterior horn cells, and loss of posterior funiculus in the spinal cord.

A family with autosomal dominant mutilating neuropathy not linked to either Charcot-Marie-Tooth disease type 2B (CMT2B) or hereditary sensory neuropathy type I (HSN I) loci.

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Bellone, Emilia; Rodolico, Carmelo; Toscano, Antonio; Di Maria, Emilio; Cassandrini, Denise; Pizzuti, Antonio; Pigullo, Simona; Mazzeo, Anna; Macaione, Vincenzo; Girlanda, Paolo; Vita, Giuseppe; Ajmar, Franco; Mandich, Paola

2002-03-01

Sensory loss and ulcero-mutilating features have been observed in hereditary sensory neuropathy type I and in hereditary motor and sensory neuropathy type IIB, also referred as Charcot-Marie-Tooth disease type 2B. To date two loci associated with ulcero-mutilating neuropathy have been described: CMT2B at 3q13-q22 and HSN I at 9q22.1-q22.3. We performed linkage analysis with chromosomal markers representing the hereditary sensory neuropathy type I and Charcot-Marie-Tooth disease type 2B loci on an Italian family with a severe distal sensory loss leading to an ulcero-mutilating peripheral neuropathy. Negative likelihood-of-odds scores excluded any evidence of linkage to both chromosome 3q13 and chromosome 9q22 markers, confirming the genetic heterogeneity of this clinical entity and the presence of a third locus responsible for ulcero-mutilating neuropathies.

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.

2005-01-01

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

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.

Pes cavus and hereditary neuropathies: when a relationship should be suspected.

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Piazza, S; Ricci, G; Caldarazzo Ienco, E; Carlesi, C; Volpi, L; Siciliano, G; Mancuso, M

2010-12-01

The hereditary peripheral neuropathies are a clinically and genetically heterogeneous group of diseases of the peripheral nervous system. Foot deformities, including the common pes cavus, but also hammer toes and twisting of the ankle, are frequently present in patients with hereditary peripheral neuropathy, and often represent one of the first signs of the disease. Pes cavus in hereditary peripheral neuropathies is caused by imbalance between the intrinsic muscles of the foot and the muscles of the leg. Accurate clinical evaluation in patients with pes cavus is necessary to exclude or confirm the presence of peripheral neuropathy. Hereditary peripheral neuropathies should be suspected in those cases with bilateral foot deformities, in the presence of family history for pes cavus and/or gait impairment, and in the presence of neurological symptoms or signs, such as distal muscle hypotrophy of limbs. Herein, we review the hereditary peripheral neuropathies in which pes cavus plays a key role as a "spy sign," discussing the clinical and molecular features of these disorders to highlight the importance of pes cavus as a helpful clinical sign in these rare diseases.

Hereditary Neuropathy With Liability to Pressure Palsies: Diverse Phenotypes in Childhood.

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Harada, Yohei; Puwanant, Araya; Herrmann, David N

2016-12-01

Hereditary neuropathy with liability to pressure palsies (HNPP) is a rare autosomal-dominant disorder that most commonly produces recurrent painless focal sensory and motor neuropathies often preceded by minor, mechanical stress, or minor trauma. Herein, we report 2 pediatric cases of HNPP with atypical presentations; isolated muscle cramping and toe walking. Electrophysiologic testing disclosed multifocal sensorimotor polyneuropathy with slowing of sensory conduction velocities in both cases, which prompted PMP 22 gene deletion testing. Multifocal sensorimotor electrophysiologic abnormalities, with slowing of sensory conduction velocities should raise consideration of HNPP in childhood. These case reports emphasize that the diagnosis of HNPP in children requires a high index of suspicion.

Analysis of Genetic Mutations in a Cohort of Hereditary Optic Neuropathy in Shanghai, China.

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Gan, Dekang; Li, Mengwei; Wu, Jihong; Sun, Xinghuai; Tian, Guohong

2017-01-01

To evaluate the clinical classification and characteristics of hereditary optic neuropathy patients in a single center in China. Retrospective case study. Patients diagnosed with hereditary optic neuropathy between January 2014 and December 2015 in the neuro-ophthalmology division in Shanghai Eye and ENT Hospital of Fudan University were recruited. Clinical features as well as visual field, brain/orbital MRI, and spectrum domain optical coherence tomography (SD-OCT) were analyzed. Eighty-two patients diagnosed by gene test were evaluated, including 66 males and 16 females. The mean age of the patients was 19.4 years (range, 5-46 years). A total of 158 eyes were analyzed, including 6 unilateral, 61 bilateral, and 15 sequential. The median duration of the disease was 0.5 year (range, 0.1-20 years). Genetic test identified 68 patients with Leber hereditary optic neuropathy, 9 with dominant optic neuropathy, and 2 with a Wolfram gene mutation. There was also one case of hereditary spastic paraplegia, spinocerebellar ataxia, and polymicrogyria with optic nerve atrophy, respectively. Leber hereditary optic neuropathy is the most common detected type of hereditary optic neuropathy in Shanghai, China. The detection of other autosomal mutations in hereditary optic neuropathy is limited by the currently available technique.

Andermann syndrome can be a phenocopy of hereditary motor and sensory neuropathy--report of a discordant sibship with a compound heterozygous mutation of the KCC3 gene.

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Rudnik-Schöneborn, S; Hehr, U; von Kalle, T; Bornemann, A; Winkler, J; Zerres, K

2009-06-01

Andermann syndrome is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum (ACC), progressive motor-sensory neuropathy, mental retardation and facial features. We report on two siblings with the clinical picture of a demyelinating hereditary motor and sensory neuropathy (HMSN), where only the presence of ACC in the younger brother pointed to the diagnosis of Andermann syndrome. Mutation analysis of the KCC3 (SLC12A6) gene showed a compound heterozygous mutation; a maternal missense mutation c.1616G>A (p.G539D) and a paternal splice mutation c.1118+1G>A in both siblings. We hypothesize that mutations of the KCC3 gene may result in non-syndromic childhood onset HMSN.

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

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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

Hereditary sensory ataxic neuropathy associated with proximal muscle weakness in the lower extremities.

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Murakami, Tatsufumi; Fukai, Yuta; Rikimaru, Mitsue; Henmi, Shoji; Ohsawa, Yutaka; Sunada, Yoshihide

2010-04-15

We describe three patients from the same family with hereditary sensory ataxic neuropathy followed by proximal muscle weakness in the lower extremities. Sensory ataxic gait began as an initial symptom when patients were in their 50s. Mild proximal weakness in the lower extremities appeared several years later. Serum creatine kinase was mildly elevated. Nerve conduction studies revealed sensory dominant axonal neuropathy, and short sensory evoked potentials showed involvement of the sensory nerve axon, dorsal root ganglia and posterior funiculus of the spinal cord. Needle electromyography showed fibrillation, positive sharp waves, and multiple giant motor unit potentials, suggesting the involvement of anterior horn motor neurons or the anterior root. Autosomal recessive inheritance was considered, because of consanguinity. The disorder described here may be a new clinical entity with unique clinical manifestations. Copyright 2009 Elsevier B.V. All rights reserved.

MRI in Leber's hereditary optic neuropathy

DEFF Research Database (Denmark)

Matthews, Lucy; Enzinger, Christian; Fazekas, Franz

2015-01-01

BACKGROUND: 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...

Hereditary neuropathy with liability to pressure palsies presenting with sciatic neuropathy.

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Topakian, Raffi; Wimmer, Sibylle; Pischinger, Barbara; Pichler, Robert

2014-10-17

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal-dominant disorder associated with recurrent mononeuropathies following compression or trivial trauma. Reports on sciatic neuropathy as the presenting manifestation of HNPP are very scarce. We report on a 21-year-old previously healthy man who was admitted with sensorimotor deficits in his left leg. He had no history of preceding transient episodes of weakness or sensory loss. Clinical and electrophysiological examinations were consistent with sciatic neuropathy. Cerebrospinal fluid investigation and MRI of the nerve roots, plexus, and sciatic nerve did not indicate the underlying aetiology. When extended electrophysiological tests revealed multiple subclinical compression neuropathies in the upper limbs, HNPP was contemplated and eventually confirmed by genetic testing. 2014 BMJ Publishing Group Ltd.

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

Peripheral neuropathy in patients with HIV infection: consider dual pathology.

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Miller, R F; Bunting, S; Sadiq, S T; Manji, H

2002-12-01

Two HIV infected patients presented with peripheral neuropathy, in one patient this was originally ascribed to HIV associated mononeuritis multiplex and in the other to stavudine. Investigations confirmed these diagnoses and in both cases genetic analysis identified a second hereditary aetiology: in the first patient hereditary neuropathy with liability to pressure palsies and in the second hereditary motor and sensory neuropathy.

The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement.

Science.gov (United States)

Ishiura, Hiroyuki; Sako, Wataru; Yoshida, Mari; Kawarai, Toshitaka; Tanabe, Osamu; Goto, Jun; Takahashi, Yuji; Date, Hidetoshi; Mitsui, Jun; Ahsan, Budrul; Ichikawa, Yaeko; Iwata, Atsushi; Yoshino, Hiide; Izumi, Yuishin; Fujita, Koji; Maeda, Kouji; Goto, Satoshi; Koizumi, Hidetaka; Morigaki, Ryoma; Ikemura, Masako; Yamauchi, Naoko; Murayama, Shigeo; Nicholson, Garth A; Ito, Hidefumi; Sobue, Gen; Nakagawa, Masanori; Kaji, Ryuji; Tsuji, Shoji

2012-08-10

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal-dominant neurodegenerative disorder characterized by widespread fasciculations, proximal-predominant muscle weakness, and atrophy followed by distal sensory involvement. To date, large families affected by HMSN-P have been reported from two different regions in Japan. Linkage and haplotype analyses of two previously reported families and two new families with the use of high-density SNP arrays further defined the minimum candidate region of 3.3 Mb in chromosomal region 3q12. Exome sequencing showed an identical c.854C>T (p.Pro285Leu) mutation in the TRK-fused gene (TFG) in the four families. Detailed haplotype analysis suggested two independent origins of the mutation. Pathological studies of an autopsied patient revealed TFG- and ubiquitin-immunopositive cytoplasmic inclusions in the spinal and cortical motor neurons. Fragmentation of the Golgi apparatus, a frequent finding in amyotrophic lateral sclerosis, was also observed in the motor neurons with inclusion bodies. Moreover, TAR DNA-binding protein 43 kDa (TDP-43)-positive cytoplasmic inclusions were also demonstrated. In cultured cells expressing mutant TFG, cytoplasmic aggregation of TDP-43 was demonstrated. These findings indicate that formation of TFG-containing cytoplasmic inclusions and concomitant mislocalization of TDP-43 underlie motor neuron degeneration in HMSN-P. Pathological overlap of proteinopathies involving TFG and TDP-43 highlights a new pathway leading to motor neuron degeneration. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Overlapping molecular pathological themes link Charcot-Marie-Tooth neuropathies and hereditary spastic paraplegias.

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Timmerman, Vincent; Clowes, Virginia E; Reid, Evan

2013-08-01

In this review we focus on Charcot-Marie-Tooth (CMT) neuropathies and hereditary spastic paraplegias (HSPs). Although these diseases differ in whether they primarily affect the peripheral or central nervous system, both are genetically determined, progressive, long axonopathies that affect motor and sensory pathways. This commonality suggests that there might be similarities in the molecular pathology underlying these conditions, and here we compare the molecular genetics and cellular pathology of the two groups. Copyright © 2012 Elsevier Inc. All rights reserved.

Increased Mortality and Comorbidity Associated With Leber's Hereditary Optic Neuropathy

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Vestergaard, Nanna; Rosenberg, Thomas; Torp-Pedersen, Christian

2017-01-01

Purpose: 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. Methods...... patients (RR: 4.26, 95% CI: 1.91-9.48; P neuropathy, and alcohol-related disorders. Conclusions: The manifestation of LHON was associated...

[Experience in molecular diagnostic in hereditary neuropathies in a pediatric tertiary hospital].

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Fernández-Ramos, Joaquín A; López-Laso, Eduardo; Camino-León, Rafael; Gascón-Jiménez, Francisco J; Jiménez-González, M Dolores

2015-12-01

Charcot-Marie-Tooth (CMT) is the most common hereditary sensory motor neuropathy. Advances in molecular diagnosis have increased the diagnostic possibilities of these patients. Retrospective study of 36 pediatric patients diagnosed with CMT in a tertiary center in 2003-2015. We found 16 patients were diagnosed by a duplication in PMP22; two cases were diagnosed of hereditary neuropathy with liability to pressure palsies, one with a point mutation in PMP22; a male with a mild demyelinating phenotype, without family history, was diagnosed with GJB1 mutation; in a patient with a peripheral hypotonia at birth and axonal pattern in EMG by mutation in MFN2; a gypsy patient, with consanguineous family, CMT4D, was identified by a mutation in the gene NDRG1; a patient with multiplex congenital arthrogryposis and vocal cord paralysis, whose mother had a scapular-peroneal syndrome, had a congenital spinal muscular atrophy with mild distal axonal neuropathy by mutation in gene TRPV4; three girls, from a gypsy consanguineous family, with axonal CMT with neuromyotonic discharges were diagnosed by a mutation in the gene HINT1; twelve patients haven't molecular diagnosis currently. CMT1A predominated in our series (44%), as previous studies. We emphasize the description of a patient with a mutation in TRPV4 recently described as a cause of CMT2C and three cases, of gypsy consanguineous family, with the same mutation in HINT1 gene, recently described as a cause of axonal neuropathy with neuromyotonia, autosomal recessive (AR-CMT2). The proportion of patients without molecular diagnosis is similar to main European series.

[Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is caused by a mutation in TFG].

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Ishiura, Hiroyuki; Tsuji, Shoji

2013-01-01

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal dominant neurodegenerative disease characterized by proximal predominant weakness and muscle atrophy accompanied by distal sensory disturbance. Linkage analysis using 4 families identified a region on chromosome 3 showing a LOD score exceeding 4. Further refinement of candidate region was performed by haplotype analysis using high-density SNP data, resulting in a minimum candidate region spanning 3.3 Mb. Exome analysis of an HMSN-P patient revealed a mutation (c.854C>T, p.Pro285Leu) in TRK-fused gene (TFG). The identical mutation was found in the four families, which cosegregated with the disease. The mutation was neither found in Japanese control subjects nor public databases. Detailed haplotype analysis suggested two independent origins of the mutation. These findings indicate that the mutation in TFG causes HMSN-P.

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

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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.

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.

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

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Davidson, G L; Murphy, S M; Polke, J M; Laura, M; Salih, M A M; Muntoni, F; Blake, J; Brandner, S; Davies, N; Horvath, R; Price, S; Donaghy, M; Roberts, M; Foulds, N; Ramdharry, G; Soler, D; Lunn, M P; Manji, H; Davis, M B; Houlden, H; Reilly, M M

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.

Expression analysis of the N-Myc downstream-regulated gene 1 indicates that myelinating Schwann cells are the primary disease target in hereditary motor and sensory neuropathy-Lom.

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Berger, Philipp; Sirkowski, Erich E; Scherer, Steven S; Suter, Ueli

2004-11-01

Mutations in the gene encoding N-myc downstream-regulated gene-1 (NDRG1) lead to truncations of the encoded protein and are associated with an autosomal recessive demyelinating neuropathy--hereditary motor and sensory neuropathy-Lom. NDRG1 protein is highly expressed in peripheral nerve and is localized in the cytoplasm of myelinating Schwann cells, including the paranodes and Schmidt-Lanterman incisures. In contrast, sensory and motor neurons as well as their axons lack NDRG1. NDRG1 mRNA levels in developing and injured adult sciatic nerves parallel those of myelin-related genes, indicating that the expression of NDRG1 in myelinating Schwann cells is regulated by axonal interactions. Oligodendrocytes also express NDRG1, and the subtle CNS deficits of affected patients may result from a lack of NDRG1 in these cells. Our data predict that the loss of NDRG1 leads to a Schwann cell autonomous phenotype resulting in demyelination, with secondary axonal loss.

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.

New allelic variant of autosomal recessive hereditary motor and sensory neuropathy type 2S resulted from mutations in gene IGHMBP2

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E. L. Dadali

2016-01-01

Full Text Available Hereditary motor and sensory neuropathy (HMSN, Charcot–Marie–Tooth disease is a group of genetically heterogeneous disorders with more than 80 genes linked to different phenotypes, including IGHMBP2 gene responsible for HMSN type 2S (OMIM 616155. Until recently, mutations in IGHMBP2 were exclusively associated with neonatal distal spinal muscular atrophy with respiratory distress (SMARD1, OMIM 604320. A case report presents a boy with infant onset decreased distal muscle tone and weakness, distal wasting and deformation in legs and hands, areflexia and decreased sensation without respiratory involvement; at age seven he had severe fixed kypho-scoliosis. EMG revealed signs distal axonal neuropathy. The exsome sequencing confirmed the allelic variant of two compound heterozygous mutations in gene IGHMBP2: known missens mutation с.1616С>Т (р.Ser539Leu in exone 11 and a novel deletion с.2601_2602delGA in exone 13. The diagnosis of infant HMSN type 2S was confirmed. The phenotype of HMSN type 2S and its diagnostics differences between SMARD1 are discussed.

Neuromyelitis optica antibody in Leber hereditary optic neuropathy: case report

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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.

Variable phenotypic expression and onset in MYH14 distal hereditary motor neuropathy phenotype in a large, multigenerational North American family.

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Iyadurai, Stanley; Arnold, W David; Kissel, John T; Ruhno, Corey; Mcgovern, Vicki L; Snyder, Pamela J; Prior, Thomas W; Roggenbuck, Jennifer; Burghes, Arthur H; Kolb, Stephen J

2017-08-01

Distal hereditary motor neuropathy (dHMN) causes distal-predominant weakness without prominent sensory loss. Myosin heavy chain disorders most commonly result in distal myopathy and cardiomyopathy with or without hearing loss, but a complex phenotype with dHMN, myopathy, hoarseness, and hearing loss was reported in a Korean family with a c.2822G>T mutation in MYH14. In this study we report phenotypic features in a North American family with the c.2822G>T in MYH14. Clinical and molecular characterization was performed in a large, 6-generation, Caucasian family with MYH14 dHMN. A total of 11 affected and 7 unaffected individuals were evaluated and showed varying age of onset and severity of weakness. Genotypic concordance was confirmed with molecular analysis. Electrophysiological studies demonstrated distal motor axonal degeneration without myopathy in all affected subjects tested. Mutation of MYH14 can result in a range of neuromuscular phenotypes that includes a dHMN and hearing loss phenotype with variable age of onset. Muscle Nerve 56: 341-345, 2017. © 2016 Wiley Periodicals, Inc.

The N355K atlastin 1 mutation is associated with hereditary sensory neuropathy and pyramidal tract features.

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Leonardis, L; Auer-Grumbach, M; Papić, L; Zidar, J

2012-07-01

  Mutations in atlastin-1 (ATL-1), a gene known to cause pure, early-onset autosomal dominant hereditary spastic paraplegia SPG3A, have been recently reported to cause hereditary sensory neuropathy I (HSN I). We describe the detailed clinical and electrophysiologic findings in the first family with ulcero-mutilating sensory neuropathy carrying the c. C1065A, p.N355K mutation in ATL-1.   Detailed clinical and electrophysiologic studies were performed in affected and at-risk family members. Motor and sensory nerve conductions studies (NCS) were carried out in upper and lower limbs. ATL-1 was screened for mutations by direct sequencing.   Ten patients were found to carry the N355K mutation. With the exception of the two youngest patients, all had trophic skin changes in the feet consisting mainly of painless ulcers. Frequently, amputation of toes, feet, or even more proximal parts of the lower legs became necessary. A variable degree of increased muscle tone was observed in younger patients, whilst some older affected individuals only presented with hyperreflexia of patellar tendon reflexes. NCS revealed signs of an axonal motor and sensory neuropathies.   Our family carrying the N355K ATL1 mutation, which was initially diagnosed as HSN I, enlarges the SPG3A phenotype. We therefore suggest that patients with HSN I excluded for more common causes of HSN I, and in particular, affected individuals who exhibit additional pyramidal tract features should also be screened for mutations in ATL1. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

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

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

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

Terminal changes in hereditary sensory and autonomic neuropathy: a long-term follow-up of a sporadic case.

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Lee, Sang-Soo; Lee, Sung-Hyun; Han, Seol-Heui

2003-07-01

We describe terminal changes in a long-term follow-up of a 51-year-old man with sporadic hereditary sensory and autonomic neuropathy (HSAN). From the age of 15 years onwards, he suffered from multiple painless ulcers of his feet and fingers, necessitating amputation. Neurological studies revealed almost complete sensory loss affecting all modalities in the upper and lower limbs, minimal involvement of motor fibers, and areflexia. A neurophysiological abnormality involved an absence of sensory action potentials with relatively normal motor nerve conduction velocities. Biopsy of the sural nerve showed almost total loss of myelinated fibers with a mild decrease in unmyelinated fibers. Despite the late onset of the disease, the progressive course, and the lancinating pain, the terminal features of this patient, which involved a selective loss of myelinated fibers and widespread sensory loss, seem to be symptomatic of HSAN II, the progressive form of autosomal recessive sensory neuropathy, and emphasize the clinical heterogeneity of HSAN.

Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.

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Guelly, Christian; Zhu, Peng-Peng; Leonardis, Lea; Papić, Lea; Zidar, Janez; Schabhüttl, Maria; Strohmaier, Heimo; Weis, Joachim; Strom, Tim M; Baets, Jonathan; Willems, Jan; De Jonghe, Peter; Reilly, Mary M; Fröhlich, Eleonore; Hatz, Martina; Trajanoski, Slave; Pieber, Thomas R; Janecke, Andreas R; Blackstone, Craig; Auer-Grumbach, Michaela

2011-01-07

Hereditary sensory neuropathy type I (HSN I) is an axonal form of autosomal-dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Unrecognized, these can result in delayed wound healing and osteomyelitis, necessitating distal amputations. To elucidate the genetic basis of an HSN I subtype in a family in which mutations in the few known HSN I genes had been excluded, we employed massive parallel exon sequencing of the 14.3 Mb disease interval on chromosome 14q. We detected a missense mutation (c.1065C>A, p.Asn355Lys) in atlastin-1 (ATL1), a gene that is known to be mutated in early-onset hereditary spastic paraplegia SPG3A and that encodes the large dynamin-related GTPase atlastin-1. The mutant protein exhibited reduced GTPase activity and prominently disrupted ER network morphology when expressed in COS7 cells, strongly supporting pathogenicity. An expanded screen in 115 additional HSN I patients identified two further dominant ATL1 mutations (c.196G>C [p.Glu66Gln] and c.976 delG [p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders.

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

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...... and OPA3 mutations in cases of suspected hereditary optic neuropathy, even in absence of a family history of the disease....... novel OPA1 mutations reported here. The statistical analysis of this large set of mutations has led us to propose a diagnostic strategy that should help with the molecular work-up of optic neuropathies. Our results highlight the importance of investigating LHON-causing mtDNA mutations as well as OPA1...

Ultrasonographic findings in hereditary neuropathy with liability to pressure palsies.

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Bayrak, Ayse O; Bayrak, Ilkay Koray; Battaloglu, Esra; Ozes, Burcak; Yildiz, Onur; Onar, Musa Kazim

2015-02-01

The aims of this study were to evaluate the sonographic findings of patients with hereditary neuropathy with liability to pressure palsies (HNPP) and to examine the correlation between sonographic and electrophysiological findings. Nine patients whose electrophysiological findings indicated HNPP and whose diagnosis was confirmed by genetic analysis were enrolled in the study. The median, ulnar, peroneal, and tibial nerves were evaluated by ultrasonography. We ultrasonographically evaluated 18 median, ulnar, peroneal, and tibial nerves. Nerve enlargement was identified in the median, ulnar, and peroneal nerves at the typical sites of compression. None of the patients had nerve enlargement at a site of noncompression. None of the tibial nerves had increased cross-sectional area (CSA) values. There were no significant differences in median, ulnar, and peroneal nerve distal motor latencies (DMLs) between the patients with an increased CSA and those with a normal CSA. In most cases, there was no correlation between electrophysiological abnormalities and clinical or sonographic findings. Although multiple nerve enlargements at typical entrapment sites on sonographic evaluation can suggest HNPP, ultrasonography cannot be used as a diagnostic tool for HNPP. Ultrasonography may contribute to the differential diagnosis of HNPP and other demyelinating polyneuropathies or compression neuropathies; however, further studies are required.

Hereditary neuropathy with liability to pressure palsy: a brief review with a case report.

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Rana, Abdul Qayyum; Masroor, Mohamed Sufian

2012-03-01

Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) is an autosomal dominant disorder and is usually characterized by episodes of recurrent and painless focal motor and sensory peripheral mononeuropathy. This condition is usually localized around areas of entrapment (predominantly the wrists, knees, elbows, and shoulders). The genetic locus of the disease is chromosome 17p12. A deletion of the PMP22 gene results in the lack of peripheral myelin protein, a key component to the myelin sheet of peripheral nerves. However, this disease may be completely asymptomatic until an event, such as a minor trauma, triggers these episodes, as seen in our presented case report. The diagnosis of HNPP can be somewhat challenging, as other diseases, such as Charcot-Marie-Tooth disease type 1A (CMT) and Hereditary Neuralgic Amyotrophy (HNA) must be included in the differential diagnosis due to their overlapping clinical features. There are currently no treatments to cure the disease, but therapies seek to alleviate the symptoms and recurring episodes.

Generation of patient-specific induced pluripotent stem cells from Leber's hereditary optic neuropathy

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Huai-En Lu

2018-04-01

Full Text Available Leber's hereditary optic neuropathy (LHON is a maternally inherited mitochondrial disease caused by homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. In this report, we generated an induced pluripotent stem cell (iPSCs line, TVGH-iPSC-010-09, from the peripheral blood mononuclear cells of a female patient with Leber's hereditary optic neuropathy (LHON by using the Sendai-virus delivery system. The resulting iPSCs retained the disease-causing mitochondrial DNA mutation, expressed pluripotent markers and could differentiate into the three germ layers. We believe LHON patient-specific iPSCs provide a powerful in vitro model for evaluating the pathological phenotypes of the disease.

Genes for hereditary sensory and autonomic neuropathies : a genotype-phenotype correlation

NARCIS (Netherlands)

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

Atypical hereditary sensory and autonomic neuropathy type IV with neither mental retardation nor pain insensitivity.

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Jung, Chae Lim; Ki, Chang-Seok; Kim, Byoung Joon; Lee, Jong-Hyuck; Sung, Ki-Sun; Kim, Jong-Won; Park, Youn-Soo

2013-12-01

Hereditary sensory and autonomic neuropathy type IV is an autosomal recessive disorder characterized by severe mental retardation and self-mutilation-related complications. Recently, we investigated a 16-year-old Korean boy with normal intelligence. He had preserved pain sensation but was suspected of having hereditary sensory and autonomic neuropathy type IV because of the recurrent bone fractures and painless joint destruction in the absence of any predisposing medical conditions. Genetic analysis of the NTRK1 gene revealed compound heterozygous mutations including c.851-33T>A and c.2303C>T (p.Pro768Leu) in the NTRK1 gene. The p.Pro768Leu mutation has been identified in 2 Japanese patients with a mild phenotype. Therefore, although it is rare, hereditary sensory and autonomic neuropathy type IV should be considered in patients with recurrent bone fractures and painless joint destruction who do not have any predisposing conditions even when they do not have typical clinical features such as mental retardation or pain insensitivity.

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…

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

Science.gov (United States)

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

2014-03-19

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 usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. The prevalence of HNPP is not well known. CMT1A usually presents in the first two decades with difficulty walking or running. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. Sonography of the nerves can be useful. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. The mode of inheritance is autosomal dominant and de novo mutations occur. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. Prenatal testing is possible; requests for prenatal testing are not common. Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing. Life expectancy is normal.

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

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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

[Clinical report of hereditary motor and sensory neuropathy with proximal dominance in Shiga prefecture].

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Takahashi, Mitsuo; Mitsui, Yoshiyuki; Yorifuji, Shiro; Nakamura, Yuusaku; Tsukamoto, Yoshihumi; Nishimoto, Kazuhiro

2007-09-01

We followed eight hereditary motor and sensory neuropathy patients with proximal dominance (HMSN-P) in Shiga prefecture from 1984 to 2007. There were 4 men and 4 women from two families showing autosomal and dominant prepotency. These families were related by marriage. The average onset of disease was at 53.4 +/- 8.9 (40-68) years-old. Initial symptoms were difficulty of standing up, difficulty elevating their arms, limping, or numbness. The main feature was neurogenic muscular atrophy with proximal dominance. All deep tendon reflexes were decreased or nonexistent. Paresthesia in the hands and feet and/or decreased vibratory sense in the legs were found in six patients. High CK blood levels were recognized in three patients. EMG in four patients revealed neurogenic pattern. Nerve conduction study was conducted in two patients. MCV of the median nerve and of the tibial posterior nerve, also SCV of the median nerve and of the sural nerve were within normal range in all nerves. Amplitudes of sensory action potential or of M wave were decreased or nonexistent in five of eight nerves, and distal latency of M waves was delayed in three of four nerves. These data suggests dysfunction of distal parts of the peripheral nerve fibers and axonal degeneration of the nerve trunk. Seven patients have died, and their average death age was 69.1 +/- 8.2 (52-77) years-old. Their average affected period was 16.6 (4-30) years. Their clinical history resembles Okinawa-type HMSN-P, but without the painful muscle cramps which are distinctive Okinawa-type signs.

Hereditary sensory and autonomic neuropathy type I in a Chinese family: British C133W mutation exists in the Chinese.

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Bi, Hongyan; Gao, Yunying; Yao, Sheng; Dong, Mingrui; Headley, Alexander Peter; Yuan, Yun

2007-10-01

Hereditary sensory and autonomic neuropathy type I (HSAN I) is an autosomal dominant disorder of the peripheral nervous system characterized by marked progressive sensory loss, with variable autonomic and motor involvement. The HSAN 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). Sequencing in HSAN I families have previously identified mutations in exons 5, 6 and 13 of this gene. Here we report the clinical, electrophysiological and pathological findings of a proband in a Chinese family with HSAN I. The affected members showed almost typical clinical features. Electrophysiological findings showed an axonal, predominantly sensory, neuropathy with motor and autonomic involvement. Sural nerve biopsy showed loss of myelinated and unmyelinated fibers. SPTLC1 mutational analysis revealed the C133W mutation, a mutation common in British HSAN I families.

[Hereditary sensory and autonomic neuropathy type II A: early neurological and skeletal findings].

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Esmer, C; Díaz Zambrano, S; Santos Díaz, M A; González Huerta, L M; Cuevas Covarrubias, S A; Bravo Oro, A

2014-04-01

The hereditary sensory and autonomic neuropathies are genetic disorders characterized by the loss of sensation including pain, tactile and temperature. Its clinical and molecular features vary widely; the symptoms may begin from birth or be noticed in the first or second decade, with different types of complications of trauma to the extremities such as ulcers, mutilations and acral amputations. They are classified into six groups from I to VI, determined by the abnormality in eleven genes leading to phenotypic variations in the age of onset and the presence or absence of dysautonomia signs. With the exception of type I, all are autosomal recessive. The type II of these neuropathies is characterized by insensitivity to pain, heat and proprioception. We describe three members of a Mexican family with WNK1 gene mutation that caused hereditary neuropathy IIA. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

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

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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"…

The natural history of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) in 97 Japanese patients.

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Fujisaki, Natsumi; Suwazono, Shugo; Suehara, Masahito; Nakachi, Ryo; Kido, Miwako; Fujiwara, Yoshihisa; Oshiro, Saki; Tokashiki, Takashi; Takashima, Hiroshi; Nakagawa, Masanori

2018-02-01

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is a motor and sensory neuronopathy with autosomal dominant inheritance, adult onset, slowly progressive course, and is associated with TRK-fused gene (TFG) mutation. At advanced stages, respiratory failure and dysphagia becomes life-threatoning, and patients typically die by their 70s. Although there is currently no evidence for effective treatment, a therapy may be found by elucidation of the function of TFG. Recently its pathomechanism has been proposed to be associated with abnormalities in protein transfer from the endoplasmic reticulum. Such pathomechanisms might involve a similar process in amyotrophic lateral sclerosis; thus, its pathomechanisms and treatment strategy might make it a good model for neurodegenerative disorders. It is of great value to clarify the natural history of HMSN-P, in oder to judge the treatment effect. By evaluating 97 patients (79 out of 97 were examined and all confirmed with p.Pro 285 Leu mutation) in this study, it was confirmed that this disease follows a uniform course in the earlier stages, and there are individual differences in the onset between 20 and 30 years. Such uniformity might be due to the proposed single gene abnormality. At advanced stages, there are larger individual differences in the progression, but the reasons for these are unknown. Longer survival might be achieved with a better care for respiratory failure and dysphagia if such cares were undertaken at appropriate times.

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

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Yakup Ergül

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.

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

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Ergül, Yakup; Ekici, Bariş; Keskin, Sabiha

2011-01-01

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.

Mutations in the nervous system--specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II.

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Shekarabi, Masoud; Girard, Nathalie; Rivière, Jean-Baptiste; Dion, Patrick; Houle, Martin; Toulouse, André; Lafrenière, Ronald G; Vercauteren, Freya; Hince, Pascale; Laganiere, Janet; Rochefort, Daniel; Faivre, Laurence; Samuels, Mark; Rouleau, Guy A

2008-07-01

Hereditary sensory and autonomic neuropathy type II (HSANII) is an early-onset autosomal recessive disorder characterized by loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves. Mutations in hereditary sensory neuropathy type II (HSN2), a single-exon ORF originally identified in affected families in Quebec and Newfoundland, Canada, were found to cause HSANII. We report here that HSN2 is a nervous system-specific exon of the with-no-lysine(K)-1 (WNK1) gene. WNK1 mutations have previously been reported to cause pseudohypoaldosteronism type II but have not been studied in the nervous system. Given the high degree of conservation of WNK1 between mice and humans, we characterized the structure and expression patterns of this isoform in mice. Immunodetections indicated that this Wnk1/Hsn2 isoform was expressed in sensory components of the peripheral nervous system and CNS associated with relaying sensory and nociceptive signals, including satellite cells, Schwann cells, and sensory neurons. We also demonstrate that the novel protein product of Wnk1/Hsn2 was more abundant in sensory neurons than motor neurons. The characteristics of WNK1/HSN2 point to a possible role for this gene in the peripheral sensory perception deficits characterizing HSANII.

Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

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Shekarabi, Masoud; Girard, Nathalie; Rivière, Jean-Baptiste; Dion, Patrick; Houle, Martin; Toulouse, André; Lafrenière, Ronald G.; Vercauteren, Freya; Hince, Pascale; Laganiere, Janet; Rochefort, Daniel; Faivre, Laurence; Samuels, Mark; Rouleau, Guy A.

2008-01-01

Hereditary sensory and autonomic neuropathy type II (HSANII) is an early-onset autosomal recessive disorder characterized by loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves. Mutations in hereditary sensory neuropathy type II (HSN2), a single-exon ORF originally identified in affected families in Quebec and Newfoundland, Canada, were found to cause HSANII. We report here that HSN2 is a nervous system–specific exon of the with-no-lysine(K)–1 (WNK1) gene. WNK1 mutations have previously been reported to cause pseudohypoaldosteronism type II but have not been studied in the nervous system. Given the high degree of conservation of WNK1 between mice and humans, we characterized the structure and expression patterns of this isoform in mice. Immunodetections indicated that this Wnk1/Hsn2 isoform was expressed in sensory components of the peripheral nervous system and CNS associated with relaying sensory and nociceptive signals, including satellite cells, Schwann cells, and sensory neurons. We also demonstrate that the novel protein product of Wnk1/Hsn2 was more abundant in sensory neurons than motor neurons. The characteristics of WNK1/HSN2 point to a possible role for this gene in the peripheral sensory perception deficits characterizing HSANII. PMID:18521183

Bilateral vision loss due to Leber's hereditary optic neuropathy after long-term alcohol, nicotine and drug abuse.

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Maass, Johanna; Matthé, Egbert

2018-04-01

Leber's hereditary optic neuropathy is relatively rare, and no clinical pathognomonic signs exist. We present a rare case of bilateral vision loss of a patient with multiple drug abuse in the history. A 31-year-old man presented with a history of progressive, decreased vision in both eyes for 6 month. On examination, his visual acuity was hand motion in both eyes. Funduscopy demonstrated a temporal pallor of the optic disc. Goldmann visual field perimetry showed a crescent visual field in the right eye and a circular decrease to less than 50 ° in the left eye. Electroretinogram showed a scotopic b-wave amplitude reduction. Optical coherence tomographies, Heidelberg Retina tomography, visual evoked potentials, and magnetic resonance imaging with contrast as well as blood tests were normal. The patient reported to consume various kinds of drugs as well as recreational drug use and alcohol consumption since he was 16 years old. We started a hemodilution therapy, believing the patient suffered from a bilateral, toxic optic neuropathy due to his lifestyle. Laboratory results later on showed Leber's hereditary optic neuropathy. Leber's hereditary optic neuropathy is a rare disease without a typical, pathognomonic presentation. Even though the patient gave good reasons for a toxic optic neuropathy, one should never stop to test for other diseases.

Role of stretch therapy in comprehensive physical habilitation of patients with Charcot–Marie–Tooth hereditary neuropathy

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N. A. Shnayder

2015-01-01

Full Text Available Charcot–Marie–Tooth hereditary neuropathy (Charcot–Marie–Tooth disease, CMT is the most common form of hereditary neuropathies, accompanied by sensory disorders, progressive muscle weakness with the formation of disabling contractures of the limbs. Currently, the main treatment program is effective CMT habilitation, which can prevent the development of limb deformities and thereby improve the life quality of the patient. Stretch therapy is one of the most effective methods of prevention and treatment of contractures in patients with CMT. This article provides a brief review of the literature regarding the use of stretching as physical therapy program of CMT habilitation.

Genes for hereditary sensory and autonomic neuropathies: a genotype–phenotype correlation

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

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 and RAB7) and five genes for autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and IKBKAP). We performed a systematic mutation screening of the coding sequences of six of these genes on a cohort of 100 familial and isolated patients diagnosed with HSAN. In addition, we screened the functional candidate gene NGFR (p75/NTR) encoding the nerve growth factor receptor. We identified disease-causing mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1 in 19 patients, of which three mutations have not previously been reported. The phenotypes associated with mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital insensitivity to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy, respectively. RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B (CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced ulcero-mutilations. In SPTLC1, we detected a novel mutation (S331F) corresponding to a previously unknown severe and early-onset HSAN phenotype. No mutations were found in NGFB, CCT5 and NGFR. Overall disease-associated mutations were found in 19% of the studied patient group, suggesting that additional genes are associated with HSAN. Our genotype–phenotype correlation study broadens the spectrum of HSAN and provides additional insights for molecular and clinical diagnosis. PMID:19651702

Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2

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Züchner, Stephan; de Jonghe, Peter; Jordanova, Albena; Claeys, Kristl G.; Guergueltcheva, Velina; Cherninkova, Sylvia; Hamilton, Steven R.; van Stavern, Greg; Krajewski, Karen M.; Stajich, Jeffery; Tournev, Ivajlo; Verhoeven, Kristien; Langerhorst, Christine T.; de Visser, Marianne; Baas, Frank; Bird, Thomas; Timmerman, Vincent; Shy, Michael; Vance, Jeffery M.

2006-01-01

OBJECTIVE: Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms, but the genetic cause of this disease has

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

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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.

Leber hereditary optic neuropathy: current perspectives

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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

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

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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.

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

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Barros, Pedro; Morais, Hugo; Santos, Catarina; Roriz, José; Coutinho, Paula

2014-04-01

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. To study a new Portuguese family with these characteristics. To describe the clinical and neurophysiologic characteristics of one family with features of sensory neuropathy associated with cough and gastroesophageal erflux. Three of five siblings presented a similar history of paroxysmal cough (5th decade). About a decade later they experienced numbness and paraesthesia in the feet 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. 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.

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

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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.

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

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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.

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

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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.

Clinical and genetic characteristics of autosomal recessive axonal neuropathy with neuromyotonia in Russian patients

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E. L. Dadali

2017-01-01

Full Text Available Introduction. Hereditary motor and sensory neuropathies are genetically heterogeneous group of disorders characterized by a progressive muscle weakness, atrophy of hand and leg muscles often associated with deformations, and mild to moderate sensory loss. Axonal neuropathy with neuromyotonia (AR-ANM is one of the rarest autosomal recessive hereditary neuropathies. Materials and methods. Six (6 patients (4 men, 2 women aged 14–40 years from unrelated families with suspicion of HMSN were examined clinically, neurophysiologically and using DNA analysis. Results. Neurophysiological examination revealed motor and sensory neuropathy with neuromyotonia signs in all patients. In all cases homozygous variant of recessive mutations с.110G/C (р.Arg37Pro in the gene encoding the histidine triad nucleotide binding protein 1 (HINT1 has been revealed. Conclusion. There is the first description of the clinical and neurophysiological features of six patients with AR-ANM in Russia. 

Mitochondrial DNA Mutation Associated with Leber's Hereditary Optic Neuropathy

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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.

Inflammation and neuropathic attacks in hereditary brachial plexus neuropathy

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Klein, C; Dyck, P; Friedenberg, S; Burns, T; Windebank, A; Dyck, P

2002-01-01

Objective: To study the role of mechanical, infectious, and inflammatory factors inducing neuropathic attacks in hereditary brachial plexus neuropathy (HBPN), an autosomal dominant disorder characterised by attacks of pain and weakness, atrophy, and sensory alterations of the shoulder girdle and upper limb muscles. Methods: Four patients from separate kindreds with HBPN were evaluated. Upper extremity nerve biopsies were obtained during attacks from a person of each kindred. In situ hybridisation for common viruses in nerve tissue and genetic testing for a hereditary tendency to pressure palsies (HNPP; tomaculous neuropathy) were undertaken. Two patients treated with intravenous methyl prednisolone had serial clinical and electrophysiological examinations. One patient was followed prospectively through pregnancy and during the development of a stereotypic attack after elective caesarean delivery. Results: Upper extremity nerve biopsies in two patients showed prominent perivascular inflammatory infiltrates with vessel wall disruption. Nerve in situ hybridisation for viruses was negative. There were no tomaculous nerve changes. In two patients intravenous methyl prednisolone ameliorated symptoms (largely pain), but with tapering of steroid dose, signs and symptoms worsened. Elective caesarean delivery did not prevent a typical postpartum attack. Conclusions: Inflammation, probably immune, appears pathogenic for some if not all attacks of HBPN. Immune modulation may be useful in preventing or reducing the neuropathic attacks, although controlled trials are needed to establish efficacy, as correction of the mutant gene is still not possible. The genes involved in immune regulation may be candidates for causing HBPN disorders. PMID:12082044

[Hereditary neuropathy with liability to pressure palsies in childhood: Report of three cases].

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Bar, C; Villéga, F; Espil, C; Husson, M; Pedespan, J-M; Rouanet, M-F

2017-03-01

Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant neuropathy. It is characterized by recurrent sensory and motor nerve palsies, usually precipitated by minor trauma or compression. Even though rare in childhood, this disorder is probably underdiagnosed given its wide spectrum of clinical symptoms. We review three separate cases of HNPP diagnosed in children with various phenotypes: fluctuating and distal paresthesias disrupting learning at school, cramps related to intensive piano practice, and discrete muscle weakness with no functional complaint. Family history should be carefully reviewed to identify potential undiagnosed HNPP cases, as in our three reports. Electrophysiological study is essential for the diagnosis, with a double advantage: to confirm the presence of focal abnormalities in clinically symptomatic areas and to guide molecular biology by revealing an underlying demyelinating polyneuropathy. The diagnosis of HNPP is confirmed by genetic testing, which in 90% of cases shows a 1.5-Mb deletion of chromosome 17p11.2 including the PMP22 gene. Patients are expected to make a full recovery after each relapse. However, it is very important for both the patient and his or her family to establish a diagnosis in order to prevent recurrent palsy brought on by situations involving prolonged immobilizations leading to nerve compression. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

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

The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy.

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Suriyanarayanan, Saranya; Auranen, Mari; Toppila, Jussi; Paetau, Anders; Shcherbii, Maria; Palin, Eino; Wei, Yu; Lohioja, Tarja; Schlotter-Weigel, Beate; Schön, Ulrike; Abicht, Angela; Rautenstrauss, Bernd; Tyynismaa, Henna; Walter, Maggie C; Hornemann, Thorsten; Ylikallio, Emil

2016-03-01

Hereditary sensory and autonomic neuropathy 1 (HSAN1) is an autosomal dominant disorder that can be caused by variants in SPTLC1 or SPTLC2, encoding subunits of serine palmitoyl-CoA transferase. Disease variants alter the enzyme's substrate specificity and lead to accumulation of neurotoxic 1-deoxysphingolipids. We describe two families with autosomal dominant HSAN1C caused by a new variant in SPTLC2, c.547C>T, p.(Arg183Trp). The variant changed a conserved amino acid and was not found in public variant databases. All patients had a relatively mild progressive distal sensory impairment, with onset after age 50. Small fibers were affected early, leading to abnormalities on quantitative sensory testing. Sural biopsy revealed a severe chronic axonal neuropathy with subtotal loss of myelinated axons, relatively preserved number of non-myelinated fibers and no signs for regeneration. Skin biopsy with PGP9.5 labeling showed lack of intraepidermal nerve endings early in the disease. Motor manifestations developed later in the disease course, but there was no evidence of autonomic involvement. Patients had elevated serum 1-deoxysphingolipids, and the variant protein produced elevated amounts of 1-deoxysphingolipids in vitro, which proved the pathogenicity of the variant. Our results expand the genetic spectrum of HSAN1C and provide further detail about the clinical characteristics. Sequencing of SPTLC2 should be considered in all patients presenting with mild late-onset sensory-predominant small or large fiber neuropathy.

Acute optic neuropathy associated with a novel MFN2 mutation.

Science.gov (United States)

Leonardi, Luca; Marcotulli, Christian; Storti, Eugenia; Tessa, Alessandra; Serrao, Mariano; Parisi, Vincenzo; Santorelli, F M; Pierelli, Francesco; Casali, Carlo

2015-07-01

Mutations in the mitofusin 2 (MFN2) gene cause CMT2A the most common form of autosomal dominant axonal Charcot-Marie-Tooth (CMT). In addition, mutations in MFN2 have been shown to be responsible for Hereditary Motor Sensory Neuropathy type VI (HSMN VI), a rare early-onset axonal CMT associated with optic neuropathy. Most reports of HMSN VI presented with a sub-acute form of optic neuropathy. Herein, we report a CMT2A patient, who developed very rapidly progressing severe optic neuropathy. A 40-year-old Caucasian man was evaluated for gait disturbance and lower limbs weakness, slowly progressed over the last 2 years. Due to clinical data and family history, a diagnosis of CMT2 was made. The novel heterozygous c.775C > T (p.Arg259Cys) mutation in MFN2 was detected in the patient and his clinical affected mother. Interestingly, the patient developed a severe sudden bilateral visual deterioration few years early, with clinical and instrumental picture suggestive of acute bilateral optic neuropathy. Our report expands the spectrum of MFN2-related manifestation because it indicates that visual symptoms of HMSN VI may enter in the differential with acquired or hereditary acute optic neuropathies, and that severe optic neuropathy is not invariably an early manifestation of the disease but may occur as disease progressed. This report could have an impact on clinicians who evaluate patients with otherwise unexplainable bilateral acute-onset optic neuropathy, especially if associated with a motor and sensory axonal neuropathy.

A case report of congenital sensory neuropathy with anhidrosis

International Nuclear Information System (INIS)

Lee, Won Hyong; Chang, Hae Soon; Han, Man Chung; Lee, Suck Hyun; Lee, Duk Yong

1974-01-01

Congenital sensory neuropathy with anhidrosis is rare disease and may be confused with other cause of pain insensitivity or indifference. Other cause of pain insensitivity include congenital indifference to pain, congenital sensory neuropathy, hereditary sensory radicular neuropathy, nonprogressive sensory radicular neuropathy, syringomyelia, and hysterical analgesia. It is hereditary disease which is transmitted with autosomal recessive trait. The patient is 8 years old Korean male with complaint of swelling and local heat on right knee joint. Generalized analgesia is noted on physical examination. The skin is dry and coarse with no evidence of sweating. Delayed motor development was noted on early children. Mental development is retarded. On past history, patient showed unpredictable rises of temperature, though the general condition remained good. Multiple painless fracture on right humerus and right metatasal bone was occurred. Rt.knee radiograms show marked swelling of soft tissue and periosteal calcification on distal femru,which are resemble with neurotrophic joint

A case report of congenital sensory neuropathy with anhidrosis

Energy Technology Data Exchange (ETDEWEB)

Lee, Won Hyong; Chang, Hae Soon; Han, Man Chung; Lee, Suck Hyun; Lee, Duk Yong [Seoul National University College of Medicine, Seoul (Korea, Republic of)

1974-10-15

Congenital sensory neuropathy with anhidrosis is rare disease and may be confused with other cause of pain insensitivity or indifference. Other cause of pain insensitivity include congenital indifference to pain, congenital sensory neuropathy, hereditary sensory radicular neuropathy, nonprogressive sensory radicular neuropathy, syringomyelia, and hysterical analgesia. It is hereditary disease which is transmitted with autosomal recessive trait. The patient is 8 years old Korean male with complaint of swelling and local heat on right knee joint. Generalized analgesia is noted on physical examination. The skin is dry and coarse with no evidence of sweating. Delayed motor development was noted on early children. Mental development is retarded. On past history, patient showed unpredictable rises of temperature, though the general condition remained good. Multiple painless fracture on right humerus and right metatasal bone was occurred. Rt.knee radiograms show marked swelling of soft tissue and periosteal calcification on distal femru,which are resemble with neurotrophic joint.

Hereditary neuropathy with liability to pressure palsy: an investigation in a rare and large Chinese family.

Science.gov (United States)

He, Yuan; Wu, Qiang; Xu, Zhipeng; Wang, Qianqian; Wang, Weili; Li, Dezhong; Liu, Wanhong; He, Xiaohua

2012-01-01

Hereditary neuropathy with liability to pressure palsy (HNPP), mainly associated with the peripheral myelin protein 22 (PMP22) gene, is generally an autosomal-dominant inherited peripheral neuropathy. The present large family including four generations provides an exciting opportunity to gain important insights into HNPP in China. A large 43-member family with ten members suspected to be affected by HNPP was studied. Neurologic examinations, electrophysiological and neuropathological studies and molecular genetic testing were used for these kindred. Clinically, the proband had limb hyposthenia and atrophy, and his mother showed declined tendon reflexes in the right lower limb. Electrophysiologically, sensory and motor nerve conduction velocities were generalized reduced. Sural nerve biopsy for the proband showed focal thickesning of the myelin sheaths. Furthermore, real-time quantitative PCR demonstrated that the PMP22 gene has a higher Ct value than reference gene in all suspected patients. These results indicated that the family is indeed a rare and large pedigree of HNPP caused by the deletion of PMP22 gene. Given that the suspected patient in the fourth generation is absent, this family is still worthy of further follow-up study. Copyright © 2012 S. Karger AG, Basel.

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

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

Hereditary sensory and autonomic neuropathy type IV and orthopaedic complications.

Science.gov (United States)

Kim, W; Guinot, A; Marleix, S; Chapuis, M; Fraisse, B; Violas, P

2013-11-01

Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) is a very rare autosomal recessive disorder characterized by recurrent episodes of unexplained fever, extensive anhidrosis, total insensitivity to pain, hypotonia, and mental retardation. The most frequent complications of this disease are corneal scarring, multiple fractures, joint deformities, osteomyelitis, and disabling self-mutilations. We reported the case of a 12-year-old boy. The goal was to discuss our decision-making and compare this case with cases described in the literature. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Diagnostic approach to peripheral neuropathy

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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.

Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) and genetic heterogeneity.

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Maeda, Kouji; Kaji, Ryuji; Yasuno, Katsuhito; Jambaldorj, Jamiyansuren; Nodera, Hiroyuki; Takashima, Hiroshi; Nakagawa, Masanori; Makino, Satoshi; Tamiya, Gen

2007-01-01

Hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) is an adult-onset peripheral neurodegenerative disorder which has been reported only in the Okinawa Islands, Japan. The disease locus of "Okinawa-type" HMSN-P has been previously mapped to 3q13.1, with all affected individuals sharing an identical haplotype around the locus, suggesting that the undiscovered causative mutation in HMSN-P originated from a single founder. We have newly found two large families from the western part of Japan within which multiple members developed symptoms similar to those exhibited by HMSN-P patients from Okinawa, with no record of affinal connection between the islands. Using these pedigrees with "Kansai-type" HMSN-P, we carried out a linkage study utilizing eight microsatellite markers and identified a candidate region on 3q13.1 cosegregating with the disease (maximum two-point LOD score of 8.44 at theta=0.0) overlapping with the Okinawa-type HMSN-P locus. However, the disease haplotype shared among all affected members in these families was different from that in the Okinawa kindred, suggesting allelic heterogeneity. Such allelic variation should aid in the identification of the disease-causative gene. Moreover, the allelic heterogeneity of HMSN-P in the Japanese population suggests that HMSN-P may be more common across other ethnic groups, but classified into other disease categories.

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...... 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....

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.

Autosomal recessive Charcot-Marie-Tooth neuropathy.

Science.gov (United States)

Espinós, Carmen; Calpena, Eduardo; Martínez-Rubio, Dolores; Lupo, Vincenzo

2012-01-01

Charcot-Marie-Tooth (CMT) disease, a hereditary motor and sensory neuropathy that comprises a complex group of more than 50 diseases, is the most common inherited neuropathy. CMT is generally divided into demyelinating forms, axonal forms and intermediate forms. CMT is also characterized by a wide genetic heterogeneity with 29 genes and more than 30 loci involved. The most common pattern of inheritance is autosomal dominant (AD), although autosomal recessive (AR) forms are more frequent in Mediterranean countries. In this chapter we give an overview of the associated genes, mechanisms and epidemiology of AR-CMT forms and their associated phenotypes.

HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 Mutation

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Ji-Yon Kim

2016-01-01

Full Text Available The Charcot-Marie-Tooth disease 2F (CMT2F and distal hereditary motor neuropathy 2B (dHMN2B are caused by autosomal dominantly inherited mutations of the heat shock 27 kDa protein 1 (HSPB1 gene and there are no specific therapies available yet. Here, we assessed the potential therapeutic effect of HDAC6 inhibitors on peripheral neuropathy with HSPB1 mutation using in vitro model of motor neurons derived from induced pluripotent stem cells (iPSCs of CMT2F and dHMN2B patients. The absolute velocity of mitochondrial movements and the percentage of moving mitochondria in axons were lower both in CMT2F-motor neurons and in dHMN2B-motor neurons than those in controls, and the severity of the defective mitochondrial movement was different between the two disease models. CMT2F-motor neurons and dHMN2B-motor neurons also showed reduced α-tubulin acetylation compared with controls. The newly developed HDAC6 inhibitors, CHEMICAL X4 and CHEMICAL X9, increased acetylation of α-tubulin and reversed axonal movement defects of mitochondria in CMT2F-motor neurons and dHMN2B-motor neurons. Our results suggest that the neurons derived from patient-specific iPSCs can be used in drug screening including HDAC6 inhibitors targeting peripheral neuropathy.

Autosomal dominant hereditary sensory neuropathy with chronic cough and gastro-oesophageal reflux: clinical features in two families linked to chromosome 3p22-p24.

Science.gov (United States)

Spring, Penelope J; Kok, Cindy; Nicholson, Garth A; Ing, Alvin J; Spies, Judith M; Bassett, Mark L; Cameron, John; Kerlin, Paul; Bowler, Simon; Tuck, Roger; Pollard, John D

2005-12-01

Autosomal dominant hereditary sensory neuropathy (HSN I) is a clinically and genetically heterogeneous group of disorders, and in some families it is due to mutations in the serine palmitoyltransferase (SPTLC1) gene. We have characterized two families with HSN I associated with cough and gastro-oesophageal reflux (GOR). From a large Australian family, 27 individuals and from a smaller family, 11 individuals provided clinical information and blood for genetic analysis. Affected individuals had an adult onset of paroxysmal cough, GOR and distal sensory loss. Cough could be triggered by noxious odours or by pressure in the external auditory canal (Arnold's ear-cough reflex). Other features included throat clearing, hoarse voice, cough syncope and sensorineural hearing loss. Neurophysiological and pathological studies demonstrated a sensory axonal neuropathy. Gastric emptying studies were normal, and autonomic function and sweat tests were either normal or showed distal hypohidrosis. Cough was likely to be due to a combination of denervation hypersensitivity of the upper airways and oesophagus, and prominent GOR. Most affected individuals were shown on 24 h ambulatory oesophageal pH monitoring to have multiple episodes of GOR, closely temporally associated with coughing. Hoarse voice was probably attributable to acid-induced laryngeal damage, and there was no evidence of vocal cord palsy. No other cause for cough was found on most respiratory or otorhinological studies. Linkage to chromosome 3p22-p24 has been found in both families, with no evidence of linkage to loci for known HSN I, autosomal dominant hereditary motor and sensory neuropathy, hereditary GOR or triple A syndrome. These families represent a genetically novel variant of HSN I, with a distinctive cough owing to involvement of the upper aerodigestive tract.

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

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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.

Oral manifestations and prosthetic rehabilitation in hereditary sensory and autonomic neuropathy (HSAN)type IV: a case report.

Science.gov (United States)

Ofluoglu, Duygu; Altin, Nazli; Yaman, Elif; Tuna İnce, Elif Bahar; Aytepe, Zeynep; Tanyeri, Hakki

2016-01-01

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.

Proximal dominant hereditary motor and sensory neuropathy with proximal dominance association with mutation in the TRK-fused gene.

Science.gov (United States)

Lee, Sang-Soo; Lee, Hye Jin; Park, Jin-Mo; Hong, Young Bin; Park, Kee-Duk; Yoo, Jeong Hyun; Koo, Heasoo; Jung, Sung-Chul; Park, Hyung Soon; Lee, Ji Hyun; Lee, Min Goo; Hyun, Young Se; Nakhro, Khriezhanou; Chung, Ki Wha; Choi, Byung-Ok

2013-05-01

Hereditary motor and sensory neuropathy with proximal dominance (HMSN-P) has been reported as a rare type of autosomal dominant adult-onset Charcot-Marie-Tooth disease. HMSN-P has been described only in Japanese descendants since 1997, and the causative gene has not been found. To identify the genetic cause of HMSN-P in a Korean family and determine the pathogenic mechanism. Genetic and observational analysis. Translational research center for rare neurologic disease. Twenty-eight individuals (12 men and 16 women) from a Korean family with HMSN-P. Whole-exome sequencing, linkage analysis, and magnetic resonance imaging. Through whole-exome sequencing, we revealed that HMSN-P is caused by a mutation in the TRK-fused gene (TFG). Clinical heterogeneities were revealed in HMSN-P between Korean and Japanese patients. The patients in the present report showed faster progression of the disease compared with the Japanese patients, and sensory nerve action potentials of the sural nerve were lost in the early stages of the disease. Moreover, tremor and hyperlipidemia were frequently found. Magnetic resonance imaging of the lower extremity revealed a distinct proximal dominant and sequential pattern of muscular involvement with a clearly different pattern than patients with Charcot-Marie-Tooth disease type 1A. Particularly, endoneural blood vessels revealed marked narrowing of the lumen with swollen vesicular endothelial cells. The underlying cause of HMSN-P proves to be a mutation in TFG that lies on chromosome 3q13.2. This disease is not limited to Japanese descendants, and marked narrowing of endoneural blood vessels was noted in the present study. We believe that TFG can affect the peripheral nerve tissue.

Leber's Hereditary Optic Neuropathy: A Case Report

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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.

Genetically determined optic neuropathies

DEFF Research Database (Denmark)

Milea, Dan; Amati-Bonneau, Patrizia; Reynier, Pascal

2010-01-01

The present review focuses on recent advances in the knowledge of hereditary optic neuropathies resulting from retinal ganglion cell degeneration, mostly due to mitochondrial dysfunctions.......The present review focuses on recent advances in the knowledge of hereditary optic neuropathies resulting from retinal ganglion cell degeneration, mostly due to mitochondrial dysfunctions....

Partial Gene Deletions of PMP22 Causing Hereditary Neuropathy with Liability to Pressure Palsies

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Sun-Mi Cho

2014-01-01

Full Text Available Hereditary neuropathy with liability to pressure palsies (HNPP is an autosomal neuropathy that is commonly caused by a reciprocal 1.5 Mb deletion on chromosome 17p11.2, at the site of the peripheral myelin protein 22 (PMP22 gene. Other patients with similar phenotypes have been shown to harbor point mutations or small deletions, although there is some clinical variation across these patients. In this report, we describe a case of HNPP with copy number changes in exon or promoter regions of PMP22. Multiplex ligation-dependent probe analysis revealed an exon 1b deletion in the patient, who had been diagnosed with HNPP in the first decade of life using molecular analysis.

Is distal motor and/or sensory demyelination a distinctive feature of anti-MAG neuropathy?

Science.gov (United States)

Lozeron, Pierre; Ribrag, Vincent; Adams, David; Brisset, Marion; Vignon, Marguerite; Baron, Marine; Malphettes, Marion; Theaudin, Marie; Arnulf, Bertrand; Kubis, Nathalie

2016-09-01

To report the frequency of the different patterns of sensory and motor electrophysiological demyelination distribution in patients with anti-MAG neuropathy in comparison with patients with IgM neuropathy without MAG reactivity (IgM-NP). Thirty-five anti-MAG patients at early disease stage (20.1 months) were compared to 23 patients with IgM-NP; 21 CIDP patients and 13 patients with CMT1a neuropathy were used as gold standard neuropathies with multifocal and homogeneous demyelination, respectively. In all groups, standard motor and sensory electrophysiological parameters, terminal latency index and modified F ratio were investigated. Motor electrophysiological demyelination was divided in four profiles: distal, homogeneous, proximal, and proximo-distal. Distal sensory and sensorimotor demyelination were evaluated. Anti-MAG neuropathy is a demyelinating neuropathy in 91 % of cases. In the upper limbs, reduced TLI is more frequent in anti-MAG neuropathy, compared to IgM-NP. But, predominant distal demyelination of the median nerve is encountered in only 43 % of anti-MAG neuropathy and is also common in IgM-NP (35 %). Homogeneous demyelination was the second most frequent pattern (31 %). Concordance of electrophysiological profiles across motor nerves trunks is low and median nerve is the main site of distal motor conduction slowing. Reduced sensory conduction velocities occurs in 14 % of patients without evidence of predominant distal slowing. Simultaneous sensory and motor distal slowing was more common in the median nerve of anti-MAG neuropathy than IgM-NP. Electrophysiological distal motor demyelination and sensory demyelination are not a distinctive feature of anti-MAG reactivity. In anti-MAG neuropathy it is mainly found in the median nerve suggesting a frequent nerve compression at wrist.

Frequency of sensory motor neuropathy in type 2 diabetics

International Nuclear Information System (INIS)

Ather, N.A.; Sattar, R.A.; Ara, J.

2008-01-01

To determine the frequency of sensory motor neuropathy in type 2 diabetics at the time of presentation to the hospital. The study was conducted at Medical Unit-1, Jinnah Postgraduate Medical Center, Karachi, from November 2005 to April 2006. Patients of different ages and either gender with history of confirmed diabetes for ten years and above, on regular follow up were included. Those with non-diabetic causes of hyperglycemia or neuropathy were excluded. Relevant features like age, gender, treatment, symptoms , signs, nerve conduction study (NCS) results, duration of Diabetes mellitus (DM), fasting blood sugar (FBS) and serum values of glycosylated hemoglobin (HB1Ac) were recorded. Out of a total of 300 patients, there were 111 female and 189 male patients. Mean age was 58 +- 11.23 years. Mean duration of diabetes was 13.6+-5.48 years. One hundred and twenty three patients had symptoms of neuropathy. Clinical examination revealed mixed sensory and motor signs in 135 (45%) patients. Nerve conduction studies revealed abnormalities in 159 (53%) patients. Among patients having an abnormal NCS, the fasting blood glucose (FBS) was 120mg/dl in 147 (91%) patients. The glycosylated hemoglobin ranged from 4-15% with mean of 8.1% and standard deviation of 2.5%. This showed significant association (p <0.001) of peripheral neuropathy with abnormal FBS, HB1Ac and duration of diabetes. NCS diagnosed the neuropathy in more than half of the total number of patients, including both symptomatic and asymptomatic patients. Majority of the patients revealed symmetrical and a mixed type (motor and sensory) polyneuropathy. This shows that nerve conduction may not be concordant with the clinical signs and symptoms. NCS detects neuropathy much earlier, before it becomes evident clinically. The neuropathy is associated with abonromal fasting blood sugar, HBIAC and duration of diabetes. (author)

A knock-in/knock-out mouse model of HSPB8-associated distal hereditary motor neuropathy and myopathy reveals toxic gain-of-function of mutant Hspb8.

Science.gov (United States)

Bouhy, Delphine; Juneja, Manisha; Katona, Istvan; Holmgren, Anne; Asselbergh, Bob; De Winter, Vicky; Hochepied, Tino; Goossens, Steven; Haigh, Jody J; Libert, Claude; Ceuterick-de Groote, Chantal; Irobi, Joy; Weis, Joachim; Timmerman, Vincent

2018-01-01

Mutations in the small heat shock protein B8 gene (HSPB8/HSP22) have been associated with distal hereditary motor neuropathy, Charcot-Marie-Tooth disease, and recently distal myopathy. It is so far not clear how mutant HSPB8 induces the neuronal and muscular phenotypes and if a common pathogenesis lies behind these diseases. Growing evidence points towards a role of HSPB8 in chaperone-associated autophagy, which has been shown to be a determinant for the clearance of poly-glutamine aggregates in neurodegenerative diseases but also for the maintenance of skeletal muscle myofibrils. To test this hypothesis and better dissect the pathomechanism of mutant HSPB8, we generated a new transgenic mouse model leading to the expression of the mutant protein (knock-in lines) or the loss-of-function (functional knock-out lines) of the endogenous protein Hspb8. While the homozygous knock-in mice developed motor deficits associated with degeneration of peripheral nerves and severe muscle atrophy corroborating patient data, homozygous knock-out mice had locomotor performances equivalent to those of wild-type animals. The distal skeletal muscles of the post-symptomatic homozygous knock-in displayed Z-disk disorganisation, granulofilamentous material accumulation along with Hspb8, αB-crystallin (HSPB5/CRYAB), and desmin aggregates. The presence of the aggregates correlated with reduced markers of effective autophagy. The sciatic nerve of the homozygous knock-in mice was characterized by low autophagy potential in pre-symptomatic and Hspb8 aggregates in post-symptomatic animals. On the other hand, the sciatic nerve of the homozygous knock-out mice presented a normal morphology and their distal muscle displayed accumulation of abnormal mitochondria but intact myofiber and Z-line organisation. Our data, therefore, suggest that toxic gain-of-function of mutant Hspb8 aggregates is a major contributor to the peripheral neuropathy and the myopathy. In addition, mutant Hspb8 induces

Sonographic and electrodiagnostic features of hereditary neuropathy with liability to pressure palsies.

Science.gov (United States)

Ginanneschi, Federica; Filippou, Georgios; Giannini, Fabio; Carluccio, Maria A; Adinolfi, Antonella; Frediani, Bruno; Dotti, Maria T; Rossi, Alessandro

2012-12-01

In hereditary neuropathy with liability to pressure palsies (HNPP), the increase in distal motor latencies (DMLs) is often out of proportion to the slowing of conduction velocities, but the pathophysiological mechanism is still unclear. We used a combined electrophysiological and ultrasonographic (US) approach to provide insight into this issue. Twelve HNPP subjects underwent extensive electrophysiological studies and US measurements of the cross-sectional area (CSA) of several peripheral nerves. US nerve enlargement was only observed in the carpal tunnel, Guyon's canal, the elbow and the fibular head. We did not observe US abnormalities at sites where nerve entrapment is uncommon. An increase in DMLs was observed regardless of US nerve enlargement. The increased nerve CSA only in common sites of entrapment likely reflected the well-documented nerve vulnerability to mechanical stress in HNPP. No morphometric changes were seen in the distal nerve segments where compression/entrapment is unlikely, despite the fact that the DMLs were increased. These data suggest that factors other than mechanical stress are responsible for the distal slowing of action potential propagation. We speculate that a mixture of mechanical insults and an axon-initiated process in the distal nerves underlies the distal slowing and/or conduction failure in HNPP. © 2012 Peripheral Nerve Society.

A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy -- Russe (HMSNR).

Science.gov (United States)

Hantke, Janina; Chandler, David; King, Rosalind; Wanders, Ronald J A; Angelicheva, Dora; Tournev, Ivailo; McNamara, Elyshia; Kwa, Marcel; Guergueltcheva, Velina; Kaneva, Radka; Baas, Frank; Kalaydjieva, Luba

2009-12-01

Hereditary Motor and Sensory Neuropathy -- Russe (HMSNR) is a severe autosomal recessive disorder, identified in the Gypsy population. Our previous studies mapped the gene to 10q22-q23 and refined the gene region to approximately 70 kb. Here we report the comprehensive sequencing analysis and fine mapping of this region, reducing it to approximately 26 kb of fully characterised sequence spanning the upstream exons of Hexokinase 1 (HK1). We identified two sequence variants in complete linkage disequilibrium, a G>C in a novel alternative untranslated exon (AltT2) and a G>A in the adjacent intron, segregating with the disease in affected families and present in the heterozygote state in only 5/790 population controls. Sequence conservation of the AltT2 exon in 16 species with invariable preservation of the G allele at the mutated site, strongly favour the exonic change as the pathogenic mutation. Analysis of the Hk1 upstream region in mouse mRNA from testis and neural tissues showed an abundance of AltT2-containing transcripts generated by extensive, developmentally regulated alternative splicing. Expression is very low compared with ubiquitous Hk1 and all transcripts skip exon1, which encodes the protein domain responsible for binding to the outer mitochondrial membrane, and regulation of energy production and apoptosis. Hexokinase activity measurement and immunohistochemistry of the peripheral nerve showed no difference between patients and controls. The mutational mechanism and functional effects remain unknown and could involve disrupted translational regulation leading to increased anti-apoptotic activity (suggested by the profuse regenerative activity in affected nerves), or impairment of an unknown HK1 function in the peripheral nervous system (PNS).

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...

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: T...

[A family with autosomal dominant temporal lobe epilepsy accompanied by motor and sensory neuropathy].

Science.gov (United States)

Matsuoka, Takeshi; Furuya, Hirokazu; Ikezoe, Koji; Murai, Hiroyuki; Ohyagi, Yasumasa; Yoshiura, Takashi; Sasaki, Masayuki; Tobimatsu, Syozo; Kira, Jun-ichi

2004-01-01

We report a 20-year-old man with temporal lobe epilepsy (TLE) accompanied by hereditary motor and sensory neuropathy (HMSN). He had experienced complex partial seizures (CPS), which started with a nausea-like feeling, followed by loss of consciousness and automatism, since he was 6 years old. The frequency of attacks was at first decreased by phenytoin. However, attacks increased again when he was 18 years old. On admission, neurological examination showed mild weakness of the toes, pes cavus, hammer toe and mildly impaired vibratory sensation in his legs. Ten people in four generations of his family showed a history of epilepsy in the autosomal dominant inheritance form. His younger sister and mother had a history of epilepsy accompanied with pes cavus, hammer toe, weakness of toe and finger extension and mildly impaired vibratory sensation as well. Direct sequencing of the glioma-inactivated leucine-rich gene (LGI1), in which several mutations were reported in patients with familial lateral temporal lobe epilepsy, showed no specific mutation in this family. On consecutive video-EEG monitoring, paroxysmal rhythmic activity was confirmed in his left fronto-temporal region when he showed automatism, and then a generalized slow burst activity was detected when he lost consciousness. For his seizures, TLE with secondary generalization was diagnosed. In the nerve conduction study, delayed nerve conduction, distal motor latency and decreased amplitudes of the compound muscle action potentials (CMAP) of bilateral peroneal nerves were observed, indicating the existence of mild axonal degeneration. Based on these data, we consider that this family to be a new phenotype of autosomal dominant TLE accompanied by motor and sensory neuropathy.

Oral manifestations, dental management, and a rare homozygous mutation of the PRDM12 gene in a boy with hereditary sensory and autonomic neuropathy type VIII: a case report and review of the literature.

Science.gov (United States)

Elhennawy, Karim; Reda, Seif; Finke, Christian; Graul-Neumann, Luitgard; Jost-Brinkmann, Paul-Georg; Bartzela, Theodosia

2017-08-15

Hereditary sensory and autonomic neuropathy type VIII is a rare autosomal recessive inherited disorder. Chen et al. recently identified the causative gene and characterized biallelic mutations in the PR domain-containing protein 12 gene, which plays a role in the development of pain-sensing nerve cells. Our patient's family was included in Chen and colleagues' study. We performed a literature review of the PubMed library (January 1985 to December 2016) on hereditary sensory and autonomic neuropathy type I to VIII genetic disorders and their orofacial manifestations. This case report is the first to describe the oral manifestations, and their treatment, of the recently discovered hereditary sensory and autonomic neuropathy type VIII in the medical and dental literature. We report on the oral manifestations and dental management of an 8-month-old white boy with hereditary sensory and autonomic neuropathy-VIII over a period of 16 years. Our patient was homozygous for a mutation of PR domain-containing protein 12 gene and was characterized by insensitivity to pain and thermal stimuli, self-mutilation behavior, reduced sweat and tear production, absence of corneal reflexes, and multiple skin and bone infections. Oral manifestations included premature loss of teeth, associated with dental traumata and self-mutilation, severe soft tissue injuries, dental caries and submucosal abscesses, hypomineralization of primary teeth, and mandibular osteomyelitis. The lack of scientific knowledge on hereditary sensory and autonomic neuropathy due to the rarity of the disease often results in a delay in diagnosis, which is of substantial importance for the prevention of many complications and symptoms. Interdisciplinary work of specialized medical and dental teams and development of a standardized treatment protocols are essential for the management of the disease. There are many knowledge gaps concerning the management of patients with hereditary sensory and autonomic neuropathy

Motor Neuropathy in Hypothyroidism: Clinical and Electrophysiological Findings

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Sabina Yeasmin

2009-11-01

Full Text Available Background: Hypothyroidism is a clinical condition associated with low levels of thyroid hormones with raised TSH. Peripheral neuropathy may be associated with hypothyroidism which usually develops insidiously over a long period of time due to irregular taking of drugs or lack of thyroid hormone replacement. Objectives: The present study was done to evaluate the clinical and electro-physiological findings in hypothyroid patients in order to evaluate the neuromuscular dysfunction as well as motor neuropathy. Method: In this study, 70 subjects with the age range from 20 to 50 years of both sexes were included of whom 40 hypothyroids were taken in study group (B with the duration of 6 months to 5 years and 30 healthy euthyroid subjects were taken as control (Group A. On the basis of their TSH level, group B was further divided into group B1 with TSH level <60 MIU /L (less severe and group B2 with TSH >60 MIU /L (severe group. The d latency and NCV for motor nerve function were measured by NCV machine in median and ulnar nerve for upper limb and in common peroneal nerve for lower limb. TT3, TT4 were measured by RIA and TSH by IRMA method. All these parameters were measured on the day 1 (one of their first visit. Data were analysed statistically by ANOVA and Z test. Result: Both TT3, TT4 levels were significantly (P<0.01 lower in hypothyroids in comparison to those of control. Diminished or absence of most of the deep tendon reflexes were found in all the hypothyroids. Most of the patients (67.5% showed significantly higher (P <0.01 motor distal latencies (MDL with lower (P> 0.001 conduction velocities (MNCV and all these changes were more marked in group B2. Conclusion: So, the study revealed that motor neuropathy may be a consequence of hypothyroidism.DOI: 10.3329/bsmmuj.v1i1.3692 Key Words: Hypothyroidism; neuropathy; electrophysiology BSMMU J 2008; 1(1: 15-18

Cyclosporine A does not prevent second-eye involvement in Leber's hereditary optic neuropathy.

Science.gov (United States)

Leruez, Stéphanie; Verny, Christophe; Bonneau, Dominique; Procaccio, Vincent; Lenaers, Guy; Amati-Bonneau, Patrizia; Reynier, Pascal; Scherer, Clarisse; Prundean, Adriana; Orssaud, Christophe; Zanlonghi, Xavier; Rougier, Marie-Bénédicte; Tilikete, Caroline; Miléa, Dan

2018-02-17

Evaluation of the efficacy of oral cyclosporine A as a prophylactic agent in preventing second-eye involvement in Leber's hereditary optic neuropathy (LHON) in a prospective, open-label, non-randomized, multicenter pilot study. Only LHON patients aged 18 years or more, with confirmed primary mitochondrial DNA mutations and strictly unilateral optic neuropathy occurring within 6 months prior to enrolment, were included in the study. All these patients, receiving treatment with oral cyclosporine (Neoral®, Novartis) at 2.5 mg/kg/day, were examined at three-month intervals for a year. The primary endpoint was the best corrected visual acuity in the unaffected eye; the secondary endpoints were the best corrected visual acuity in the first eye affected, the mean visual field defect on automated perimetry, the thickness of the perifoveal retinal ganglion cell inner plexiform layer, and the thickness of the peripapillary retinal nerve fiber layer in both eyes. Among the 24 patients referred to our institution with genetically confirmed LHON, between July 2011 and April 2014, only five patients, four males and one female, fulfilled the inclusion criteria. Age at enrolment ranged from 19 to 42 years (mean: 27.2 years; median: 26 years), four patients harbored the m.11778G > A pathogenic variant, and one the m.14484 T > C pathogenic variant. The time-interval between the onset of symptoms and inclusion in the study ranged from 7 to 17 weeks (mean: 11.8 weeks; median: 9 weeks). Despite treatment with oral cyclosporine A, all patients eventually experienced bilateral eye involvement, occurring within 11-65 weeks after the initiation of treatment. Over the study time period, the average best corrected visual acuity worsened in the first eye affected; by the end of the study, both eyes were equally affected. Oral cyclosporine, at 2.5 mg/kg/day, did not prevent second-eye involvement in patients with strictly unilateral Leber's hereditary optic neuropathy

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.

Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies.

Science.gov (United States)

Dohrn, Maike F; Glöckle, Nicola; Mulahasanovic, Lejla; Heller, Corina; Mohr, Julia; Bauer, Christine; Riesch, Erik; Becker, Andrea; Battke, Florian; Hörtnagel, Konstanze; Hornemann, Thorsten; Suriyanarayanan, Saranya; Blankenburg, Markus; Schulz, Jörg B; Claeys, Kristl G; Gess, Burkhard; Katona, Istvan; Ferbert, Andreas; Vittore, Debora; Grimm, Alexander; Wolking, Stefan; Schöls, Ludger; Lerche, Holger; Korenke, G Christoph; Fischer, Dirk; Schrank, Bertold; Kotzaeridou, Urania; Kurlemann, Gerhard; Dräger, Bianca; Schirmacher, Anja; Young, Peter; Schlotter-Weigel, Beate; Biskup, Saskia

2017-12-01

Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11.6% an X-linked inheritance. The most frequently affected genes were PMP22 (16.4%), GJB1 (10.7%), MPZ, and SH3TC2 (both 9.9%), and MFN2 (8.3%). We further detected likely or known pathogenic variants in HINT1, HSPB1, NEFL, PRX, IGHMBP2, NDRG1, TTR, EGR2, FIG4, GDAP1, LMNA, LRSAM1, POLG, TRPV4, AARS, BIC2, DHTKD1, FGD4, HK1, INF2, KIF5A, PDK3, REEP1, SBF1, SBF2, SCN9A, and SPTLC2 with a declining frequency. Thirty-four novel variants were considered likely pathogenic not having previously been described in association with any disorder in the literature. In one patient, two homozygous mutations in HK1 were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in KIF5A was considered pathogenic because of the highly compatible phenotype. In one patient, the plasma sphingolipid profile could functionally prove the pathogenicity of a mutation in SPTLC2. One pathogenic mutation in MPZ was identified after being previously missed by Sanger sequencing. We conclude that panel based next generation sequencing is a useful, time- and cost-effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations. © 2017 International Society for Neurochemistry.

A mutation in an alternative untranslated exon of hexokinase 1 associated with Hereditary Motor and Sensory Neuropathy – Russe (HMSNR)

Science.gov (United States)

Hantke, Janina; Chandler, David; King, Rosalind; Wanders, Ronald JA; Angelicheva, Dora; Tournev, Ivailo; McNamara, Elyshia; Kwa, Marcel; Guergueltcheva, Velina; Kaneva, Radka; Baas, Frank; Kalaydjieva, Luba

2009-01-01

Hereditary Motor and Sensory Neuropathy – Russe (HMSNR) is a severe autosomal recessive disorder, identified in the Gypsy population. Our previous studies mapped the gene to 10q22-q23 and refined the gene region to ∼70 kb. Here we report the comprehensive sequencing analysis and fine mapping of this region, reducing it to ∼26 kb of fully characterised sequence spanning the upstream exons of Hexokinase 1 (HK1). We identified two sequence variants in complete linkage disequilibrium, a G>C in a novel alternative untranslated exon (AltT2) and a G>A in the adjacent intron, segregating with the disease in affected families and present in the heterozygote state in only 5/790 population controls. Sequence conservation of the AltT2 exon in 16 species with invariable preservation of the G allele at the mutated site, strongly favour the exonic change as the pathogenic mutation. Analysis of the Hk1 upstream region in mouse mRNA from testis and neural tissues showed an abundance of AltT2-containing transcripts generated by extensive, developmentally regulated alternative splicing. Expression is very low compared with ubiquitous Hk1 and all transcripts skip exon1, which encodes the protein domain responsible for binding to the outer mitochondrial membrane, and regulation of energy production and apoptosis. Hexokinase activity measurement and immunohistochemistry of the peripheral nerve showed no difference between patients and controls. The mutational mechanism and functional effects remain unknown and could involve disrupted translational regulation leading to increased anti-apoptotic activity (suggested by the profuse regenerative activity in affected nerves), or impairment of an unknown HK1 function in the peripheral nervous system (PNS). PMID:19536174

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

Directory of Open Access Journals (Sweden)

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

A familial case of segregation of motor sensory neuropathy type 1B with multiple exostoses in monozygous twins

Directory of Open Access Journals (Sweden)

V. P. Fedotov

2015-01-01

Full Text Available Hereditary motor-sensory neuropathy (MIM 118200 is a rare genetic variant of myelinopathy with autosomal-dominant type of inheritance. Multiple exostosis bones are signs of multiple exostoses chondrodysplasia, genetically heterogeneous form of systemic bone disease with an autosomal dominant mode of inheritance. The combination of two rare autosomal dominant diseases, affecting bone and peripheral nervous system in a pair of monozygotic twins and their father in one family, belongs to a unique clinical observations: since early childhood twins presented sharp reduction of the conduction velocity in all investigated motor nerves (>10 times together with multiple exostosis bone, confirmed by x-ray with a relatively benign course. Similar manifestations were detected in the patients father. DNA analysis confirmed the presence of 2 separate mutations in 2 different genes, с.389А>G/N gene MPZ and c.678С>А/N EXT2 gene that was inherited autosomal dominant manner, independently of each members of the same family.

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.

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

Science.gov (United States)

Weiss, Jeffrey N.; Levy, Steven; Benes, Susan C.

2016-01-01

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. PMID:27904503

Clinical, electrophysiological, genetic, and imaging features of six Chinese Han patients with hereditary neuropathy with liability to pressure palsies (HNPP).

Science.gov (United States)

Chen, Bin; Niu, Songtao; Wang, Xingao; Li, Wei; Chen, Na; Zhang, Zaiqiang

2018-02-01

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant peripheral neuropathy caused by mutations in the peripheral myelin protein 22 (PMP22) gene. This study summarizes the clinical, electrophysiological, genetic, and imaging features of six unrelated Chinese Han patients with HNPP. Age of onset was within the second decade in five patients, and 46 years of age in one patient. Weakness or numbness in a unilateral lower extremity was the most common symptom in 5 patients, and bilateral sensorineural hearing loss was also detected in one patient. Electrophysiological presentations suggested demyelinating sensory-motor polyneuropathy in the group. Magnetic resonance imaging (MRI) of the cervical and lumbar spine revealed varying degrees of degeneration in five patients, and mild kyphosis of cervical vertebral bodies in 2 teen-aged patients. In addition, cranial MRI of one patient showed scattered demyelination in the frontal lobes. Targeted next-generation-sequencing (NGS) revealed a PMP22 deletion in five patients and a heterozygous c.199G>A mutation in exon 4 of PMP22 in one patient. The I92V variant of lipopolysaccharide-induced tumor necrosis factor (LITAF) gene was found in one patient. There was no relationship between the Ile92Val variant of LITAF and age of onset in this group, albeit the sample size was very small. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genetic Testing for Wolfram Syndrome Mutations in a Sample of 71 Patients with Hereditary Optic Neuropathy and Negative Genetic Test Results for OPA1/OPA3/LHON.

Science.gov (United States)

Galvez-Ruiz, Alberto; Galindo-Ferreiro, Alicia; Schatz, Patrik

2018-04-01

In this study, the authors present a sample of 71 patients with hereditary optic neuropathy and negative genetic test results for OPA1/OPA3/LHON. All of these patients later underwent genetic testing to rule out WFS. As a result, 53 patients (74.7%) were negative and 18 patients (25.3%) were positive for some type of mutation or variation in the WFS gene. The authors believe that this study is interesting because it shows that a sizeable percentage (25.3%) of patients with hereditary optic 25 neuropathy and negative genetic test results for OPA1/OPA3/LHON had WFS mutations or variants.

[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.

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......: 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......, the supplementary motor areas and the right premotor cortex compared to controls. CONCLUSIONS: Motor cortical reorganisation may explain this result, but as no significant differences were recognised in the motor response of the unaffected limb, differences in functional demands should also be considered...

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

International Nuclear Information System (INIS)

Schwarz, Daniel; Pham, Mirko; Bendszus, Martin; Baeumer, Philipp; Weiler, Markus; Heiland, Sabine

2015-01-01

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.)

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.)

Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group

NARCIS (Netherlands)

Raeymaekers, P.; Timmerman, V.; Nelis, E.; de Jonghe, P.; Hoogendijk, J. E.; Baas, F.; Barker, D. F.; Martin, J. J.; de Visser, M.; Bolhuis, P. A.

1991-01-01

Hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT 1) is an autosomal dominant disorder of the peripheral nervous system characterized by progressive weakness and atrophy of distal limb muscles. In the majority of HMSN I families, linkage studies

Goldberg-Shprintzen megacolon syndrome with associated sensory motor axonal neuropathy.

Science.gov (United States)

Dafsari, Hormos Salimi; Byrne, Susan; Lin, Jean-Pierre; Pitt, Matthew; Jongbloed, Jan Dh; Flinter, Frances; Jungbluth, Heinz

2015-06-01

Goldberg-Shprintzen megacolon syndrome (GOSHS) (OMIM 609460) is characterized by a combination of learning difficulties, characteristic dysmorphic features and Hirschsprung's disease. Variable clinical features include iris coloboma, congenital heart defects and central nervous system abnormalities, in particular polymicrogyria. GOSHS has been attributed to recessive mutations in KIAA1279, encoding kinesin family member (KIF)-binding protein (KBP) with a crucial role in neuronal microtubule dynamics. Here we report on a 7-year-old girl with GOSHS as a result of a homozygous deletion of exons 5 and 6 of the KIAA1279 gene. She had been referred with the suspicion of an underlying neuromuscular disorder before the genetic diagnosis was established, prompted by the findings of motor developmental delay, hypotonia, ptosis and absent reflexes. Neurophysiological studies revealed unequivocal evidence of a peripheral axonal sensory motor neuropathy. We hypothesize that an axonal sensory motor neuropathy may be part of the phenotypical spectrum of KIAA1279-related GOSHS, probably reflecting the effects of reduced KBP protein expression on peripheral neuronal function. © 2015 Wiley Periodicals, Inc.

Hereditary neuropathy with liability to pressure palsy (HNPP): report of a family with a new point mutation in PMP22 gene.

Science.gov (United States)

Fusco, Carlo; Spagnoli, Carlotta; Salerno, Grazia Gabriella; Pavlidis, Elena; Frattini, Daniele; Pisani, Francesco

2017-10-27

Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disorder most commonly presenting with acute-onset, non-painful focal sensory and motor mononeuropathy. Approximately 80% of patients carry a 1.5 Mb deletion of chromosome 17p11.2 involving the peripheral myelin protein 22 gene (PMP22), the same duplicated in Charcot-Marie-Tooth 1A patients. In a small proportion of patients the disease is caused by PMP22 point mutations. We report on a familial case harbouring a new point mutation in the PMP22 gene. The proband is a 4-years-old girl with acute onset of focal numbness and weakness in her right hand. Electroneurography demonstrated transient sensory and motor radial nerves involvement. In her father, reporting chronic symptoms (cramps and exercise-induced myalgia), we uncovered mild atrophy and areflexia on clinical examination and a mixed (predominantly demyelinating) polyneuropathy with sensory-motor involvement on electrophysiological study. Both carried a nucleotidic substitution c.178 + 2 T > C on intron 3 of the PMP22 gene, involving the splicing donor site, not reported on databases but predicted to be likely pathogenic. We described a previously unreported point mutation in PMP22 gene, which led to the development of a HNPP phenotype in a child and her father. In children evaluated for a sensory and motor transient episode, HNPP disorder due to PMP22 mutations should be suspected. Clinical and electrophysiological studies should be extended to all family members even in the absence of previous episodes suggestive for HNPP.

Neuropatía óptica hereditaria de Leber Leber´s hereditary optic neuropathy

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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

Different nerve ultrasound patterns in charcot-marie-tooth types and hereditary neuropathy with liability to pressure palsies.

Science.gov (United States)

Padua, Luca; Coraci, Daniele; Lucchetta, Marta; Paolasso, Ilaria; Pazzaglia, Costanza; Granata, Giuseppe; Cacciavillani, Mario; Luigetti, Marco; Manganelli, Fiore; Pisciotta, Chiara; Piscosquito, Giuseppe; Pareyson, Davide; Briani, Chiara

2018-01-01

Nerve ultrasound in Charcot-Marie-Tooth (CMT) disease has focused mostly on the upper limbs. We performed an evaluation of a large cohort of CMT patients in which we sonographically characterized nerve abnormalities in different disease types, ages, and nerves. Seventy patients affected by different CMT types and hereditary neuropathy with liability to pressure palsies (HNPP) were evaluated, assessing median, ulnar, fibular, tibial, and sural nerves bilaterally. Data were correlated with age. Nerve dimensions were correlated with CMT type, age, and nerve site. Nerves were larger in demyelinating than in axonal neuropathies. Nerve involvement was symmetric. CMT1 patients had larger nerves than did patients with other CMT types. Patients with HNPP showed enlargement at entrapment sites. Our study confirms the general symmetry of ultrasound nerve patterns in CMT. When compared with ultrasound studies of nerves of the upper limbs, evaluation of the lower limbs did not provide additional information. Muscle Nerve 57: E18-E23, 2018. © 2017 Wiley Periodicals, Inc.

Transcranial magnetic stimulation in lower motor neuron diseases.

Science.gov (United States)

Attarian, S; Azulay, J-Ph; Lardillier, D; Verschueren, A; Pouget, J

2005-01-01

To study the diagnostic value of transcranial magnetic stimulation (TMS) in a group of patients with lower motor neuron disease (LMND). Among LMND, several chronic immune mediate motor neuropathies may simulate amyotrophic lateral sclerosis (ALS). Forty patients with LMND were included TMS was performed at the first visit. The patients were seen prospectively every 3 months for a period of 1-4 years. Three different groups were distinguished at the end of follow-up: (1) ALS group with 7 patients, (2) Pure motor neuropathy with 14 patients and (3) Other LMND including 12 patients with hereditary spinal amyotrophy, 3 patients with Kennedy's disease and 4 patients with post-poliomyelitis. On the basis of the results of TMS variables, 6 out of 7 ALS patients had abnormality of silent period (SP) associated or not with abnormality of excitatory threshold or amplitude ratio. Patients with pure motor neuropathy had normal SP and amplitude ratio. Four out of 14 patients had increased central motor conduction time (CMCT), one had increased CMCT and excitatory threshold, and one patient had a slightly increased excitatory threshold. Considering the abnormality of TMS variables in the groups, SP, excitatory threshold, and amplitude ratio were chosen in a post-hoc attempt to select variables yielding high sensitivity and specificity. The overall sensitivity of TMS for diagnosis of ALS among LMND was 85.7%, its specificity was 93.9%. When only the abnormality of SP was taken into account, the sensitivity was unchanged. But the specificity was improved to 100%. TMS helped to distinguish suspected ALS from pure motor neuropathy.

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

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.

Hereditary spastic paraplegias: membrane traffic and the motor pathway

OpenAIRE

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 wo...

Treatment strategies for chemotherapy-induced peripheral neuropathy: potential role of exercise

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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.

Novel mutation in the replication focus targeting sequence domain of DNMT1 causes hereditary sensory and autonomic neuropathy IE.

Science.gov (United States)

Yuan, Junhui; Higuchi, Yujiro; Nagado, Tatsui; Nozuma, Satoshi; Nakamura, Tomonori; Matsuura, Eiji; Hashiguchi, Akihiro; Sakiyama, Yusuke; Yoshimura, Akiko; Takashima, Hiroshi

2013-03-01

DNMT1, encoding DNA methyltransferase 1 (Dnmt1), is a critical enzyme which is mainly responsible for conversion of unmethylated DNA into hemimethylated DNA. To date, two phenotypes produced by DNMT1 mutations have been reported, including hereditary sensory and autonomic neuropathy (HSAN) type IE with mutations in exon 20, and autosomal dominant cerebellar ataxia, deafness, and narcolepsy caused by mutations in exon 21. We report a sporadic case in a Japanese patient with loss of pain and vibration sense, chronic osteomyelitis, autonomic system dysfunctions, hearing loss, and mild dementia, but without definite cerebellar ataxia. Electrophysiological studies revealed absent sensory nerve action potential with nearly normal motor nerve conduction studies. Brain magnetic resonance imaging revealed mild diffuse cerebral and cerebellar atrophy. Using a next-generation sequencing system, 16 candidate genes were analyzed and a novel missense mutation, c.1706A>G (p.His569Arg), was identified in exon 21 of DNMT1. Our findings suggest that mutation in exon 21 of DNMT1 may also produce a HSAN phenotype. Because all reported mutations of DNMT1 are concentrated in exons 20 and 21, which encode the replication focus targeting sequence (RFTS) domain of Dnmt1, the RFTS domain could be a mutation hot spot. © 2013 Peripheral Nerve Society.

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

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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.  

Novel NTRK1 mutations cause hereditary sensory and autonomic neuropathy type IV: demonstration of a founder mutation in the Turkish population.

Science.gov (United States)

Tüysüz, Beyhan; Bayrakli, Fatih; DiLuna, Michael L; Bilguvar, Kaya; Bayri, Yasar; Yalcinkaya, Cengiz; Bursali, Aysegul; Ozdamar, Elif; Korkmaz, Baris; Mason, Christopher E; Ozturk, Ali K; Lifton, Richard P; State, Matthew W; Gunel, Murat

2008-05-01

Hereditary sensory and autonomic neuropathy type IV (HSAN IV), or congenital insensitivity to pain with anhidrosis, is an autosomal recessive disorder characterized by insensitivity to noxious stimuli, anhidrosis from deinnervated sweat glands, and delayed mental and motor development. Mutations in the neurotrophic tyrosine kinase receptor type 1 (NTRK1), a receptor in the neurotrophin signaling pathway phosphorylated in response to nerve growth factor, are associated with this disorder. We identified six families from Northern Central Turkey with HSAN IV. We screened the NTRK1 gene for mutations in these families. Microsatellite and single nucleotide polymorphism (SNP) markers on the Affymetrix 250K chip platform were used to determine the haplotypes for three families harboring the same mutation. Screening for mutations in the NTRK1 gene demonstrated one novel frameshift mutation, two novel nonsense mutations, and three unrelated kindreds with the same splice-site mutation. Genotyping of the three families with the identical splice-site mutation revealed that they share the same haplotype. This report broadens the spectrum of mutations in NTRK1 that cause HSAN IV and demonstrates a founder mutation in the Turkish population.

Hereditary sensory and autosomal peripheral neuropathy-type IV: case series and review of literature.

Science.gov (United States)

Ashwin, D P; Chandan, G D; Jasleen, Handa Kaur; Rajkumar, G C; Rudresh, K B; Prashanth, R

2015-06-01

Hereditary sensory and autonomic neuropathy (HSAN) IV is a rare autosomal recessive disorder which is characterized by a decrease in the number of myelinated and non-myelinated nerve fibers of peripheral nerves which causes diminished or absent pain sensation leading to increase in self-mutilative habits. A retrospective study of eight cases ranging from age group of 4 to 17 years for oral and digital signs and symptoms is presented. All the patients showed congenital insensitivity to pain and anhidrosis. Oral self-mutilations, such as autoextraction of teeth and severe bite injuries (with resultant scarring) of the finger tips and oral soft tissues (tongue, lip, and buccal mucosa) were found in most patients. Our study suggests that early diagnosis and specific treatment plan are important for prevention of characteristic of the oral as well as digital trauma associated with this disorder.

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.

Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation.

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Bansagi, Boglarka; Phan, Vietxuan; Baker, Mark R; O'Sullivan, Julia; Jennings, Matthew J; Whittaker, Roger G; Müller, Juliane S; Duff, Jennifer; Griffin, Helen; Miller, James A L; Gorman, Grainne S; Lochmüller, Hanns; Chinnery, Patrick F; Roos, Andreas; Swan, Laura E; Horvath, Rita

2018-05-22

To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog ( PTEN ), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases. We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patient's fibroblasts. The predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) PTEN variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN-deficient mice. We describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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.

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

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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.

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.

Clinical variability in hereditary optic neuropathies: Two novel mutations in two patients with dominant optic atrophy and Wolfram syndrome.

Science.gov (United States)

Galvez-Ruiz, Alberto

2015-01-01

Dominant optic atrophy (DOA) and Wolfram syndrome share a great deal of clinical variability, including an association with hearing loss and the presence of optic atrophy at similar ages. The objective of this paper was to discuss the phenotypic variability of these syndromes with respect to the presentation of two clinical cases. We present two patients, each with either DOA or Wolfram syndrome, and contribute to the research literature through our findings of two novel mutations. The overlapping of several clinical characteristics in hereditary optic neuropathies can complicate the differential diagnosis. Future studies are needed to better determine the genotype-phenotype correlation for these diseases.

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...... ganglion cells containing the photopigment melanopsin. These cells give origin to the retinohypothalamic tract and support the non-image-forming visual functions of the eye, which include the photoentrainment of circadian rhythms, light-induced suppression of melatonin secretion and pupillary light reflex...... 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...

Genetics Home Reference: congenital cataracts, facial dysmorphism, and neuropathy

Science.gov (United States)

... Eye Institute: Facts About Cataracts National Institute of Neurological Disorders and Stroke: Hereditary Neuropathies Educational Resources (5 links) Boston Children's Hospital: Cataracts in Children Centers for Disease Control ...

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

International Nuclear Information System (INIS)

Liang, Min; Guan, Minqiang; Zhao, Fuxing; Zhou, Xiangtian; Yuan, Meixia; Tong, Yi; Yang, Li; Wei, Qi-Ping; Sun, Yan-Hong; Lu, Fan; Qu, Jia

2009-01-01

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.

Antiretroviral therapy-induced Leber's hereditary optic neuropathy

African Journals Online (AJOL)

2014-06-01

Jun 1, 2014 ... Optic neuropathy in HIV-infected patients results from the HIV ... individuals was triggered by NRTI drugs lamivudine and tenofovir when ... in disseminated tuberculosis where its prolonged use over ... Fungal: cryptococcal meningitis .... Genetic testing of LHON by polymerase chain reaction and restriction.

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.

Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland.

Science.gov (United States)

Bansagi, Boglarka; Antoniadi, Thalia; Burton-Jones, Sarah; Murphy, Sinead M; McHugh, John; Alexander, Michael; Wells, Richard; Davies, Joanna; Hilton-Jones, David; Lochmüller, Hanns; Chinnery, Patrick; Horvath, Rita

2015-08-01

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.

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

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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.

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

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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.

Hereditary sensory and autonomic neuropathies: types II, III, and IV

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Axelrod Felicia B

2007-10-01

Full Text Available Abstract The hereditary sensory and autonomic neuropathies (HSAN encompass a number of inherited disorders that are associated with sensory dysfunction (depressed reflexes, altered pain and temperature perception and varying degrees of autonomic dysfunction (gastroesophageal reflux, postural hypotention, excessive sweating. Subsequent to the numerical classification of four distinct forms of HSAN that was proposed by Dyck and Ohta, additional entities continue to be described, so that identification and classification are ongoing. As a group, the HSAN are rare diseases that affect both sexes. HSAN III is almost exclusive to individuals of Eastern European Jewish extraction, with incidence of 1 per 3600 live births. Several hundred cases with HSAN IV have been reported. The worldwide prevalence of HSAN type II is very low. This review focuses on the description of three of the disorders, HSAN II through IV, that are characterized by autosomal recessive inheritance and onset at birth. These three forms of HSAN have been the most intensively studied, especially familial dysautonomia (Riley-Day syndrome or HSAN III, which is often used as a prototype for comparison to the other HSAN. Each HSAN disorder is likely caused by different genetic errors that affect specific aspects of small fiber neurodevelopment, which result in variable phenotypic expression. As genetic tests are routinely used for diagnostic confirmation of HSAN III only, other means of differentiating between the disorders is necessary. Diagnosis is based on the clinical features, the degree of both sensory and autonomic dysfunction, and biochemical evaluations, with pathologic examinations serving to further confirm differences. Treatments for all these disorders are supportive.

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

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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.

African Journal of Neurological Sciences - 2009 Vol. 28 No 1

African Journals Online (AJOL)

Key words: hereditary neuropathy, Charcot-Marie-Tooth disease, genetic, ..... Molecular genetics of autosomal-dominant demyelinating Charcot- ..... Dominantly inherited motor and sensory neuropathy with excessive myelin folding complex.

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

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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...

[Hereditary sensory and autonomic neuropathy type IV: a report on two cases].

Science.gov (United States)

Achouri, E; Gribaa, M; Bouguila, J; Haddad, S; Souayeh, N; Saad, A; Essoussi, A S

2011-04-01

Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is a very rare autosomal recessive disorder characterized by recurrent episodes of unexplained fever, extensive anhidrosis, total insensitivity to pain, hypotonia, and mental retardation. The absence of urticarial reaction to intradermal injection of histamine is a sign of great diagnostic value, but this is common to all types of HSAN. The most frequent complications of this disease are corneal scarring, multiple fractures, joint deformities, osteomyelitis, and disabling self-mutilations. Malignant hyperthermia and sepsis are major causes of mortality. We relate the first observations of two Tunisian children with genetically confirmed HSAN IV. Our goal is to review the clinical aspects of this mysterious neuropathy and to emphasize the peculiarities of its management. These two patients are brothers from 1st-degree consanguineous parents (cousins) with no particular medical history. The 1st patient, the family's 1st child, presented in the 1st h of life with hypotonia and persistent fever, which was refractory to antipyretics. At the age of 8 months, the patient presented recurrent febrile seizures and developed significant self-mutilations of the fingers and tongue. He died 3 months later in a context of multivisceral failure from sepsis and malignant hyperthermia. The 2nd patient, currently aged 4 years, was born after a normal sister. He consulted in the neonatal period for a high fever. The diagnosis of HSAN IV was rapidly suspected and genetically confirmed. In fact, this patient is homozygous for the NTRK1 gene, whereas his sister and both parents are heterozygous. Special predispositions have been taken to improve the course of the disease such as air conditioning to control hyperthermia, a dental tray to reduce the injuries resulting from self-mutilation, regular moistening of the eyes to avoid corneal drying, and chlorpromazine to control hyperactivity and reduce injuries. The good progression

Vasculitic Neuropathies.

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Naddaf, Elie; Dyck, P James Bonham

2015-10-01

From pathological standpoint, we divide vasculitic neuropathies in two categories: nerve large arteriole vasculitides and nerve microvasculitis. It is also important to determine whether a large arteriole vasculitis has an infectious etiology as it entails different treatment approach. Treatment of non-infectious large arteriole vasculitides consists initially of induction therapy with corticosteroids. Adding an immunosuppressant, mainly cyclophosphamide, is often needed. Treatment of infectious large arteriole vasculitides needs a multidisciplinary approach to target both the underlying infection and the vasculitis. Corticosteroids are the first-line therapy for classic non-systemic vasculitic neuropathy. Stable or improving patients without biopsy evidence of active vasculitis can be either observed or treated. Currently, adding an immunosuppressant is only indicated for patients who continue to progress on corticosteroids alone or patients with a rapidly progressive course. The treatment of the radiculoplexus neuropathies such as diabetic lumbosacral radiculoplexus neuropathy, lumbosacral radiculoplexus neuropathy (in non-diabetic patients), and diabetic cervical radiculoplexus neuropathy, as well as painless diabetic motor neuropathy, is not well established yet. We treat patients, if they present early on in the disease course or if they have severe disabling symptoms, with IV methylprednisolone 1 g once a week for 12 weeks.

Autosomal dominant spastic paraplegia with peripheral neuropathy maps to chr12q23-24.

Science.gov (United States)

Schüle, R; Bonin, M; Dürr, A; Forlani, S; Sperfeld, A D; Klimpe, S; Mueller, J C; Seibel, A; van de Warrenburg, B P; Bauer, P; Schöls, L

2009-06-02

Hereditary spastic paraplegias (HSP) are genetically exceedingly heterogeneous. To date, 37 genetic loci for HSP have been described (SPG1-41), among them 16 loci for autosomal dominant disease. Notwithstanding, further genetic heterogeneity is to be expected in HSP, as various HSP families do not link to any of the known HSP loci. In this study, we aimed to map the disease locus in a German family segregating autosomal dominant complicated HSP. A genome-wide linkage analysis was performed using the GeneChip Mapping 10Kv2.0 Xba Array containing 10,204 SNP markers. Suggestive loci were further analyzed by mapping of microsatellite markers. One locus on chromosome 12q23-24, termed SPG36, was confirmed by high density microsatellite fine mapping with a significant LOD score of 3.2. SPG36 is flanked by markers D12S318 and D12S79. Linkage to SPG36 was excluded in >20 additional autosomal dominant HSP families. Candidate genes were selected and sequenced. No disease-causing mutations were identified in the coding regions of ATXN2, HSPB8, IFT81, Myo1H, UBE3B, and VPS29. SPG36 is complicated by a sensory and motor neuropathy; it is therefore the eighth autosomal dominant subtype of complicated HSP. We report mapping of a new locus for autosomal dominant hereditary spastic paraplegia (HSP) (SPG36) on chromosome 12q23-24 in a German family with autosomal dominant HSP complicated by peripheral neuropathy.

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

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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.

Four novel cases of periaxin-related neuropathy and review of the literature.

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Marchesi, C; Milani, M; Morbin, M; Cesani, M; Lauria, G; Scaioli, V; Piccolo, G; Fabrizi, G M; Cavallaro, T; Taroni, F; Pareyson, D

2010-11-16

To report 4 cases of autosomal recessive hereditary neuropathy associated with novel mutations in the periaxin gene (PRX) with a review of the literature. Periaxin protein is required for the maintenance of peripheral nerve myelin. Patients with PRX mutations have early-onset autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4F) or Déjèrine-Sottas neuropathy (DSN). Only 12 different mutations have been described thus far. Case reports and literature review. Four patients from 3 unrelated families (2 siblings and 2 unrelated patients) were affected by an early-onset, slowly progressive demyelinating neuropathy with relevant sensory involvement. All carried novel frameshift or nonsense mutations in the PRX gene. The 2 siblings were compound heterozygotes for 2 PRX null mutations (p.Q547X and p.K808SfsX2), the third patient harbored a homozygous nonsense mutation (p.E682X), and the last patient had a homozygous 2-nt insertion predicting a premature protein truncation (p.S259PfsX55). Electrophysiologic analysis showed a severe slowing of motor nerve conduction velocities (MNCVs, between 3 and 15.3 m/s) with undetectable sensory nerve action potentials (SNAPs). Sural nerve biopsy, performed in 2 patients, demonstrated a severe demyelinating neuropathy and onion bulb formations. Interestingly, we observed some variability of disease severity within the same family. These cases and review of the literature indicate that PRX-related neuropathies have early onset but overall slow progression. Typical features are prominent sensory involvement, often with sensory ataxia; a moderate-to-dramatic reduction of MNCVs and almost invariable absence of SNAPs; and pathologic demyelination with classic onion bulbs, and less commonly myelin folding and basal lamina onion bulbs.

[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.

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

International Nuclear Information System (INIS)

Zhao, Fuxin; Guan, Minqiang; Zhou, Xiangtian; Yuan, Meixia; Liang, Ming; Liu, Qi; Liu, Yan; Zhang, Yongmei; Yang, Li; Tong, Yi; Wei, Qi-Ping; Sun, Yan-Hong; Qu, Jia

2009-01-01

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.

Paraneoplastic neuropathies.

Science.gov (United States)

Antoine, Jean-Christophe; Camdessanché, Jean-Philippe

2017-10-01

To review recent advances in paraneoplastic neuropathies with emphasis on their definition, different forms and therapeutic development. A strict definition of definite paraneoplastic neuropathies is necessary to avoid confusion. With carcinoma, seronegative sensory neuronopathies and neuronopathies and anti-Hu and anti-CV2/Contactin Response Mediator Protein 5 antibodies are the most frequent. With lymphomas, most neuropathies occur with monoclonal gammopathy including AL amyloidosis, Polyneuropathy-Organomegaly-Endocrinopathy-M component-Skin changes (POEMS) syndrome, type I cryoglobulinemia and antimyelin-associated glycoprotein (MAG) neuropathies and Waldenström's disease. Neuropathies improving with tumor treatment are occasional, occur with a variety of cancer and include motor neuron disease, chronic inflammatory demyelinating neuropathy and nerve vasculitis. If antibodies toward intracellular antigens are well characterized, it is not the case for antibodies toward cell membrane proteins. Contactin-associated protein-2 antibodies occur with neuromyotonia and thymoma with the Morvan's syndrome in addition to Netrin 1 receptor antibodies but may not be responsible for peripheral nerve hyperexcitability. The treatment of AL amyloidosis, POEMS syndrome, anti-MAG neuropathy and cryoglobulinemia is now relatively well established. It is not the case with onconeural antibodies for which the rarity of the disorders and a short therapeutic window are limiting factors for the development of clinical trials. A strict definition of paraneoplastic neuropathies helps their identification and is necessary to allow an early diagnosis of the underlying tumor.

Bilateral optic neuropathy in a patient with familial amyloidotic polyneuropathy

DEFF Research Database (Denmark)

Hamann, Steffen; Jensen, Peter Koch; Fledelius, Hans Callø

2013-01-01

Amyloidogenic transthyretin (ATTR)-related familial amyloidotic polyneuropathy (FAP) is an autosomal-dominant hereditary disease characterised by slowly progressive peripheral sensorimotor and autonomic neuropathy and tissue involvement of the heart, kidneys and central nervous system. Secondary...... ATTR Val30Met mutation. After 11 years of ophthalmic follow-up best-corrected visual acuity was 20/100 in his seeing eye, which further had visual field findings suggestive of optic neuropathy. This was also the diagnosis underlying the preceding insidious full loss of vision in the fellow eye......, with colour Doppler imaging to support an ischaemic aetiology. To our knowledge, this is the first report of ischaemic optic neuropathy in this familial amyloid disorder....

Neuropathy in a petrol sniffer.

Science.gov (United States)

Hall, D M; Ramsey, J; Schwartz, M S; Dookun, D

1986-09-01

A 4 year old boy developed a profound motor neuropathy after repeated deliberate inhalation of petroleum vapour. The condition was characterised by extreme slowing of the nerve conduction velocity. He made a gradual recovery over six months. The neuropathy was attributed to the N-hexane component of petroleum.

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....

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.

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...

Treatment strategies for inherited optic neuropathies: past, present and future

OpenAIRE

Yu-Wai-Man, P; Votruba, M; Moore, A T; Chinnery, P F

2014-01-01

Bilateral visual loss secondary to inherited optic neuropathies is an important cause of registrable blindness among children and young adults. The two prototypal disorders seen in clinical practice are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 90% of LHON cases are due to one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A, and m.14484T>C, which affect critical complex I subunits of the mitochondrial respiratory chain...

Non-motor Symptoms In Patients With Hereditary Spastic Paraplegia Caused By Spg4 Mutations.

OpenAIRE

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

2016-01-01

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 sc...

Peripheral neuropathy in patients with myotonic dystrophy type 2.

Science.gov (United States)

Leonardis, L

2017-05-01

Myotonic dystrophy type 2 (dystrophia myotonica type 2-DM2) is an autosomal dominant multi-organ disorder. The involvement of the peripheral nervous system was found in 25%-45% of patients with myotonic dystrophy type 1, although limited data are available concerning polyneuropathy in patients with DM2, which was the aim of this study with a thorough presentation of the cases with peripheral neuropathy. Patients with genetically confirmed DM2 underwent motor nerve conduction studies of the median, ulnar, tibial and fibular nerves and sensory nerve conduction studies of the median (second finger), ulnar (fifth finger), radial (forearm) and sural nerves. Seventeen adult patients with DM2 participated in the study. Fifty-three percent (9/17) of our patients had abnormality of one or more attributes (latency, amplitude or conduction velocity) in two or more separate nerves. Four types of neuropathies were found: (i) predominantly axonal motor and sensory polyneuropathy, (ii) motor polyneuropathy, (iii) predominantly demyelinating motor and sensory polyneuropathy and (iv) mutilating polyneuropathy with ulcers. The most common forms are axonal motor and sensory polyneuropathy (29%) and motor neuropathy (18% of all examined patients). No correlations were found between the presence of neuropathy and age, CCTG repeats, blood glucose or HbA1C. Peripheral neuropathy is common in patients with DM2 and presents one of the multisystemic manifestations of DM2. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Early-onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation.

Science.gov (United States)

Suh, Bum Chun; Hong, Young Bin; Nakhro, Khriezhanuo; Nam, Soo Hyun; Chung, Ki Wha; Choi, Byung-Ok

2014-02-01

Hereditary sensory and autonomic neuropathy type I (HSAN I) is an autosomal dominant disease characterized by prominent sensory impairment, resulting in foot ulcers or amputations and has a juvenile to adult onset. The major underlying causes of HSAN I are mutations in SPTLC1, which encodes the first subunit of serine palmitoyltransferase (SPT). To date, there have been no reports with regard to an HSAN patient of Korean origin. In this report we discussed an HSAN I patient with a missense mutation in SPTLC1 (c.992C>T: p.S331F). The patient had noticed frequent falls, lower leg weakness and hand tremors at age five. The patient also presented with foot ulcers, muscle hypotrophy, cataracts, hoarseness, vocal cord palsy and respiratory difficulties and succumbed to the condition at the age of 28 years. In accordance with previous reports, a mutation in Ser331 in the present patient was associated with early-onset and a severe phenotype. Therefore, Ser331 in SPTLC1 is a crucial amino acid, which characterizes the HSAN I phenotype.

From genes to pain: nerve growth factor and hereditary sensory and autonomic neuropathy type V.

Science.gov (United States)

Capsoni, Simona

2014-02-01

Hereditary sensory and autonomic neuropathy type V (HSAN V) is an autosomal recessive disorder characterized by the loss of deep pain perception. The anomalous pain and temperature sensations are due to the absence of nociceptive sensory innervation. The neurotrophin nerve growth factor (NGF), by binding to tropomyosin receptor A (TrkA) and p75NTR receptors, is essential for the development and survival of sensory neurons, and for pain perception during adulthood. Recently a homozygous missense mutation (R100W) in the NGF gene has been identified in HSAN V patients. Interestingly, alterations in NGF signalling, due to mutations in the NGF TRKA gene, have also been involved in another congenital insensitivity to pain, HSAN IV, characterized not only by absence of reaction to painful stimuli, but also anhidrosis and mental retardation. These symptoms are absent in HSAN V patients. Unravelling the mechanisms that underlie the differences between HSAN IV and V could assist in better understanding NGF biology. This review highlights the recent key findings in the understanding of HSAN V, including insights into the molecular mechanisms of the disease, derived from genetic studies of patients with this disorder. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Quality assessment of online patient education resources for peripheral neuropathy.

Science.gov (United States)

Hansberry, David R; Suresh, Ragha; Agarwal, Nitin; Heary, Robert F; Goldstein, Ira M

2013-03-01

Given its practicality, the internet is a primary resource for patients afflicted with diseases like peripheral neuropathy. Therefore, it is important that the readily available online resources on peripheral neuropathy are tailored to the general public, particularly concerning readability. Patient education resources were downloaded from the US National Library of Medicine, Mayo Clinic, National Institute of Neurological Disorders and Stroke, Neuropathy.org, GBS/CIDP Foundation International, Hereditary Neuropathy Foundation, Charcot-Marie-Tooth Association, Foundation for Peripheral Neuropathy, and Neuropathy Action Foundation websites. All patient education material related to peripheral neuropathy was evaluated for its level of readability using the Flesch Reading Ease (FRE) and Flesch-Kincaid Grade Level. The FRE scores averaged 43.4 with only the US National Library of Medicine scoring above 60 (76.5). The Flesch-Kincaid Grade Level scores averaged 11.0. All scores were above a seventh-grade level except the US National Library of Medicine, which had a score of a fifth-grade reading level. Most Americans may not fully benefit from patient education resources concerning peripheral neuropathy education on many of the websites. Only the US National Library of Medicine, which is written at a fifth-grade level, is likely to benefit the average American. © 2013 Peripheral Nerve Society.

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....

Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation.

Science.gov (United States)

Yuan, Junhui; Matsuura, Eiji; Higuchi, Yujiro; Hashiguchi, Akihiro; Nakamura, Tomonori; Nozuma, Satoshi; Sakiyama, Yusuke; Yoshimura, Akiko; Izumo, Shuji; Takashima, Hiroshi

2013-04-30

To identify the clinical features of Japanese patients with suspected hereditary sensory and autonomic neuropathy (HSAN) on the basis of genetic diagnoses. On the basis of clinical, in vivo electrophysiologic, and pathologic findings, 9 Japanese patients with sensory and autonomic nervous dysfunctions were selected. Eleven known HSAN disease-causing genes and 5 related genes were screened using a next-generation sequencer. A homozygous mutation, c.3993delGinsTT, was identified in exon 22 of SCN9A from 2 patients/families. The clinical phenotype was characterized by adolescent or congenital onset with loss of pain and temperature sensation, autonomic nervous dysfunctions, hearing loss, and hyposmia. Subsequently, this mutation was discovered in one of patient 1's sisters, who also exhibited sensory and autonomic nervous system dysfunctions, with recurrent fractures being the most predominant feature. Nerve conduction studies revealed definite asymmetric sensory nerve involvement in patient 1. In addition, sural nerve pathologic findings showed loss of large myelinated fibers in patient 1, whereas the younger patient showed normal sural nerve pathology. We identified a novel homozygous mutation in SCN9A from 2 Japanese families with autosomal recessive HSAN. This loss-of-function SCN9A mutation results in disturbances in the sensory, olfactory, and autonomic nervous systems. We propose that SCN9A mutation results in the new entity of HSAN type IID, with additional symptoms including hyposmia, hearing loss, bone dysplasia, and hypogeusia.

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

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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.

The Importance of Rare Subtypes in Diagnosis and Treatment of Peripheral Neuropathy: A Review.

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Callaghan, Brian C; Price, Raymond S; Chen, Kevin S; Feldman, Eva L

2015-12-01

Peripheral neuropathy is a prevalent condition that usually warrants a thorough history and examination but has limited diagnostic evaluation. However, rare localizations of peripheral neuropathy often require more extensive diagnostic testing and different treatments. To describe rare localizations of peripheral neuropathy, including the appropriate diagnostic evaluation and available treatments. References were identified from PubMed searches conducted on May 29, 2015, with an emphasis on systematic reviews and randomized clinical trials. Articles were also identified through the use of the authors' own files. Search terms included common rare neuropathy localizations and their causes, as well as epidemiology, pathophysiology, diagnosis, and treatment. Diffuse, nonlength-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, nonlength-dependent neuropathies are Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and amyotrophic lateral sclerosis. Effective disease-modifying therapies exist for many diffuse, nonlength-dependent neuropathies including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, 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 amyotrophy (radiculoplexus neuropathy) is lacking. Recognition of rare localizations of peripheral neuropathy is essential given the implications for diagnostic testing and treatment. Electrodiagnostic studies are an important

Immune-mediated neuropathies our experience over 3 years

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Sadanandavalli Retnaswami Chandra

2018-01-01

Full Text Available Introduction: Immune-mediated peripheral neuropathy is the term applied to a spectrum of peripheral nerve disorders where immune dysregulation plays a role. Therefore, they are treatable. We analyzed the cases seen in the past 3 years by us and evaluated the clinical, laboratory, and outcome parameters in these patients. Patients and Methods: Consecutive patients seen by the authors and diagnosed as immune-mediated neuropathy were analyzed for etiology, pathology, and outcome assessed. Results: A total of sixty patients, 31 acute and 29 chronic neuropathies, were identified. Their subtypes treatment and outcome assessed. Males were significantly more in both acute and chronic cases. Miller Fisher 4, AMAN 1, paraplegic type 1, motor dominant type 19, Sensory-motor 1, MADSAM 3, Bifacial 2. Nonsystemic vasculitis was seen in 16 out of 29 chronic neuropathy and HIV, POEMS, and diabetes mellitus one each. Discussion: There is a spectrum of immune-mediated neuropathy which varies in clinical course, response to treatment, etc., Small percentage of uncommon cases are seen. In this group, mortality was nil and morbidity was minimal. Conclusion: Immune-mediated neuropathies are treatable and hence should be diagnosed early for good quality outcome.

Evaluation and Prevention of Diabetic Neuropathy

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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.

Correlation of Michigan neuropathy screening instrument, United Kingdom screening test and electrodiagnosis for early detection of diabetic peripheral neuropathy.

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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

Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy.

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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.

Leber's hereditary optic neuropathy is associated with the mitochondrial ND6 T14484C mutation in three Chinese families

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Sun Yanhong; Wei Qiping; Zhou Xiangtian; Qian Yaping; Zhou Jian; Lu Fan; Qu Jia; Guan Minxin

2006-01-01

We report here the clinical, genetic, and molecular characterization of three Chinese families with maternally transmitted Leber's hereditary optic neuropathy (LHON). Clinical and genetic evaluations revealed the variable severity and age-of-onset in visual impairment in these families. In the affected matrilineal relatives, the loss of central vision is bilateral, the fellow eye becoming affected either simultaneously (45%) or sequentially (55%). The penetrances of vision loss in these pedigrees were 27%, 50%, and 60%, respectively. The age-at-onset of vision loss in these families was 14, 19, and 24 years, respectively. Furthermore, the ratios between affected male and female matrilineal relatives were 1:1, 1:1.2, and 1:2, respectively. Mutational analysis of mitochondrial DNA revealed the presence of homoplasmic ND6 T14484C mutation, which has been associated with LHON. The incomplete penetrance and phenotypic variability implicate the involvement of nuclear modifier gene(s), environmental factor(s) or mitochondrial haplotype(s) in the phenotypic expression of the LHON-associated T14484C mutation in these Chinese pedigrees

KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2.

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Rivière, Jean-Baptiste; Ramalingam, Siriram; Lavastre, Valérie; Shekarabi, Masoud; Holbert, Sébastien; Lafontaine, Julie; Srour, Myriam; Merner, Nancy; Rochefort, Daniel; Hince, Pascale; Gaudet, Rébecca; Mes-Masson, Anne-Marie; Baets, Jonathan; Houlden, Henry; Brais, Bernard; Nicholson, Garth A; Van Esch, Hilde; Nafissi, Shahriar; De Jonghe, Peter; Reilly, Mary M; Timmerman, Vincent; Dion, Patrick A; Rouleau, Guy A

2011-08-12

Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare autosomal-recessive disorder characterized by peripheral nerve degeneration resulting in a severe distal sensory loss. Although mutations in FAM134B and the HSN2 exon of WNK1 were associated with HSANII, the etiology of a substantial number of cases remains unexplained. In addition, the functions of WNK1/HSN2 and FAM134B and their role in the peripheral nervous system remain poorly understood. Using a yeast two-hybrid screen, we found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon. In parallel to this screen, we performed genome-wide homozygosity mapping in a consanguineous Afghan family affected by HSANII and identified a unique region of homozygosity located on chromosome 2q37.3 and spanning the KIF1A gene locus. Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype. Subsequent sequencing of KIF1A in a series of 112 unrelated patients with features belonging to the clinical spectrum of ulcero-mutilating sensory neuropathies revealed truncating mutations in three additional families, thus indicating that mutations in KIF1A are a rare cause of HSANII. Similarly to WNK1 mutations, pathogenic mutations in KIF1A were almost exclusively restricted to an alternatively spliced exon. This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Toxins'' and nerve. ; Discussion on the pathogenesis of acrylamide intoxication, giant axonal neuropathy and krabbe disease. Doku'' to shinkei. ; Acrylamide chudoku, kyodaijikusaku neuropathy, Krabbe byo no byotai seiri wo meguru ichikosatsu

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Igusu, H. (University of Occupational and Environmental Health, Kitakyushu (Japan))

1992-06-01

Considerations were given on such neurological diseases as acrylamide intoxication, giant axonal neuropathy, and Krabbe disease. The point common to acrylamide intoxication and giant axonal neuropathy is that both peripheral nerves and central nerves suffer the lesion, and that tumefaction is seen in axonal terminals accompanying an increase in neurofilaments. Further, adding acrylamide to normally cultivated cells generates intermediate filament coagulation, and the same change can be seen in cells of giant axonal neuropathy patients. This suggests that a common pathophysiological mechanism is acting upon both diseases. However, acrylamide intoxication which is exogenous differs from giant axonal neuropathy in that it is an endogenous disease. On the other hand, a serious neuropathy of the Krabbe disease which is a hereditary neuropathy could be caused from actions of highly toxic psychosine. These facts suggest that toxicological approached would be effective in discussing pathologic manifestations. 37 refs., 2 figs., 1 tab.

Dyslipidemia as a contributory factor in etiopathogenesis of diabetic neuropathy

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Fakhir S Al-Ani

2011-01-01

Full Text Available Objectives: The pathogenesis of neuropathy in type 2 diabetes mellitus is multifactorial.Dyslipidemia may contribute to the development of diabetic neuropathy. This study aimed to assess the atherogenic lipid indices in type 2 diabetic patients with neuropathy.Material and Methods: Fifty-one patients with type 2 diabetes mellitus and 31 healthy subjects were studied in the Unit of Neurophysiology at the University Hospital of Medical College, Al-Nahrin University in Baghdad, Iraq, from January 2002 to January 2003. Neuropathy total symptom score (NTSS, neuropathy impairment score in the lower leg (NIS-LL, and electrophysiological study of sensory (ulnar and sural and motor (ulnar and common peroneal nerves were used to assess nerve function. Fasting venous blood was obtained from each participant for determination of lipid profile and atherogenic lipid ratios. Results: The frequency of high blood pressure was significantly higher in neuropathic patients. The electrophysiology study revealed significant decrease in conduction velocity of ulnar (sensory and motor components, sural, and common peroneal nerves. The minimum F-wave latency of motor nerve was significantly prolonged. Among the lipid fractions, only high-density lipoprotein-cholesterol was significantly reduced by 14% of healthy participant′s value. Atherogenic lipid ratios were significantly higher in diabetic patients than corresponding healthy ratios. Conclusion: Metabolic lipid disturbances in terms of atherogenicity co-existwith neuropathy in type 2 diabetes mellitus, irrespective of duration of disease.

Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3.

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Kornak, Uwe; Mademan, Inès; Schinke, Marte; Voigt, Martin; Krawitz, Peter; Hecht, Jochen; Barvencik, Florian; Schinke, Thorsten; Gießelmann, Sebastian; Beil, F Timo; Pou-Serradell, Adolf; Vílchez, Juan J; Beetz, Christian; Deconinck, Tine; Timmerman, Vincent; Kaether, Christoph; De Jonghe, Peter; Hübner, Christian A; Gal, Andreas; Amling, Michael; Mundlos, Stefan; Baets, Jonathan; Kurth, Ingo

2014-03-01

Many neurodegenerative disorders present with sensory loss. In the group of hereditary sensory and autonomic neuropathies loss of nociception is one of the disease hallmarks. To determine underlying factors of sensory neurodegeneration we performed whole-exome sequencing in affected individuals with the disorder. In a family with sensory neuropathy with loss of pain perception and destruction of the pedal skeleton we report a missense mutation in a highly conserved amino acid residue of atlastin GTPase 3 (ATL3), an endoplasmic reticulum-shaping GTPase. The same mutation (p.Tyr192Cys) was identified in a second family with similar clinical outcome by screening a large cohort of 115 patients with hereditary sensory and autonomic neuropathies. Both families show an autosomal dominant pattern of inheritance and the mutation segregates with complete penetrance. ATL3 is a paralogue of ATL1, a membrane curvature-generating molecule that is involved in spastic paraplegia and hereditary sensory neuropathy. ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network. Mutant ATL3 p.Tyr192Cys fails to localize to branch points, but instead disrupts the structure of the tubular endoplasmic reticulum, suggesting that the mutation exerts a dominant-negative effect. Identification of ATL3 as novel disease-associated gene exemplifies that long-term sensory neuronal maintenance critically depends on the structural organisation of the endoplasmic reticulum. It emphasizes that alterations in membrane shaping-proteins are one of the major emerging pathways in axonal degeneration and suggests that this group of molecules should be considered in neuroprotective strategies.

Clinical spectrum of Castleman disease-associated neuropathy.

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Naddaf, Elie; Dispenzieri, Angela; Mandrekar, Jay; Mauermann, Michelle L

2016-12-06

To define the peripheral neuropathy phenotypes associated with Castleman disease. We conducted a retrospective chart review for patients with biopsy-proven Castleman disease evaluated between January 2003 and December 2014. Patients with associated peripheral neuropathy were identified and divided into 2 groups: those with Castleman disease without POEMS syndrome (CD-PN) and those with Castleman disease with POEMS syndrome (CD-POEMS). We used a cohort of patients with POEMS as controls. Clinical, electrodiagnostic, and laboratory characteristics were collected and compared among patient subgroups. There were 7 patients with CD-PN, 20 with CD-POEMS, and 122 with POEMS. Patients with CD-PN had the mildest neuropathy characterized by predominant sensory symptoms with no pain and mild distal sensory deficits (median Neuropathy Impairment Score of 7 points). Although both patients with CD-POEMS and patients with POEMS had a severe sensory and motor neuropathy, patients with CD-POEMS were less affected (median Neuropathy Impairment Score of 33 and 66 points, respectively). The degree of severity was also reflected on electrodiagnostic testing in which patients with CD-PN demonstrated a mild degree of axonal loss, followed by patients with CD-POEMS and then those with POEMS. Demyelinating features, defined by European Federation of Neurologic Societies/Peripheral Nerve Society criteria, were present in 43% of the CD-PN, 78% of the CD-POEMS, and 86% of the POEMS group. There is a spectrum of demyelinating peripheral neuropathies associated with Castleman disease. CD-PN is sensory predominant and is the mildest phenotype, whereas CD-POEMS is a more severe sensory and motor neuropathy. Compared to the POEMS cohort, those with CD-POEMS neuropathy have a similar but less severe phenotype. Whether these patients respond differently to treatment deserves further study. © 2016 American Academy of Neurology.

Clinical spectrum of Castleman disease–associated neuropathy

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Naddaf, Elie; Dispenzieri, Angela; Mandrekar, Jay

2016-01-01

Objective: To define the peripheral neuropathy phenotypes associated with Castleman disease. Methods: We conducted a retrospective chart review for patients with biopsy-proven Castleman disease evaluated between January 2003 and December 2014. Patients with associated peripheral neuropathy were identified and divided into 2 groups: those with Castleman disease without POEMS syndrome (CD-PN) and those with Castleman disease with POEMS syndrome (CD-POEMS). We used a cohort of patients with POEMS as controls. Clinical, electrodiagnostic, and laboratory characteristics were collected and compared among patient subgroups. Results: There were 7 patients with CD-PN, 20 with CD-POEMS, and 122 with POEMS. Patients with CD-PN had the mildest neuropathy characterized by predominant sensory symptoms with no pain and mild distal sensory deficits (median Neuropathy Impairment Score of 7 points). Although both patients with CD-POEMS and patients with POEMS had a severe sensory and motor neuropathy, patients with CD-POEMS were less affected (median Neuropathy Impairment Score of 33 and 66 points, respectively). The degree of severity was also reflected on electrodiagnostic testing in which patients with CD-PN demonstrated a mild degree of axonal loss, followed by patients with CD-POEMS and then those with POEMS. Demyelinating features, defined by European Federation of Neurologic Societies/Peripheral Nerve Society criteria, were present in 43% of the CD-PN, 78% of the CD-POEMS, and 86% of the POEMS group. Conclusion: There is a spectrum of demyelinating peripheral neuropathies associated with Castleman disease. CD-PN is sensory predominant and is the mildest phenotype, whereas CD-POEMS is a more severe sensory and motor neuropathy. Compared to the POEMS cohort, those with CD-POEMS neuropathy have a similar but less severe phenotype. Whether these patients respond differently to treatment deserves further study. PMID:27807187

Laryngeal and phrenic nerve involvement in a patient with hereditary neuropathy with liability to pressure palsies (HNPP).

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Cortese, A; Piccolo, G; Lozza, A; Schreiber, A; Callegari, I; Moglia, A; Alfonsi, E; Pareyson, D

2016-07-01

Lower cranial and phrenic nerve involvement is exceptional in hereditary neuropathy with liability to pressure palsies (HNPP). Here we report the occurrence of reversible laryngeal and phrenic nerve involvement in a patient with HNPP. The patient recalled several episodes of reversible weakness and numbness of his feet and hands since the age of 30 years. His medical history was uneventful, apart from chronic obstructive pulmonary disease (COPD). At age 44, following severe weight loss, he presented with progressive dysphonia and hoarseness. EMG of cricoarytenoid and thyroarytenoid muscles and laryngeal fibroscopy confirmed vocal cord paralysis. These speech disturbances gradually regressed. Two years later, he reported rapidly worsening dyspnea. Electroneurography showed increased distal latency of the right phrenic nerve and diaphragm ultrasonography documented reduced right hemi-diaphragm excursion. Six months later and after optimization of CODP treatment, his respiratory function had improved and both phrenic nerve conduction and diaphragm excursion were completely restored. We hypothesize that chronic cough and nerve stretching in the context of CODP, together with severe weight loss, may have triggered the nerve paralysis in this patient. Our report highlights the need for optimal management of comorbidities such as CODP as well as careful control of weight in HNPP patients to avoid potentially harmful complications. Copyright © 2016 Elsevier B.V. All rights reserved.

Severe pulmonary hypertension associated with the acute motor sensory axonal neuropathy subtype of Guillain-Barré syndrome.

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Rooney, Kris A; Thomas, Neal J

2010-01-01

To evaluate pulmonary hypertension associated with acute motor sensory axonal neuropathy subtype of Guillain-Barré syndrome. Guillain-Barré syndrome consists of a group of autoimmune disorders that generally manifest as symmetric, progressive, ascending paralysis. There are five subtypes of Guillain-Barré syndrome, and autonomic involvement has been described in all subtypes, including cardiovascular, vasomotor, or pseudomotor dysfunction of both the sympathetic and parasympathetic systems. Case report. Tertiary care pediatric intensive care unit. Three-yr-old female patient. None. Serial measurements of pulmonary artery pressure. We report the case of a young girl with acute motor sensory axonal neuropathy who presented with severe cardiovascular collapse secondary to severe pulmonary hypertension. In this patient, multiple factors may have played a role in the development of pulmonary hypertension including autonomic dysfunction, hypoventilation, and immobility as a risk for thrombosis and pulmonary emboli. It is possible that many other individuals suffering from severe forms of Guillain-Barré syndrome, especially those with significant autonomic dysfunction, may actually have undiagnosed and therefore untreated pulmonary hypertension. Therefore, it is recommended that clinicians caring for critically ill children with Guillain-Barré syndrome have a high index of suspicion for pulmonary hypertension and consider echocardiography if there are clinical signs of this potentially fatal process.

Identification of IFRD1 variant in a Han Chinese family with autosomal dominant hereditary spastic paraplegia associated with peripheral neuropathy and ataxia.

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Lin, Pengfei; Zhang, Dong; Xu, Guangrun; Yan, Chuanzhu

2018-04-01

Spinocerebellar ataxias (SCAs) are a group of autosomal dominant, clinically heterogeneous neurodegenerative disorders. SCA18 is a rare autosomal dominant sensory/motor neuropathy with ataxia (OMIM#607458) associated with a single missense variant c.514 A>G in the interferon related developmental regulator 1 (IFRD1) gene previously reported in a five-generation American family of Irish origin. However, to date, there have been no other reports of the IFRD1 mutation to confirm its role in SCA. Here, we report a Han Chinese family with SCA18; the family members presented with a slowly progressing gait ataxia, pyramidal tract signs, and peripheral neuropathy. We identified a missense variant (c.514 A>G, p.I172V) in IFRD1 gene in the family using targeted next-generation sequencing and Sanger direct sequencing with specific primers. Our results suggest that the IFRD1 gene may be the causative allele for SCA18.

De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy

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Lee, Jae Ran; Srour, Myriam; Kim, Doyoun; Hamdan, Fadi F.; Lim, So Hee; Brunel-Guitton, Catherine; Décarie, Jean Claude; Rossignol, Elsa; Mitchell, Grant A.; Schreiber, Allison; Moran, Rocio; Van Haren, Keith; Richardson, Randal; Nicolai, Joost; Oberndorff, Karin M E J; Wagner, Justin D.; Boycott, Kym M.; Rahikkala, Elisa; Junna, Nella; Tyynismaa, Henna; Cuppen, Inge; Verbeek, Nienke E.; Stumpel, Connie T R M; Willemsen, Michel A.; de Munnik, Sonja A.; Rouleau, Guy A.; Kim, Eunjoon; Kamsteeg, Erik Jan; Kleefstra, Tjitske; Michaud, Jacques L.

2015-01-01

KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations

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

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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...

Lipid-lowering drugs (statins) and peripheral neuropathy.

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Emad, Mohammadreza; Arjmand, Hosein; Farpour, Hamid Reza; Kardeh, Bahareh

2018-03-01

Peripheral neuropathy is a disorder with often unknown causes. Some drugs, including statins, are proposed to be among the causes of peripheral neuropathy. This study aimed at evaluating this condition by electrodiagnostic study among patients who had received statins. This case-control study was conducted in Shiraz, Iran in 2015, and included 39 patients aged 35-55 who had received statins for at least 6 months, and 39 healthy matched controls. Using electrodiagnosis, the sensory and motor wave features (amplitude, latency and nerve conduction velocity) of the peripheral nerves (Median, Ulnar, Tibial, Sural, and Peroneal) were evaluated among the subjects. Data were analyzed using SPSS software and pneuropathy, there were no significant differences in any of the definitions presented for peripheral neuropathy. However, the difference was close to significance for one definition [2 abnormalities in 2 nerves (p=0.055)]. Regarding mean values of the features, significant differences were observed in two features: amplitude of the peroneal motor nerve (p=0.048) and amplitude of the sural sensory nerve (p=0.036). Since statins are widely used, awareness regarding their side-effects would lead to better treatment. Even though no significant differences were found between the groups regarding the occurrence of peripheral neuropathy, there were significant differences in amplitudes of the sural sensory response and the peroneal motor response. This indicates the involvement of peripheral nerves. Therefore, we recommend that patients and physicians should be informed about the possible symptoms of this condition.

Peripheral neuropathy is a common manifestation of mitochondrial diseases: a single-centre experience.

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Luigetti, M; Sauchelli, D; Primiano, G; Cuccagna, C; Bernardo, D; Lo Monaco, M; Servidei, S

2016-06-01

Peripheral neuropathy in mitochondrial diseases (MDs) may vary from a subclinical finding in a multisystem syndrome to a severe, even isolated, manifestation in some patients. To investigate the involvement of the peripheral nervous system in MDs extensive electrophysiological studies were performed in 109 patients with morphological, biochemical and genetic diagnosis of MD [12 A3243G progressive external ophthalmoplegia (PEO)/mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), 16 myoclonic epilepsy with ragged-red fibres (MERRF), four mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), 67 PEO with single or multiple deletions of mitochondrial DNA, 10 others]. A neuropathy was found in 49 patients (45%). The incidence was very high in MNGIE (100%), MELAS (92%) and MERRF (69%), whilst 28% of PEO patients had evidence of peripheral involvement. The most frequent abnormality was a sensory axonal neuropathy found in 32/49 patients (65%). A sensory-motor axonal neuropathy was instead detected in 16% of the patients and sensory-motor axonal demyelinating neuropathy in 16%. Finally one Leigh patient had a motor axonal neuropathy. It is interesting to note that the great majority had preserved tendon reflexes and no sensory disturbances. In conclusion, peripheral involvement in MD is frequent even if often mild or asymptomatic. The correct identification and characterization of peripheral neuropathy through electrophysiological studies represents another tile in the challenge of MD diagnosis. © 2016 EAN.

Muscular atrophy in diabetic neuropathy

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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...... 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...

Waardenburg syndrome: a rare cause of inherited neuropathy due to SOX10 mutation.

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Bogdanova-Mihaylova, Petya; Alexander, Michael D; Murphy, Raymond P J; Murphy, Sinéad M

2017-09-01

Waardenburg syndrome (WS) is a rare disorder comprising sensorineural deafness and pigmentation abnormalities. Four distinct subtypes are defined based on the presence or absence of additional symptoms. Mutations in six genes have been described in WS. SOX10 mutations are usually associated with a more severe phenotype of WS with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, and Hirschsprung disease. Here we report a 32-year-old man with a novel heterozygous missense variant in SOX10 gene, who presented with congenital deafness, Hirschsprung disease, iris heterochromia, foot deformity, and intermediate conduction velocity length-dependent sensorimotor neuropathy. This case highlights that the presence of other non-neuropathic features in a patient with presumed hereditary neuropathy should alert the clinician to possible atypical rare causes. © 2017 Peripheral Nerve Society.

Cellular Pathways of Hereditary Spastic Paraplegia*

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Blackstone, Craig

2012-01-01

Human voluntary movement is controlled by the pyramidal motor system, a long CNS pathway comprising corticospinal and lower motor neurons. Hereditary spastic paraplegias (HSPs) are a large, genetically diverse group of inherited neurologic disorders characterized by a length-dependent distal axonopathy of the corticospinal tracts, resulting in lower limb spasticity and weakness. A range of studies are converging on alterations in the shaping of organelles, particularly the endoplasmic reticul...

Knockdown of Pnpla6 protein results in motor neuron defects in zebrafish

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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.

Neurolysis and myocutaneous flap for radiation induced brachial plexus neuropathy

International Nuclear Information System (INIS)

Hirachi, Kazuhiko; Minami, Akio; Kato, Hiroyuki; Nishio, Yasuhiko; Ohnishi, Nobuki

1998-01-01

Surgical treatment for radiation induced brachial plexus neuropathy is difficult. We followed 9 patients of radiation induced brachial plexus neuropathy who were surgically treated with neurolysis and myocutaneous flap coverage. Their ages ranged from 29 to 72 years old. Their diagnoses were breast cancer in 6 patients, lingual cancer in 1, thyroid cancer in 1 and malignant lymphoma in 1. Total dose of radiation ranged from 44 to 240 Gy. Interval from radiation therapy to our surgery ranged from 1 to 18 years (mean 6.7 years). Chief complaints were dysesthesia in 9 patients, motor weakness in 7 patients and dullach in scar formation of radiated skin in 7 patients. Preoperative neural functions were slight palsy in 1, moderate palsy in 5 and complete palsy in 3. In surgical treatment, neurolysis of the brachial plexus was done and it was covered by latissimus dorsi myocutaneous flap. We evaluated about dysesthesia and motor recovery after treatment for neuropathy. Follow up periods ranged from 1 to 11 years (average in 5 years). Dysesthesia improved in 6 patients and got worse in 3 patients. Motor weakness recovered in only 2 patients and got worse in 7 patients. From our results, intolerable dysesthesia which was first complaint of these patients improved. But motor function had not recovered. Our treatment was thought to be effective for extraneural factor like an compression neuropathy by scar formation and poor vascularity. But it was not effective for intraneural damage by radiation therapy. (author)

A De Novo Mutation in Causes Generalized Dystonia in 2 Unrelated Children

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Yasemin Gulcan Kurt MD

2016-03-01

Full Text Available Dystonia is often associated with the symmetrical basal ganglia lesions of Leigh syndrome. However, it has also been associated with mitochondrial ND mutations, with or without Leber hereditary optic neuropathy. The m.14459G>A mutation in ND6 causes dystonia with or without familial Leber hereditary optic neuropathy. We report heteroplasmic 14459G>A mutations in 2 unrelated children with nonmaternally inherited generalized dystonia and showing bilateral magnetic resonance imaging lesions in nucleus pallidus and putamen. Both children have reached their teenage years, and they are intellectually active, despite their motor problems.

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

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Hana Starobova

2017-05-01

Full Text Available Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle—leading to cell death and tumor degradation—and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches.

Nerve sonography in multifocal motor neuropathy and chronic inflammatory demyelinating polyneuropathy

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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. 

Detection of antibodies in neuropathy patients by synthetic GM1 mimics

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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

Evaluation of pre-existing neuropathy and bortezomib retreatment as risk factors to develop severe neuropathy in a mouse model.

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Bruna, Jordi; Alé, Albert; Velasco, Roser; Jaramillo, Jessica; Navarro, Xavier; Udina, Esther

2011-09-01

Pre-existing neuropathy, a not uncommon feature in oncologic patients, is a potential but non-confirmed risk factor to develop early or severe chemotherapy-induced neuropathy. The main goal of this study is to evaluate the role of pre-existing neuropathy induced by vincristine (VNC) or bortezomib (BTZ) as a risk factor to develop more severe BTZ-induced neuropathy in a mouse model. VNC, at doses of 1 and 1.5 mg/kg given twice per week for 4 weeks, induced a moderate and severe sensory-motor neuropathy, primarily axonal, with predominant involvement of myelinated sensory axons. The neuropathy induced by BTZ at dose of 1 mg/kg given twice per week for 6 weeks was a mild axonal sensory neuropathy involving myelinated and unmyelinated fibers. The neuropathy in mice previously treated and retreated with the same schedule of BTZ after 4 weeks of washout period was similar in profile and severity to the one observed after the first treatment. When basal neuropathy was classified as moderate (most of BTZ-treated animals) or severe (all VNC-treated animals and two BTZ-treated animals), there was a more marked decline in sensory nerve function during BTZ retreatment in the group with basal severe neuropathy (-86%) than in the groups with basal mild (-57%) or without neuropathy (-52%; p < 0.001). Histopathological findings supported the functional results. Therefore, this study shows that the presence of a severe neuropathy previous to treatment with an antitumoral agent, such as BTZ, results in a more marked involvement of peripheral nerves. © 2011 Peripheral Nerve Society.

Acute motor and sensory axonal neuropathy-associated syndrome of inappropriate antidiuretic hormone secretion

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Weeraporn Srisung

2015-10-01

Full Text Available A 36-year-old man presented with a six week history of progressive ascending　weakness. Physical examination showed generalized motor weakness, more severe in　the lower extremities (LE, muscle wasting, absent LE reflexes, dysesthesia, and no　cranial nerve involvement. Neurologic workup was consistent with acute motor and sensory　axonal neuropathy (AMSAN, a variant of Guillain-Barre syndrome. Concomitantly　on admission, serum chemistry panel showed a sodium (Na 115 mmol/L with normal　kidney function. Urine showed Na <20 mmol/L, and specific gravity 1.045. Urine osmolality　was not available initially. He received IV fluid for volume expansion. The Na did　not significantly improve after he became euvolemic. Fluid restriction was then tried with　mild improvement. Endocrine work-up ruled out hypothyroidism and adrenal insufficiency.　Repeat labs showed serum Na 124 mmol/L, urine Na 191 mmol/L and urine Osm 531　mOsm, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH was　diagnosed. Our case report suggests that SIADH should be high on the differential diagnosis　for hyponatremia in patients with AMSAN, especially in the setting of euvolemia.

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

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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

Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy.

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Sadun, Alfredo A; Chicani, Carlos Filipe; Ross-Cisneros, Fred N; Barboni, Piero; Thoolen, Martin; Shrader, William D; Kubis, Kenneth; Carelli, Valerio; Miller, Guy

2012-03-01

To evaluate the safety and efficacy of a new therapeutic agent, EPI-743, in Leber hereditary optic neuropathy (LHON) using standard clinical, anatomic, and functional visual outcome measures. Open-label clinical trial. University medical center. Patients  Five patients with genetically confirmed LHON with acute loss of vision were consecutively enrolled and treated with the experimental therapeutic agent EPI-743 within 90 days of conversion. Intervention  During the course of the study, 5 consecutive patients received EPI-743, by mouth, 3 times daily (100-400 mg per dose). Treatment effect was assessed by serial measurements of anatomic and functional visual indices over 6 to 18 months, including Snellen visual acuity, retinal nerve fiber layer thickness measured by optical coherence tomography, Humphrey visual fields (mean decibels and area with 1-log unit depression), and color vision. Treatment effect in this clinical proof of principle study was assessed by comparison of the prospective open-label treatment group with historical controls. Of 5 subjects treated with EPI-743, 4 demonstrated arrest of disease progression and reversal of visual loss. Two patients exhibited a total recovery of visual acuity. No drug-related adverse events were recorded. In a small open-label trial, EPI-743 arrested disease progression and reversed vision loss in all but 1 of the 5 consecutively treated patients with LHON. Given the known natural history of acute and rapid progression of LHON resulting in chronic and persistent bilateral blindness, these data suggest that the previously described irreversible priming to retinal ganglion cell loss may be reversed.

Peripheral neuropathy in genetically characterized patients with mitochondrial disorders: A study from south India.

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Bindu, Parayil Sankaran; Govindaraju, Chikanna; Sonam, Kothari; Nagappa, Madhu; Chiplunkar, Shwetha; Kumar, Rakesh; Gayathri, Narayanappa; Bharath, M M Srinivas; Arvinda, Hanumanthapura R; Sinha, Sanjib; Khan, Nahid Akthar; Govindaraj, Periyasamy; Nunia, Vandana; Paramasivam, Arumugam; Thangaraj, Kumarasamy; Taly, Arun B

2016-03-01

There are relatively few studies, which focus on peripheral neuropathy in large cohorts of genetically characterized patients with mitochondrial disorders. This study sought to analyze the pattern of peripheral neuropathy in a cohort of patients with mitochondrial disorders. The study subjects were derived from a cohort of 52 patients with a genetic diagnosis of mitochondrial disorders seen over a period of 8 years (2006-2013). All patients underwent nerve conduction studies and those patients with abnormalities suggestive of peripheral neuropathy were included in the study. Their phenotypic features, genotype, pattern of peripheral neuropathy and nerve conduction abnormalities were analyzed retrospectively. The study cohort included 18 patients (age range: 18 months-50 years, M:F- 1.2:1).The genotype included mitochondrial DNA point mutations (n=11), SURF1 mutations (n=4) and POLG1(n=3). Axonal neuropathy was noted in 12 patients (sensori-motor:n=4; sensory:n=4; motor:n=4) and demyelinating neuropathy in 6. Phenotype-genotype correlations revealed predominant axonal neuropathy in mtDNA point mutations and demyelinating neuropathy in SURF1. Patients with POLG related disorders had both sensory ataxic neuropathy and axonal neuropathy. A careful analysis of the family history, clinical presentation, biochemical, histochemical and structural analysis may help to bring out the mitochondrial etiology in patients with peripheral neuropathy and may facilitate targeted gene testing. Presence of demyelinating neuropathy in Leigh's syndrome may suggest underlying SURF1 mutations. Sensory ataxic neuropathy with other mitochondrial signatures should raise the possibility of POLG related disorder. Copyright © 2015. Published by Elsevier B.V.

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

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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

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

Acupuncture and Reflexology for Chemotherapy-Induced Peripheral Neuropathy in Breast Cancer.

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Ben-Horin, Idan; Kahan, Peretz; Ryvo, Larisa; Inbar, Moshe; Lev-Ari, Shahar; Geva, Ravit

2017-09-01

Treatment of chemotherapy-induced peripheral neuropathy (CIPN), which affects approximately 30% to 40% of patients treated with neuropathy-causing agents, is mainly symptomatic. Currently available interventions are of little benefit. This study was conducted as a retrospective analysis of the efficacy of acupuncture and reflexology in alleviating CIPN in breast cancer patients. Medical records of 30 consecutive breast cancer patients who received both chemotherapy and treatment for CIPN according to our Acupuncture and Reflexology Treatment for Neuropathy (ART-N) protocol between 2011 and 2012 were reviewed. Symptom severity was rated at baseline, during, and after treatment. The records of 30 breast cancer patients who had been concomitantly treated with chemotherapy and ART-N for CIPN were retrieved. Two records were incomplete, leaving a total of 28 patients who were enrolled into the study. Twenty patients (71%) had sensory neuropathy, 7 (25%) had motor neuropathy, and 1 (4%) had both sensory and motor neuropathy. Only 2 (10%) of the 20 patients with grades 1 to 2 neuropathy still reported symptoms at 12 months since starting the ART-N protocol. All 8 patients who presented with grades 3 to 4 neuropathy were symptom-free at the 12-month evaluation. Overall, 26 patients (93%) had complete resolution of CIPN symptoms. The results of this study demonstrated that a joint protocol of acupuncture and reflexology has a potential to improve symptoms of CIPN in breast cancer patients. The protocol should be validated on a larger cohort with a control group. It also warrants testing as a preventive intervention.

Subtle neuropsychiatric and neurocognitive changes in hereditary gelsolin amyloidosis (AGel amyloidosis)

OpenAIRE

Kantanen, Mari; Kiuru-Enari, Sari; Salonen, Oili; Kaipainen, Markku; Hokkanen, Laura

2014-01-01

Hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant form of systemic amyloidosis caused by a c.640G>A or c.640G>T mutation in the gene coding for gelsolin. Principal clinical manifestations include corneal lattice dystrophy, cranial neuropathy and cutis laxa with vascular fragility. Signs of minor CNS involvement have also been observed, possibly related to cerebral amyloid angiopathy (CAA). To investigate further if AGel amyloidosis carries a risk for a specific neuro...

Approach to Peripheral Neuropathy for the Primary Care Clinician.

Science.gov (United States)

Doughty, Christopher T; Seyedsadjadi, Reza

2018-02-02

Peripheral neuropathy is commonly encountered in the primary care setting and is associated with significant morbidity, including neuropathic pain, falls, and disability. The clinical presentation of neuropathy is diverse, with possible symptoms including weakness, sensory abnormalities, and autonomic dysfunction. Accordingly, the primary care clinician must be comfortable using the neurologic examination-including the assessment of motor function, multiple sensory modalities, and deep tendon reflexes-to recognize and characterize neuropathy. Although the causes of peripheral neuropathy are numerous and diverse, careful review of the medical and family history coupled with limited, select laboratory testing can often efficiently lead to an etiologic diagnosis. This review offers an approach for evaluating suspected neuropathy in the primary care setting. It will describe the most common causes, suggest an evidence-based workup to aid in diagnosis, and highlight recent evidence that allows for selection of symptomatic treatment of patients with neuropathy. Copyright © 2018 Elsevier Inc. All rights reserved.

[Pure trigeminal motor neuropathy presenting with temporo-mandibular joint dysfunction in a patient with HIV and HCV infections].

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Anheim, M; Echaniz-Laguna, A; Rey, D; Tranchant, C

2006-01-01

Pure trigeminal motor neuropathy (PTMN) is a rarely described condition. We report the case of a 41-year-old woman infected with the human immunodeficiency virus (HIV1) and hepatitis C virus who presented with weakness of left temporalis and masseter muscles and painful left temporomandibular joint dysfunction (TMD) a few months after cerebral toxoplasmosis revealing acquired immunodeficiency syndrome (AIDS). Magnetic resonance imaging revealed severe wasting and fat replacement of the left temporalis, pterygoid and masseter muscles and showed neither abnormalities in the left motor nucleus of the trigeminal nerve nor compression of the left trigeminal nerve. Electromyographic examination gave evidence of denervation in the left temporalis, masseter and pterygoid muscles and blink reflex studies were normal, confirming the diagnosis of PTMN which was probably secondary to HIV and HCV co-infection.

Another cause of occupational entrapment neuropathy: la main du cuisinier (the chef's hand).

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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.

Peripheral neuropathies in childhood: a neuropathological approach Neuropatias periféricas na infância: uma abordagem neuropatológica

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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

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

Restless leg syndrome in different types of demyelinating neuropathies: a single-center pilot study.

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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.

Wolff-Parkinson-White syndrome and noncompaction in Leber's hereditary optic neuropathy due to the variant m.3460G>A.

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Finsterer, Josef; Stollberger, Claudia; Gatterer, Edmund

2018-05-01

This report describes a 66-year-old Caucasian male who acutely developed severe, bilateral impairment of visual acuity at 24 years of age. Leber's hereditary optic neuropathy (LHON) was suspected but the diagnosis was not genetically confirmed until the age of 49 years when the primary LHON mutation m.3460G>A was detected. Since onset, visual acuity had slightly improved. The family history was positive for LHON (brother, two sisters of mother, female cousin) and genetically confirmed in his brother and one aunt. Since the age of 65 years, he had experienced recurrent vertigo. His cardiological history was positive for arterial hypertension, noncompaction, myocardial thickening, intermittent right bundle-branch-block (RBBB) and Wolff-Parkinson-White (WPW) syndrome. In addition to LHON, he presented with polyneuropathy, hyperCKaemia, carotid artery occlusion, and a history of stroke. Cardiological investigations at 66 years of age revealed mildly reduced systolic function, enlarged atria, and nonsustained ventricular tachycardias. He underwent an electrophysiological investigation, but radiofrequency ablation was ruled out due to a 'bizarre' cardiac conduction system. Instead, an implantable cardioverter defibrillator was proposed but refused by the patient. Since the vertigo did not resolve it was attributed to polyneuropathy. This case demonstrates that LHON may be associated with noncompaction, myocardial thickening, reduced systolic function, enlarged atria, RBBB, WPW syndrome and nonsustained ventricular tachycardias. WPW syndrome in LHON may require invasive antiarrhythmic treatment.

Leber's hereditary optic neuropathy is associated with the mitochondrial ND4 G11696A mutation in five Chinese families

International Nuclear Information System (INIS)

Zhou Xiangtian; Wei Qiping; Yang Li; Tong Yi; Zhao Fuxin; Lu Chunjie; Qian Yaping; Sun Yanghong; Lu Fan; Qu Jia; Guan Minxin

2006-01-01

We report here the clinical, genetic, and molecular characterization of five Chinese families with Leber's hereditary optic neuropathy (LHON). Clinical and genetic evaluations revealed the variable severity and age-of-onset in visual impairment in these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical ND4 G11696A mutation associated with LHON. Indeed, this mutation is present in homoplasmy only in the maternal lineage of those pedigrees but not other members of these families. In fact, the occurrence of the G11696A mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. Furthermore, the N405D in the ND5 and G5820A in the tRNA Cys , showing high evolutional conservation, may contribute to the phenotypic expression of G11696A mutation in the WZ10 pedigree. However, there was the absence of functionally significant mtDNA mutations in other four Chinese pedigrees carrying the G11696A mutation. Therefore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of the LHON-associated G11696A mutation in these Chinese pedigrees

Employment status of patients with neuromuscular diseases in relation to personal factors, fatigue and health status: a secondary analysis.

NARCIS (Netherlands)

Minis, M.A.H; Kalkman, J.S.; Akkermans, R.P.; Engels, J.A.; Huijbregts, P.A.; Bleijenberg, G.; Oostendorp, R.A.B.; Engelen, B.G.M. van

2010-01-01

OBJECTIVE: To determine the number of employed people in a group of patients with neuromuscular diseases and in 3 separate subgroups (facioscapulo-humeral dystrophy, hereditary motor and sensory neuropathy, and myotonic dystrophy) to investigate any differences in employment status between the

Severe sensory neuropathy in patients with adult-onset multiple acyl-CoA dehydrogenase deficiency.

Science.gov (United States)

Wang, Zhaoxia; Hong, Daojun; Zhang, Wei; Li, Wurong; Shi, Xin; Zhao, Danhua; Yang, Xu; Lv, He; Yuan, Yun

2016-02-01

Multiple Acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation. Most patients with late-onset MADD are clinically characterized by lipid storage myopathy with dramatic responsiveness to riboflavin treatment. Abnormalities of peripheral neuropathy have rarely been reported in patients with late-onset MADD. We describe six patients who presented with proximal limb weakness and loss of sensation in the distal limbs. Muscle biopsy revealed typical myopathological patterns of lipid storage myopathy and blood acylcarnitine profiles showed a combined elevation of multiple acylcarnitines supporting the diagnosis of MADD. However, nerve conduction investigations and sural nerve biopsies in these patients indicated severe axonal sensory neuropathy. Causative ETFDH gene mutations were found in all six cases. No other causative gene mutations were identified in mitochondrial DNA and genes associated with hereditary neuropathies through next-generation-sequencing panel. Late-onset patients with ETFDH mutations can present with proximal muscle weakness and distal sensory neuropathy, which might be a new phenotypic variation, but the precise underlying pathogenesis remains to be elucidated. Copyright © 2015. Published by Elsevier B.V.

Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment

OpenAIRE

Mo, Michelle; Erdelyi, Ildiko; Szigeti-Buck, Klara; Benbow, Jennifer H.; Ehrlich, Barbara E.

2012-01-01

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 obs...

Median and ulnar neuropathies in university guitarists.

Science.gov (United States)

Kennedy, Rachel H; Hutcherson, Kimberly J; Kain, Jennifer B; Phillips, Alicia L; Halle, John S; Greathouse, David G

2006-02-01

Descriptive study. To determine the presence of median and ulnar neuropathies in both upper extremities of university guitarists. Peripheral nerve entrapment syndromes of the upper extremities are well documented in musicians. Guitarists and plucked-string musicians are at risk for entrapment neuropathies in the upper extremities and are prone to mild neurologic deficits. Twenty-four volunteer male and female guitarists (age range, 18-26 years) were recruited from the Belmont University School of Music and the Vanderbilt University Blair School of Music. Individuals were excluded if they were pregnant or had a history of recent upper extremity or neck injury. Subjects completed a history form, were interviewed, and underwent a physical examination. Nerve conduction status of the median and ulnar nerves of both upper extremities was obtained by performing motor, sensory, and F-wave (central) nerve conduction studies. Descriptive statistics of the nerve conduction study variables were computed using Microsoft Excel. Six subjects had positive findings on provocative testing of the median and ulnar nerves. Otherwise, these guitarists had normal upper extremity neural and musculoskeletal function based on the history and physical examinations. When comparing the subjects' nerve conduction study values with a chart of normal nerve conduction studies values, 2 subjects had prolonged distal motor latencies (DMLs) of the left median nerve of 4.3 and 4.7 milliseconds (normal, DMLs are compatible with median neuropathy at or distal to the wrist. Otherwise, all electrophysiological variables were within normal limits for motor, sensory, and F-wave (central) values. However, comparison studies of median and ulnar motor latencies in the same hand demonstrated prolonged differences of greater than 1.0 milliseconds that affected the median nerve in 2 additional subjects, and identified contralateral limb involvement in a subject with a prolonged distal latency. The other 20

Employment status of patients with neuromuscular diseases in relation to personal factors, fatigue and health status : A secondary analysis

NARCIS (Netherlands)

Rob Oostendorp; Peter Huijbregts; Marie-Antoinette Minis; Joke Kalkman; Baziel Engelen; Reinier Akkermans; Gijs Bleijenberg; Josephine Engels

2010-01-01

To determine the number of employed people in a group of patients with neuromuscular diseases and in 3 separate subgroups (facioscapulo-humeral dystrophy, hereditary motor and sensory neuropathy, and myotonic dystrophy) to investigate any differences in employment status between the patient groups,

Comparison of Efficiencies of Michigan Neuropathy Screening Instrument, Neurothesiometer, and Electromyography for Diagnosis of Diabetic Neuropathy

Directory of Open Access Journals (Sweden)

Turkan Mete

2013-01-01

Full Text Available Aim. This study compares the effectiveness of Michigan Neuropathy Screening Instrument (MNSI, neurothesiometer, and electromyography (EMG in detecting diabetic peripheral neuropathy in patients with diabetes type 2. Materials and Methods. 106 patients with diabetes type 2 treated at the outpatient clinic of Ankara Numune Education and Research Hospital Department of Endocrinology between September 2008 and May 2009 were included in this study. Patients were evaluated by glycemic regulation tests, MNSI (questionnaire and physical examination, EMG (for detecting sensorial and motor defects in right median, ulnar, posterior tibial, and bilateral sural nerves, and neurothesiometer (for detecting alterations in cold and warm sensations as well as vibratory sensations. Results. According to the MNSI score, there was diabetic peripheral neuropathy in 34 (32.1% patients (score ≥2.5. However, when the patients were evaluated by EMG and neurothesiometer, neurological impairments were detected in 49 (46.2% and 79 (74.5% patients, respectively. Conclusion. According to our findings, questionnaires and physical examination often present lower diabetic peripheral neuropathy prevalence. Hence, we recommend that in the evaluation of diabetic patients neurological tests should be used for more accurate results and thus early treatment options to prevent neuropathic complications.

Current concepts in the treatment of hereditary ataxias

Directory of Open Access Journals (Sweden)

Pedro Braga Neto

2016-03-01

Full Text Available ABSTRACT Hereditary ataxias (HA represents an extensive group of clinically and genetically heterogeneous neurodegenerative diseases, characterized by progressive ataxia combined with extra-cerebellar and multi-systemic involvements, including peripheral neuropathy, pyramidal signs, movement disorders, seizures, and cognitive dysfunction. There is no effective treatment for HA, and management remains supportive and symptomatic. In this review, we will focus on the symptomatic treatment of the main autosomal recessive ataxias, autosomal dominant ataxias, X-linked cerebellar ataxias and mitochondrial ataxias. We describe management for different clinical symptoms, mechanism-based approaches, rehabilitation therapy, disease modifying therapy, future clinical trials and perspectives, genetic counseling and preimplantation genetic diagnosis.

Taking pain out of NGF: a "painless" NGF mutant, linked to hereditary sensory autonomic neuropathy type V, with full neurotrophic activity.

Directory of Open Access Journals (Sweden)

Simona Capsoni

2011-02-01

Full Text Available During adulthood, the neurotrophin Nerve Growth Factor (NGF sensitizes nociceptors, thereby increasing the response to noxious stimuli. The relationship between NGF and pain is supported by genetic evidence: mutations in the NGF TrkA receptor in patients affected by an hereditary rare disease (Hereditary Sensory and Autonomic Neuropathy type IV, HSAN IV determine a congenital form of severe pain insensitivity, with mental retardation, while a mutation in NGFB gene, leading to the aminoacid substitution R100W in mature NGF, determines a similar loss of pain perception, without overt cognitive neurological defects (HSAN V. The R100W mutation provokes a reduced processing of proNGF to mature NGF in cultured cells and a higher percentage of neurotrophin secreted is in the proNGF form. Moreover, using Surface Plasmon Resonance we showed that the R100W mutation does not affect NGF binding to TrkA, while it abolishes NGF binding to p75NTR receptors. However, it remains to be clarified whether the major impact of the mutation is on the biological function of proNGF or of mature NGF and to what extent the effects of the R100W mutation on the HSAN V clinical phenotype are developmental, or whether they reflect an impaired effectiveness of NGF to regulate and mediate nociceptive transmission in adult sensory neurons. Here we show that the R100 mutation selectively alters some of the signaling pathways activated downstream of TrkA NGF receptors. NGFR100 mutants maintain identical neurotrophic and neuroprotective properties in a variety of cell assays, while displaying a significantly reduced pain-inducing activity in vivo (n = 8-10 mice/group. We also show that proNGF has a significantly reduced nociceptive activity, with respect to NGF. Both sets of results jointly contribute to elucidating the mechanisms underlying the clinical HSAN V manifestations, and to clarifying which receptors and intracellular signaling cascades participate in the pain

Treatment of diabetic neuropathy in the lower limb

African Journals Online (AJOL)

Diabetic peripheral neuropathy (DPN) is defined as 'the presence of symptoms and/or ... painful, paralytic and ataxic), type of fibres affected (motor, sensory, ... alcohol abuse and smoking. In fact, ... prevents or slows the progression of diabetic ...

Myelopathy and peripheral neuropathy after X-ray therapy

Energy Technology Data Exchange (ETDEWEB)

Berstad, J.

1986-03-01

Three patients with injury to the spinal cord after X-ray therapy are reported. One patient suffered from a chronic progressive myelopathy, whereas two others were considered to have a peripheral motor neuropathy due to selective damage to the motoneurons. The prognosis of patients with peripheral motor neuropathy is good, in contrast to chronic progressive myelopathy which most often leads to severe disability and death. Characteristically there is a latent interval from months to years between completed radiation therapy and the appearance of neurological symptoms. The mechanism for delayed radiation injury to the cord is at present unknown, but the possibilities of fibrosis, injury to the microcirculation, or direct injury to the nervous tissue are discussed. The importance of a correct diagnosis before further treatment is decided upon is stressed. The most difficult differential diagnosis is intraspinal metastases.

Myelopathy and peripheral neuropathy after X-ray therapy

International Nuclear Information System (INIS)

Berstad, J.

1986-01-01

Three patients with injury to the spinal cord after X-ray therapy are reported. One patient suffered from a chronic progressive myelopathy, whereas two others were considered to have a peripheral motor neuropathy due to selective damage to the motoneurons. The prognosis of patients with peripheral motor neuropathy is good, in contrast to chronic progressive myelopathy which most often leads to severe disability and death. Characteristically there is a latent interval from months to years between completed radiation therapy and the appearance of neurological symptoms. The mechanism for delayed radiation injury to the cord is at present unknown, but the possibilities of fibrosis, injury to the microcirculation, or direct injury to the nervous tissue are discussed. The importance of a correct diagnosis before further treatment is decided upon is stressed. The most difficult differential diagnosis is intraspinal metastases

Distal truncation of KCC3 in non-French Canadian HMSN/ACC families.

NARCIS (Netherlands)

Salin-Cantegrel, A.; Riviere, J.B.; Dupre, N.; Charron, F.M.; Shekarabi, M.; Karemera, L.; Gaspar, C.; Horst, J. van der; Tekin, M.; Deda, G.; Krause, A.; Lippert, M.M.; Willemsen, M.A.A.P.; Jarrar, R.; Lapointe, J.Y.; Rouleau, G.A.

2007-01-01

BACKGROUND: Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a severe and progressive autosomal recessive polyneuropathy. Mutations in the potassium-chloride cotransporter 3 gene (KCC3) were identified as responsible for HMSN/ACC in the French Canadian (FC)

Does Peripheral Neuropathy Associate with Cranial Nerves Neuropathy in Type 2 diabetes Patients?

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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.

[Acrodystrophic neuropathy in an alcoholic].

Science.gov (United States)

Yamamura, Y; Hironaka, M; Shimoyama, M; Toyota, Y; Kurokawa, M; Kohriyama, T; Nakamura, S

1993-01-01

The patient was a 48-year-old alcoholic man with no contributory family history. At age 36 he had developed sensory dominant polyneuropathy with highly impaired temperature sensation and deep sensation in the lower extremities, recurrent ulcers of the toes, and sexual impotence. A sural nerve biopsy at this time revealed marked loss of myelinated fibers with relative preservation of the population of unmyelinated fibers. Subsequently, he developed muscle atrophy of the lower thighs, urinary incontinence, and Wernicke's encephalopathy, and became non-ambulatory at age 44. The peripheral nerve conduction findings suggested predominantly axonal degeneration. The entire course was characterized by alternative progression and partial recovery influenced by his alcohol intake and nutritional state. Alcoholic neuropathy is a major cause of solitary acrodystrophic neuropathy (ADN). Manifestations of autonomic and motor neuropathy are more marked in alcoholic ADN than in HSAN-I, and central nervous system involvement is the hallmark of alcoholic ADN. In the treatment of patients with alcoholic ADN, attention should be paid to diabetes mellitus, malnutritional state, and vitamin deficiency, which frequently complicate alcoholism.

Only male matrilineal relatives with Leber's hereditary optic neuropathy in a large Chinese family carrying the mitochondrial DNA G11778A mutation

International Nuclear Information System (INIS)

Qu Jia; Li Ronghua; Tong Yi; Hu Yongwu; Zhou Xiangtian; Qian Yaping; Lu Fan; Guan Minxin

2005-01-01

We report here the characterization of a five-generation large Chinese family with Leber's hereditary optic neuropathy (LHON). Very strikingly, six affected individuals of 38 matrilineal relatives (17 females/21 males) are exclusively males in this Chinese family. These matrilineal relatives in this family exhibited late-onset/progressive visual impairment with a wide range of severity, ranging from blindness to normal vision. The age of onset in visual impairment varies from 17 to 30 years. Sequence analysis of the complete mitochondrial genome in this pedigree revealed the presence of the G11778A mutation in ND4 gene and 29 other variants. This mitochondrial genome belongs to the Southern Chinese haplogroup B5b. We showed that the G11778A mutation is present at near homoplasmy in matrilineal relatives of this Chinese family but not in 164 Chinese controls. Incomplete penetrance of LHON in this family indicates the involvement of modulatory factors in the phenotypic expression of visual dysfunction associated with the G11778A mutation. However, none of other mtDNA variants are evolutionarily conserved and implicated to have significantly functional consequence. Thus, nuclear modifier gene(s) or environmental factor(s) seem to account for the penetrance and phenotypic variability of LHON in this Chinese family carrying the G11778A mutation

Electronic versus paper-pencil methods for assessing chemotherapy-induced peripheral neuropathy.

Science.gov (United States)

Knoerl, Robert; Gray, Evan; Stricker, Carrie; Mitchell, Sandra A; Kippe, Kelsey; Smith, Gloria; Dudley, William N; Lavoie Smith, Ellen M

2017-11-01

The aim of this study is to examine and compare with the validated, paper/pencil European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy Scale (QLQ-CIPN20), the psychometric properties of three electronically administered patient reported outcome (PRO) measures of chemotherapy-induced peripheral neuropathy (CIPN): (1) the two neuropathy items from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), (2) the QLQ-CIPN20, and (3) the 0-10 Neuropathy Screening Question (NSQ). We employed a descriptive, cross-sectional design and recruited 25 women with breast cancer who were receiving neurotoxic chemotherapy at an academic hospital. Participants completed the paper/pencil QLQ-CIPN20 and electronic versions of the QLQ-CIPN20, PRO-CTCAE, and NSQ. Internal consistency reliability, intraclass correlation, and concurrent and discriminant validity analyses were conducted. The alpha coefficients for the electronic QLQ-CIPN20 sensory and motor subscales were 0.76 and 0.75. Comparison of the electronic and paper/pencil QLQ-CIPN20 subscales supported mode equivalence (intraclass correlation range >0.91). Participants who reported the presence of numbness/tingling via the single-item NSQ reported higher mean QLQ-CIPN20 sensory subscale scores (p neuropathy severity and interference items correlated well with the QLQ-CIPN20 electronic and paper/pencil sensory (r = 0.76; r = 0.70) and motor (r = 0.55; r = 0.62) subscales, and with the NSQ (r = 0.72; r = 0.44). These data support the validity of the electronically administered PRO-CTCAE neuropathy items, NSQ, and QLQ-CIPN20 for neuropathy screening in clinical practice. The electronic and paper/pencil versions of the QLQ-CIPN can be used interchangeably based on evidence of mode equivalence.

Sympathetic vasoconstrictor nerve function in alcoholic neuropathy

DEFF Research Database (Denmark)

Jensen, K; Andersen, K; Smith, T

1984-01-01

(18% and 48% decrease respectively). However, in three patients with moderate neuropathy, and in one patient with no signs of neuropathy, this veno-arteriolar reflex was absent, indicating dysfunction of the peripheral sympathetic adrenergic nerve fibres. The three patients also showed a lesser degree......The peripheral sympathetic vasomotor nerve function was investigated in 18 male chronic alcoholics admitted for intellectual impairment or polyneuropathy. By means of the local 133Xenon washout technique, the sympathetic veno-arteriolar axon-reflex was studied. This normally is responsible for a 50...... comprise not only the peripheral sensory and motor nerve fibres, but also the thin pseudomotor and vasomotor nerves....

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.

A novel DNMT1 mutation associated with early onset hereditary sensory and autonomic neuropathy, cataplexy, cerebellar atrophy, scleroderma, endocrinopathy, and common variable immune deficiency.

Science.gov (United States)

Fox, Robin; Ealing, John; Murphy, Helen; Gow, David P; Gosal, David

2016-09-01

DNA methyltransferase 1 (DNMT1) is an enzyme which has a role in methylation of DNA, gene regulation, and chromatin stability. Missense mutations in the DNMT1 gene have been previously associated with two neurological syndromes: hereditary sensory and autonomic neuropathy type 1 with dementia and deafness (HSAN1E) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). We report a case showing overlap of both of these syndromes plus associated clinical features of common variable immune deficiency, scleroderma, and endocrinopathy that could also be mutation associated. Our patient was found to be heterozygous for a previously unreported frameshift mutation, c.1635_1637delCAA p.(Asn545del) in the DNMT1 gene exon 20. This case displays both the first frameshift mutation described in the literature which is associated with a phenotype with a high degree of overlap between HSAN1E and ADCA-DN and early age of onset (c. 8 years). Our case is also of interest as the patient displays a number of new non-neurological features, which could also be DNMT1 mutation related. © 2016 Peripheral Nerve Society.

"Mitochondrial neuropathies": A survey from the large cohort of the Italian Network.

Science.gov (United States)

Mancuso, Michelangelo; Orsucci, Daniele; Angelini, Corrado; Bertini, Enrico; Carelli, Valerio; Comi, Giacomo Pietro; Federico, Antonio; Minetti, Carlo; Moggio, Maurizio; Mongini, Tiziana; Tonin, Paola; Toscano, Antonio; Bruno, Claudio; Ienco, Elena Caldarazzo; Filosto, Massimiliano; Lamperti, Costanza; Diodato, Daria; Moroni, Isabella; Musumeci, Olimpia; Pegoraro, Elena; Spinazzi, Marco; Ahmed, Naghia; Sciacco, Monica; Vercelli, Liliana; Ardissone, Anna; Zeviani, Massimo; Siciliano, Gabriele

2016-01-01

Involvement of the peripheral nervous system in mitochondrial disorders has been previously reported. However, the prevalence of peripheral neuropathy in mitochondrial disorders is still unclear. Based on the large database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", we reviewed the clinical data of 1200 patients, with special regard to peripheral neuropathy (mean age at onset 24.3 ± 20.1 years; age at last evaluation 39.8 ± 22.3 years; females 52.7%; childhood onset [before age 16 years] 43.1%). Peripheral neuropathy was present in 143/1156 patients (12.4%), being one of the ten most common signs and symptoms. POLG mutations cause a potentially painful, axonal/mixed, mainly sensory polyneuropathy; TYMP mutations lead to a demyelinating sensory-motor polyneuropathy; SURF1 mutations are associated with a demyelinating/mixed sensory-motor polyneuropathy. The only mtDNA mutation consistently associated with peripheral neuropathy (although less severely than in the above-considered nuclear genes) was the m.8993T > G (or the rarer T > C) changes, which lead to an axonal, mainly sensory polyneuropathy. In conclusion, peripheral neuropathy is one of the most common features of a mitochondrial disorder, and may negatively impact on the quality of life of these patients. Furthermore, the presence or absence of peripheral neuropathy, as well as its specific forms and the association with neuropathic pain (indicative of a POLG-associated disease) can guide the molecular analysis. Copyright © 2016 Elsevier B.V. All rights reserved.

Prevalence and predictors of peripheral neuropathy in nondiabetic 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

2018-05-01

This study sought to determine the prevalence and predictors of peripheral neuropathy in nondiabetic children with chronic kidney disease (CKD). Fifty-one consecutive normally nourished children, 3-18 years of age, with CKD stages IV and V of nondiabetic etiology were enrolled from May to December 2012. Nerve conduction studies were performed in 50 children. Blood samples were analyzed for the biochemical parameters, trace elements, and micronutrients. The prevalence of peripheral neuropathy in our cohort was 52% (95% confidence interval 37.65, 66.34). The majority (80.8%) of the children had axonal neuropathy, and 11.5% had demyelinating neuropathy. Isolated motor neuropathy was identified in 92.3% of the children, and sensorimotor neuropathy was identified 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 for the purpose of optimizing medical care. Muscle Nerve 57: 792-798, 2018. © 2017 Wiley Periodicals, Inc.

Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease.

LENUS (Irish Health Repository)

Pitceathly, Robert D S

2012-09-11

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN).

Neurophthalmological conditions mimicking glaucomatous optic neuropathy: analysis of the most common causes of misdiagnosis.

Science.gov (United States)

Dias, Diego Torres; Ushida, Michele; Battistella, Roberto; Dorairaj, Syril; Prata, Tiago Santos

2017-01-10

To analyze the most common neurophthalmological conditions that may mimic glaucomatous optic neuropathy and to determine which most often lead to misdiagnosis when evaluated by a glaucoma specialist. We reviewed the charts of consecutive patients with optic neuropathies caused by neurophthalmological conditions screened in a single Eye Clinic within a period of 24 months. Within these enrolled patients, we selected the eyes whose fundoscopic appearance could resemble glaucoma based in pre-defined criteria (vertical cup-to-disc ratio ≥0.6, asymmetry of the cup-to-disc ratio ≥0.2 between eyes, presence of localized retinal nerve fiber layer and/or neuroretinal rim defects, and disc haemorrhages). Then, color fundus photographs and Humphrey Visual Field tests (HVF) of these eyes were mixed with tests from 21 consecutive glaucomatous patients (42 eyes with normal tension glaucoma). These images were mixed randomly and a masked glaucoma specialist was asked to distinguish if each set of exams was from a patient with glaucoma or with a neurophthalmologic condition. Among the 101 eyes (68 patients) enrolled with neurophthalmological diseases, 16 (15.8%) were classified as conditions that could mimic glaucoma. The most common diagnoses were ischemic optic neuropathy (25%), compressive optic neuropathy (18.7%) and hereditary optic neuropathy (18.7%). Based on the analysis of fundus photographs and HVF tests, 25% of these were misdiagnosed as glaucoma (two ischemic optic neuropathies and two congenital optic disc anomalies). Conversely, 11.9% of the glaucomatous neuropathies were misdiagnosed as neurophthalmological disorders. Overall, the glaucoma specialist correctly diagnosed 84.5% of the eyes. Some neurophthalmological disorders can mimic glaucoma. In our study, isquemic and compressive optic neuropathies were the ones that most often did so. Almost one quarter of the eyes were misdiagnosed when evaluated by a glaucoma specialist, which can lead to inadequate

A Comprehensive Functional Analysis of NTRK1 Missense Mutations Causing Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV).

Science.gov (United States)

Shaikh, Samiha S; Chen, Ya-Chun; Halsall, Sally-Anne; Nahorski, Michael S; Omoto, Kiyoyuki; Young, Gareth T; Phelan, Anne; Woods, Christopher Geoffrey

2017-01-01

Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is an autosomal recessive disorder characterized by a complete lack of pain perception and anhidrosis. Here, we studied a cohort of seven patients with HSAN IV and describe a comprehensive functional analysis of seven novel NTRK1 missense mutations, c.1550G >A, c.1565G >A, c.1970T >C, c.2096T >C, c.2254T >A, c.2288G >C, and c.2311C >T, corresponding to p.G517E, p.G522E, p.L657P, p.I699T, p.C752S, p.C763S, and p.R771C, all of which were predicted pathogenic by in silico analysis. The results allowed us to assess the pathogenicity of each mutation and to gain novel insights into tropomyosin receptor kinase A (TRKA) downstream signaling. Each mutation was systematically analyzed for TRKA glycosylation states, intracellular and cell membrane expression patterns, nerve growth factor stimulated TRKA autophosphorylation, TRKA-Y496 phosphorylation, PLCγ activity, and neurite outgrowth. We showed a diverse range of functional effects: one mutation appeared fully functional, another had partial activity in all assays, one mutation affected only the PLCγ pathway and four mutations were proved null in all assays. Thus, we conclude that complete abolition of TRKA kinase activity is not the only pathogenic mechanism underlying HSAN IV. By corollary, the assessment of the clinical pathogenicity of HSAN IV mutations is more complex than initially predicted and requires a multifaceted approach. © 2016 WILEY PERIODICALS, INC.

Multiple cranial neuropathies without limb involvements: guillain-barre syndrome variant?

Science.gov (United States)

Yu, Ju Young; Jung, Han Young; Kim, Chang Hwan; Kim, Hyo Sang; Kim, Myeong Ok

2013-10-01

Acute multiple cranial neuropathies are considered as variant of Guillain-Barre syndrome, which are immune-mediated diseases triggered by various cases. It is a rare disease which is related to infectious, inflammatory or systemic diseases. According to previous case reports, those affected can exhibit almost bilateral facial nerve palsy, then followed by bulbar dysfunctions (cranial nerves IX and X) accompanied by limb weakness and walking difficulties due to motor and/or sensory dysfunctions. Furthermore, reported cases of the acute multiple cranial neuropathies show electrophysiological abnormalities compatible with the typical Guillain-Barre syndromes (GBS). We recently experienced a patient with a benign infectious disease who subsequently developed symptoms of variant GBS. Here, we describe the case of a 48-year-old male patient who developed multiple symptoms of cranial neuropathy without limb weakness. His laboratory findings showed a positive result for anti-GQ1b IgG antibody. As compared with previously described variants of GBS, the patient exhibited widespread cranial neuropathy, which included neuropathies of cranial nerves III-XII, without limb involvement or ataxia.

Peripheral neuropathies associated with antibodies directed to intracellular neural antigens.

Science.gov (United States)

Antoine, J-C

2014-10-01

Antibodies directed to intracellular neural antigens have been mainly described in paraneoplastic peripheral neuropathies and mostly includes anti-Hu and anti-CV2/CRMP5 antibodies. These antibodies occur with different patterns of neuropathy. With anti-Hu antibody, the most frequent manifestation is sensory neuronopathy with frequent autonomic involvement. With anti-CV2/CRMP5 the neuropathy is more frequently sensory and motor with an axonal or mixed demyelinating and axonal electrophysiological pattern. The clinical pattern of these neuropathies is in keeping with the cellular distribution of HuD and CRMP5 in the peripheral nervous system. Although present in high titer, these antibodies are probably not directly responsible for the neuropathy. Pathological and experimental studies indicate that cytotoxic T-cells are probably the main effectors of the immune response. These disorders contrast with those in which antibodies recognize a cell surface antigen and are probably responsible for the disease. The neuronal cell death and axonal degeneration which result from T-cell mediated immunity explains why treating these disorders remains challenging. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Radiation-induced neuropathies: collateral damage of improved cancer prognosis

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Pradat, Pierre-Francois; Maisonobe, Thierry; Psimaras, Dimitri; Lenglet, Timothee; Porcher, Raphael; Lefaix, J.L.; Delenian, S.

2012-01-01

Because of the improvement of cancer prognosis, long-term damages of treatments become a medical and public health problem. Among the iatrogenic complications, neurological impairment is crucial to consider since motor disability and pain have a considerable impact on quality of life of long cancer survivors. However, radiation-induced neuropathies have not been the focus of great attention. The objective of this paper is to provide an updated review about the radiation-induced lesions of the peripheral nerve system. Radiation-induced neuropathies are characterized by their heterogeneity in both symptoms and disease course. Signs and symptoms depend on the affected structures of the peripheral nerve system (nerve roots, nerve plexus or nerve trunks). Early-onset complications are often transient and late complications are usually progressive and associated with a poor prognosis. The most frequent and well known is delayed radiation-induced brachial plexopathy, which may follow breast cancer irradiation. Radiation-induced lumbosacral radiculoplexopathy is characterized by pure or predominant lower motor neuron signs. They can be misdiagnosed, confused with amyotrophic lateral sclerosis (ALS) or with leptomeningeal metastases since nodular MRI enhancement of the nerve roots of the cauda equina and increased cerebrospinal fluid protein content can be observed. In the absence of specific markers of the link with radiotherapy, the diagnosis of post-radiation neuropathy may be difficult. Recently, a posteriori conformal radiotherapy with 3D dosimetric reconstitution has been developed to link a precise anatomical site to unexpected excess irradiation. The importance of early diagnosis of radiation-induced neuropathies is underscored by the emergence of new disease-modifying treatments. Although the pathophysiology is not fully understood, it is already possible to target radiation-induced fibrosis but also associated factors such as ischemia, oxidative stress and

The first de novo mutation of the connexin 32 gene associated with X linked Charcot-Marie-Tooth disease

NARCIS (Netherlands)

Meggouh, F.; Benomar, A.; Rouger, H.; Tardieu, S.; Birouk, N.; Tassin, J.; Barhoumi, C.; Yahyaoui, M.; Chkili, T.; Brice, A.; LeGuern, E.

1998-01-01

X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary motor and sensory neuropathy caused by mutations in the connexin 32 gene (Cx32). Using the SSCP technique and direct sequencing of PCR amplified genomic DNA fragments of the Cx32 gene from a Moroccan patient and her relatives, we identified

Acute nutritional axonal neuropathy.

Science.gov (United States)

Hamel, Johanna; Logigian, Eric L

2018-01-01

This study describes clinical, laboratory, and electrodiagnostic features of a severe acute axonal polyneuropathy common to patients with acute nutritional deficiency in the setting of alcoholism, bariatric surgery (BS), or anorexia. Retrospective analysis of clinical, electrodiagnostic, and laboratory data of patients with acute axonal neuropathy. Thirteen patients were identified with a severe, painful, sensory or sensorimotor axonal polyneuropathy that developed over 2-12 weeks with sensory ataxia, areflexia, variable muscle weakness, poor nutritional status, and weight loss, often with prolonged vomiting and normal cerebrospinal fluid protein. Vitamin B6 was low in half and thiamine was low in all patients when obtained before supplementation. Patients improved with weight gain and vitamin supplementation, with motor greater than sensory recovery. We suggest that acute or subacute axonal neuropathy in patients with weight loss or vomiting associated with alcohol abuse, BS, or dietary deficiency is one syndrome, caused by micronutrient deficiencies. Muscle Nerve 57: 33-39, 2018. © 2017 Wiley Periodicals, Inc.

Multigeneration family with dominant SPG30 hereditary spastic paraplegia.

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Roda, Ricardo H; Schindler, Alice B; Blackstone, Craig

2017-11-01

Autosomal recessive KIF1A missense mutations cause hereditary spastic paraplegia (HSP) type SPG30, while recessive truncations lead to sensory and autonomic neuropathy (HSN2C) and many de novo missense mutations are associated with cognitive impairment. Here, we describe family members across three generations with pure HSP. A heterozygous p.Ser69Leu KIF1A mutation segregates with those afflicted. The same variant was previously reported in a Finnish father and son with pure HSP as well as four members of a Sicilian kindred with more intrafamilial phenotypic variability. This further validates the pathogenicity of the p.Ser69Leu mutation and suggests that it may represent a mutation hot spot.

Clinical evaluation and mitochondrial DNA sequence analysis in three Chinese families with Leber's hereditary optic neuropathy

International Nuclear Information System (INIS)

Qian Yaping; Zhou Xiangtian; Hu Yongwu; Tong Yi; Li Ronghua; Lu Fan; Yang Huanming; Mo Junqin; Qu Jia; Guan Minxin

2005-01-01

We report here the clinical, genetic, and molecular characterization of three Chinese families (WZ4, WZ5, and WZ6) with Leber's hereditary optic neuropathy (LHON). Clinical and genetic evaluations revealed the variable severity and age-of-onset in visual impairment in these families. Penetrances of visual impairment in these Chinese families were 33.3%, 35.7%, and 35.5%, respectively, with an average 34.8%. Furthermore, the average age-at-onset in those Chinese families was 17, 20, and 18 years. In addition, the ratios between affected male and female matrilineal relatives in these Chinese families were 3:0, 1:1, and 1.2:1, respectively. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical G11778A mutation associated with LHON in many families. The fact that mtDNA of those pedigrees belonged to different haplogroups F1, D4, and M10 suggested that the G11778A mutation occurred sporadically and multiplied through evolution of the mtDNA in China. However, there was the absence of functionally significant mutations in tRNA and rRNAs or secondary LHON mutations in these Chinese families. The I187T mutation in the ND1, the S99A mutation in the A6, the V254I in CO3, and I58V in ND6 mutation, showing high evolutional conservation, may contribute to the phenotypic expression of the G11778A mutation in the WZ6 pedigree. By contrast, none of mtDNA variants are evolutionarily conserved and implicated to have significantly functional consequence in WZ4 and WZ5 pedigrees. Apparently, these variants do not have a potential modifying role in the development of visual impairment associated with G11778A mutation in those two families. Thus, nuclear modifier gene(s) or environmental factor(s) seem to account for the penetrance and expressivity of LHON in these three Chinese families carrying the G11778A mutation

Electrophysiological measurements of diabetic peripheral neuropathy: A systematic review.

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Shabeeb, Dheyauldeen; Najafi, Masoud; Hasanzadeh, Gholamreza; Hadian, Mohammed Reza; Musa, Ahmed Eleojio; Shirazi, Alireza

2018-03-28

Peripheral neuropathy is one of the main complications of diabetes mellitus. One of the features of diabetic nerve damage is abnormality of sensory and motor nerve conduction study. An electrophysiological examination can be reproduced and is also a non-invasive approach in the assessment of peripheral nerve function. Population-based and clinical studies have been conducted to validate the sensitivity of these methods. When the diagnosis was based on clinical electrophysiological examination, abnormalities were observed in all patients. In this research, using a review design, we reviewed the issue of clinical electrophysiological examination of diabetic peripheral neuropathy in articles from 2008 to 2017. For this purpose, PubMed, Scopus and Embase databases of journals were used for searching articles. The researchers indicated that diabetes (both types) is a very disturbing health issue in the modern world and should be given serious attention. Based on conducted studies, it was demonstrated that there are different procedures for prevention and treatment of diabetes-related health problems such as diabetic polyneuropathy (DPN). The first objective quantitative indication of the peripheral neuropathy is abnormality of sensory and motor nerve conduction tests. Electrophysiology is accurate, reliable and sensitive. It can be reproduced and also is a noninvasive approach in the assessment of peripheral nerve function. The methodological review has found that the best method for quantitative indication of the peripheral neuropathy compared with all other methods is clinical electrophysiological examination. For best results, standard protocols such as temperature control and equipment calibration are recommended. Copyright © 2018. Published by Elsevier Ltd.

Brain white matter 1 H MRS in Leber optic neuropathy mutation carriers

DEFF Research Database (Denmark)

Ostojic, Jelena; Jancic, Jasna; Kozic, Dusko

2009-01-01

OBJECTIVE: This study was conducted in order to test the hypothesis that proton MR spectroscopic (1H MRS) profile of Leber's hereditary optic neuropathy (LHON) mutation carriers group (including both symptomatic and asymptomatic) differs from group of healthy individuals and to determine metabolite...... or ratio that contributes most to differentiation. PATIENTS AND METHODS: We performed single voxel 1H MRS in normal appearing white matter of eighteen LHON mtDNA mutation carriers bearing one of three LHON mtDNA point mutations and in fifty control subjects. RESULTS: ANOVA showed significant difference...

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

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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 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.

Quantitative measurement of duplicated DNA as a diagnostic test for Charcot-Marie-Tooth disease type 1a

NARCIS (Netherlands)

Hensels, G. W.; Janssen, E. A.; Hoogendijk, J. E.; Valentijn, L. J.; Baas, F.; Bolhuis, P. A.

1993-01-01

Charcot-Marie-Tooth disease type 1 (CMT1) is a hereditary motor and sensory neuropathy. The autosomal dominant subtype is often linked with a large duplication on chromosome 17p11.2. The gene encoding the peripheral myelin protein PMP 22 (the critical gene in this subtype of CMT1) is located within

Charcot-Marie-Tooth disease type 1A: morphological phenotype of the 17p duplication versus PMP22 point mutations

NARCIS (Netherlands)

Gabreëls-Festen, A. A.; Bolhuis, P. A.; Hoogendijk, J. E.; Valentijn, L. J.; Eshuis, E. J.; Gabreëls, F. J.

1995-01-01

Charcot-Marie-Tooth disease type 1A (CMT1A) or hereditary motor and sensory neuropathy type Ia (HMSN type Ia) is an autosomal dominant demyelinating polyneuropathy, which may result from duplications as large as 1.5 Mb on chromosome 17p 11.2-p12 encompassing the gene for the peripheral myelin

Baseline demographics, clinical features, and treatment protocols of 240 patients with optic neuropathy: experiences from a neuro-ophthalmological clinic in the Aegean region of Turkey.

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Karti, Omer; Karti, Dilek Top; Kilic, İlay Hilal; Gokcay, Figen; Celebisoy, Nese

2017-12-19

To analyze the demographic patterns, clinical characteristics, and treatment protocols of optic neuropathies. The hospital data of patients with optic neuropathy admitted to the Department of Neuro-ophthalmology in a tertiary referral center in Turkey between January 2010 to January 2017 were retrospectively analyzed. Demographic patterns, clinical features, treatment protocols, and the natural disease courses were assessed. The total number of patients with optic neuropathy seen over this period was 240, which consist of 43 with idiopathic optic neuritis (17.9%), 40 with multiple sclerosis-related optic neuritis (16.7%), 12 with chronic relapsing inflammatory optic neuritis (5.0%), 12 with atypical optic neuritis (5.0%), 11 with neuromyelitis optica spectrum disorders-related optic neuritis (4.6%), 90 with non-arteritic ischemic optic neuropathy (37.5%), 4 with arteritic ischemic optic neuropathy (1.7%), 10 with traumatic optic neuropathy (4.1%), 6 with compressive optic neuropathy (2.5%), and 12 with mitochondrial optic neuropathy [9 with toxic optic neuropathy (3.7%) and 3 with Leber's hereditary optic neuropathy (1.2%)]. There were 101 males (42%) and 139 females (58%). The mean age was 43.34 ± 15.86 years. This study reported the demographics, clinical characteristics, and treatment protocols of optic neuropathies in a neuro-ophthalmology specialty clinic at a tertiary referral center in Turkey during the past decade. The data may be useful in assessing the global status of optic neuropathies.

Daspsone Induced Peripheral Neuropathy

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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.

Acupuncture in Reducing Chemotherapy-Induced Peripheral Neuropathy in Participants With Stage I-III Breast Cancer

Science.gov (United States)

2018-05-30

Anatomic Stage I Breast Cancer AJCC v8; Anatomic Stage IA Breast Cancer AJCC v8; Anatomic Stage IB Breast Cancer AJCC v8; Anatomic Stage II Breast Cancer AJCC v8; Anatomic Stage IIA Breast Cancer AJCC v8; Anatomic Stage IIB Breast Cancer AJCC v8; Anatomic Stage III Breast Cancer AJCC v8; Anatomic Stage IIIA Breast Cancer AJCC v8; Anatomic Stage IIIB Breast Cancer AJCC v8; Anatomic Stage IIIC Breast Cancer AJCC v8; Grade 1 Peripheral Motor Neuropathy, CTCAE; Grade 1 Peripheral Sensory Neuropathy, CTCAE; Grade 2 Peripheral Motor Neuropathy, CTCAE; Grade 2 Peripheral Sensory Neuropathy, CTCAE; Prognostic Stage I Breast Cancer AJCC v8; Prognostic Stage IA Breast Cancer AJCC v8; Prognostic Stage IB Breast Cancer AJCC v8; Prognostic Stage II Breast Cancer AJCC v8; Prognostic Stage IIA Breast Cancer AJCC v8; Prognostic Stage IIB Breast Cancer AJCC v8; Prognostic Stage III Breast Cancer AJCC v8; Prognostic Stage IIIA Breast Cancer AJCC v8; Prognostic Stage IIIB Breast Cancer AJCC v8; Prognostic Stage IIIC Breast Cancer AJCC v8

Motor neuron, nerve, and neuromuscular junction disease.

Science.gov (United States)

Finsterer, Josef; Papić, Lea; Auer-Grumbach, Michaela

2011-10-01

The aim is to review the most relevant findings published during the last year concerning clinical, genetic, pathogenic, and therapeutic advances in motor neuron disease, neuropathies, and neuromuscular junction disorders. Studies on animal and cell models have improved the understanding of how mutated survival motor neuron protein in spinal muscular atrophy governs the pathogenetic processes. New phenotypes of SOD1 mutations have been described. Moreover, animal models enhanced the insight into the pathogenetic background of sporadic and familial amyotrophic lateral sclerosis. Novel treatment options for motor neuron disease have been described in humans and animal models. Considerable progress has been achieved also in elucidating the genetic background of many forms of inherited neuropathies and high clinical and genetic heterogeneity has been demonstrated. Mutations in MuSK and GFTP1 have been shown to cause new types of congenital myasthenic syndromes. A third type of autoantibodies (Lrp4) has been detected to cause myasthenia gravis. Advances in the clinical and genetic characterization of motor neuron diseases, neuropathies, and neuromuscular transmission defects have important implications on the fundamental understanding, diagnosis, and management of these disorders. Identification of crucial steps of the pathogenetic process may provide the basis for the development of novel therapeutic strategies.

Mutational analysis of Greek patients with suspected hereditary neuropathy with liability to pressure palsies (HNPP): a 15-year experience.

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Karadima, Georgia; Koutsis, Georgios; Raftopoulou, Maria; Karletidi, Karolina-Maria; Zambelis, Thomas; Karandreas, Nikolaos; Panas, Marios

2015-06-01

There has been limited information from population studies regarding the overall frequency of the common 1.5-Mb 17p11.2 deletion and even scarcer data regarding the overall frequency of PMP22 micromutations in patients with a clinical suspicion of hereditary neuropathy with liability to pressure palsies (HNPP). We have analysed 100 consecutive Greek patients referred for HNPP genetic testing over a 15-year period to our Neurogenetics Unit in Athens, a reference centre for all regions of Greece. All patients were screened for the 1.5-Mb deletion and a selected subgroup of deletion-negative patients for PMP22 micromutations. Mutation-positive and mutation-negative patients were compared for various clinical parameters. In total, 54 mutation-positive patients were identified. In index cases, the deletion frequency was 47.8%, and the PMP22 micromutation frequency was 2.2%. Within mutation-positive patients, the common deletion represented 95.7% and PMP22 micromutations 4.3% of cases. Two previously reported PMP22 micromutations (c.364_365delCC and c.79-2A>G) were detected. HNPP index cases had a 2.8-1 male-to-female ratio, similar to mutation-negative patients. A typical phenotype (recurrent or isolated palsies) was present in 82.4% of symptomatic HNPP cases, significantly higher than mutation-negative patients. Sensitivity of proposed electrophysiological diagnostic criteria for HNPP was calculated at 95.7% and specificity at 80.5%. In conclusion, the common HNPP deletion accounts for ∼50% and PMP22 micromutations for ∼2% of cases in a large consecutive cohort of patients with suspected HNPP. The mutational and phenotypic spectrum of HNPP is similar in the Greek population compared with other populations. Proposed electrophysiological diagnostic criteria perform satisfactorily in everyday clinical practice. © 2015 Peripheral Nerve Society.

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.

N-hexane neuropathy with vertigo and cold allodynia in a silk screen printer: A case study

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Sunil Pradhan

2015-10-01

Full Text Available N-hexane neuropathy is an occupational disease caused by exposure to n-hexane, which is used as a solvent in silk screen printing. Here, we describe a 35-year-old man, a silk screen printer by profession, who presented with dizziness, distal swelling of both lower limbs for 10 months and tingling and burning sensation in both feet for 9.5 months along with cold allodynia. The patient had normal results of a motor and sensory system examination, apart from an impaired temperature sense. Nerve conduction tests showed a conduction block in bilateral common peroneal nerves and absence of conduction in bilateral sural nerves. These symptoms resolved when further exposure to n-hexane was ceased but cold allodynia remained. Thus, cold allodynia and impaired temperature sense can be a manifestation of n-hexane neuropathy. Hence, abnormalities on nerve conduction studies can be detected in n-hexane neuropathy patients, even before clinical examination detects any such abnormalities. In the case of the patients presenting with sensory motor neuropathy, history of occupational exposure to n-hexane becomes important, as the sooner the disease is detected, the better the chances of recovery.

Clinical and neurophysiological investigation of a large family with dominant Charcot-Marie-Tooth type 2 disease with pyramidal signs

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Eduardo Luis de Aquino Neves

2011-06-01

Full Text Available Charcot-Marie-Tooth (CMT disease is a hereditary neuropathy of motor and sensory impairment with distal predominance. Atrophy and weakness of lower limbs are the first signs of the disease. It can be classified, with the aid of electromyography and nerve conduction studies, as demyelinating (CMT1 or axonal (CMT2. OBJECTIVE: Clinical and neurophysiological investigation of a large multigenerational family with CMT2 with autosomal dominant mode of transmission. METHOD: Fifty individuals were evaluated and neurophysiological studies performed in 22 patients. RESULTS: Thirty individuals had clinical signs of motor-sensory neuropathy. Babinski sign was present in 14 individuals. Neurophysiological study showed motor-sensory axonal polyneuropathy. CONCLUSION: The clinical and neurophysiological characteristics of this family does not differ from those observed with other forms of CMT, except for the high prevalence of Babinski sign.

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

Science.gov (United States)

Yang, Shuo; Ma, Si-Qi; Wan, Xing; He, Heng; Pei, Han; Zhao, Min-Jian; Chen, Chen; Wang, Dao-Wen; Dong, Xiao-Yan; Yuan, Jia-Jia; Li, Bin

2016-08-01

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 12months 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 3months after he received gene therapy in the second eye. Animal experiments suggested that ND4 expression remains stable in the

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

Directory of Open Access Journals (Sweden)

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

The coexistence of mitochondrial ND6 T14484C and 12S rRNA A1555G mutations in a Chinese family with Leber's hereditary optic neuropathy and hearing loss

International Nuclear Information System (INIS)

Wei Qiping; Zhou Xiangtian; Yang Li; Sun Yanhong; Zhou Jian; Li Guang; Jiang, Robert; Lu Fan; Qu Jia; Guan Minxin

2007-01-01

We report here the clinical, genetic and molecular characterization of one three-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON) and hearing loss. Four of 14 matrilineal relatives exhibited the moderate central vision loss at the average age of 12.5 years. Of these, one subject exhibited both LHON and mild hearing impairment. Sequence analysis of the complete mitochondrial genomes in the pedigree showed the presence of homoplasmic LHON-associated ND6 T14484C mutation, deafness-associated 12S rRNA A1555 mutation and 47 other variants belonging to Eastern Asian haplogroup H2. None of other mitochondrial variants was evolutionarily conserved and functional significance. Therefore, the coexistence of the A1555G mutation and T14484C mutations in this Chinese family indicate that the A1555G mutation may play a synergistic role in the phenotypic manifestation of LHON associated ND6 T14484C mutation. However, the incomplete penetrance of vision and hearing loss suggests the involvement of nuclear modifier genes and environmental factors in the phenotypic expression of these mtDNA mutations

Neuronal involvement in cisplatin neuropathy

DEFF Research Database (Denmark)

Krarup-Hansen, A; Helweg-Larsen, Susanne Elisabeth; Schmalbruch, H

2007-01-01

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......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...

Hereditary Diffuse Gastric Cancer

Science.gov (United States)

... Hereditary Diffuse Gastric Cancer Request Permissions Hereditary Diffuse Gastric Cancer Approved by the Cancer.Net Editorial Board , 10/2017 What is hereditary diffuse gastric cancer? Hereditary diffuse gastric cancer (HDGC) is a rare ...

Peripheral neuropathy is associated with more frequent falls in Parkinson's disease.

Science.gov (United States)

Beaulieu, Mélanie L; Müller, Martijn L T M; Bohnen, Nicolaas I

2018-04-03

Peripheral neuropathy is a common condition in the elderly that can affect balance and gait. Postural imbalance and gait difficulties in Parkinson's disease (PD), therefore, may stem not only from the primary neurodegenerative process but also from age-related medical comorbidities. Elucidation of the effects of peripheral neuropathy on these difficulties in PD is important to provide more targeted and effective therapy. The purpose of this study was to investigate the association between lower-limb peripheral neuropathy and falls and gait performance in PD while accounting for disease-specific factors. From a total of 140 individuals with PD, 14 male participants met the criteria for peripheral neuropathy and were matched 1:1 for Hoehn & Yahr stage and duration of disease with 14 male participants without peripheral neuropathy. All participants underwent fall (retrospectively) and gait assessment, a clinical evaluation, and [ 11 C]dihydrotetrabenazine and [ 11 C]methylpiperidin-4-yl propionate PET imaging to assess dopaminergic and cholinergic denervation, respectively. The presence of peripheral neuropathy was significantly associated with more falls (50% vs. 14%, p = 0.043), as well as a shorter stride length (p = 0.011) and greater stride length variability (p = 0.004), which resulted in slower gait speed (p = 0.016) during level walking. There was no significant difference in nigrostriatal dopaminergic denervation, cortical and thalamic cholinergic denervation, and MDS-UPDRS motor examination scores between groups. Lower-limb peripheral neuropathy is significantly associated with more falls and gait difficulties in PD. Thus, treating such neuropathy may reduce falls and/or improve gait performance in PD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Corneal Confocal Microscopy Detects Small Fibre Neuropathy in Patients with Upper Gastrointestinal Cancer and Nerve Regeneration in Chemotherapy Induced Peripheral Neuropathy.

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Maryam Ferdousi

Full Text Available There are multiple neurological complications of cancer and its treatment. This study assessed the utility of the novel non-invasive ophthalmic technique of corneal confocal microscopy in identifying neuropathy in patients with upper gastrointestinal cancer before and after platinum based chemotherapy. In this study, 21 subjects with upper gastrointestinal (oesophageal or gastric cancer and 21 healthy control subjects underwent assessment of neuropathy using the neuropathy disability score, quantitative sensory testing for vibration perception threshold, warm and cold sensation thresholds, cold and heat induced pain thresholds, nerve conduction studies and corneal confocal microscopy. Patients with gastro-oesophageal cancer had higher heat induced pain (P = 0.04 and warm sensation (P = 0.03 thresholds with a significantly reduced sural sensory (P<0.01 and peroneal motor (P<0.01 nerve conduction velocity, corneal nerve fibre density (CNFD, nerve branch density (CNBD and nerve fibre length (CNFL (P<0.0001. Furthermore, CNFD correlated significantly with the time from presentation with symptoms to commencing chemotherapy (r = -0.54, P = 0.02, and CNFL (r = -0.8, P<0.0001 and CNBD (r = 0.63, P = 0.003 were related to the severity of lymph node involvement. After the 3rd cycle of chemotherapy, there was no change in any measure of neuropathy, except for a significant increase in CNFL (P = 0.003. Corneal confocal microscopy detects a small fibre neuropathy in this cohort of patients with upper gastrointestinal cancer, which was related to disease severity. Furthermore, the increase in CNFL after the chemotherapy may indicate nerve regeneration.

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

Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy [v2; ref status: indexed, http://f1000r.es/3am

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Lori Sames

2014-04-01

Full Text Available Approximately 1 in 2500 Americans suffer from Charcot-Marie-Tooth (CMT disease. The underlying disease mechanisms are unique in most forms of CMT, with many point mutations on various genes causing a toxic accumulation of misfolded proteins. Symptoms of the disease often present within the first two decades of life, with CMT1A patients having reduced compound muscle and sensory action potentials, slow nerve conduction velocities, sensory loss, progressive distal weakness, foot and hand deformities, decreased reflexes, bilateral foot drop and about 5% become wheelchair bound. In contrast, the ultra-rare disease Giant Axonal Neuropathy (GAN is frequently described as a recessively inherited condition that results in progressive nerve death. GAN usually appears in early childhood and progresses slowly as neuronal injury becomes more severe and leads to death in the second or third decade. There are currently no treatments for any of the forms of CMTs or GAN. We suggest that further clinical studies should analyse electrical impedance myography as an outcome measure for CMT. Further, additional quality of life (QoL assessments for these CMTs are required, and we need to identify GAN biomarkers as well as develop new genetic testing panels for both diseases. We propose that using the Global Registry of Inherited Neuropathy (GRIN could be useful for many of these studies. Patient advocacy groups and professional organizations (such as the Hereditary Neuropathy Foundation (HNF, Hannah's Hope Fund (HHF, The Neuropathy Association (TNA and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM can play a central role in educating clinicians and patients. Undertaking these studies will assist in the correct diagnosis of disease recruiting patients for clinical studies, and will ultimately improve the endpoints for clinical trials. By addressing obstacles that prevent industry investment in various forms of inherited neuropathies

Serum levels of TGF-β1 in patients of diabetic peripheral neuropathy and its correlation with nerve conduction velocity in type 2 diabetes mellitus.

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Hussain, Gauhar; Rizvi, S Aijaz Abbas; Singhal, Sangeeta; Zubair, Mohammad; Ahmad, Jamal

2016-01-01

To correlate serum levels of TGF-β1 with motor and sensory nerve conduction velocities in patients of type 2 diabetes mellitus The study was conducted in diagnosed type 2 diabetes mellitus patients which were divided in patients with clinically detectable peripheral neuropathy of shorter duration (n=37) and longer duration (n=27). They were compared with patients without clinical neuropathy (n=22). Clinical diagnosis was based on neuropathy symptom score (NSS) and Neuropathy disability score (NDS) for signs. Blood samples were collected for baseline investigations and estimation of serum TGF-β1. Nerve conduction velocity was measured in both upper and lower limbs. Median, Ulnar, Common Peroneal and Posterior Tibial nerves were selected for motor nerve conduction study and Median and Sural nerves were selected for sensory nerve conduction study In patients of type 2 diabetes mellitus with clinically detectable and serum TGF-β1 showed positive correlation with nerve conduction velocities High level of TGF-β1 in serum of T2DM patients with neuropathy show possible contribution in development of neuropathy. Due to its independent association this cytokine might be used as biomarker for diabetic peripheral neuropathy. Copyright © 2015 Diabetes India. Published by Elsevier Ltd. All rights reserved.

N-hexane neuropathy with vertigo and cold allodynia in a silk screen printer: A case study.

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Pradhan, Sunil; Tandon, Ruchika

2015-01-01

N-hexane neuropathy is an occupational disease caused by exposure to n-hexane, which is used as a solvent in silk screen printing. Here, we describe a 35-year-old man, a silk screen printer by profession, who presented with dizziness, distal swelling of both lower limbs for 10 months and tingling and burning sensation in both feet for 9.5 months along with cold allodynia. The patient had normal results of a motor and sensory system examination, apart from an impaired temperature sense. Nerve conduction tests showed a conduction block in bilateral common peroneal nerves and absence of conduction in bilateral sural nerves. These symptoms resolved when further exposure to n-hexane was ceased but cold allodynia remained. Thus, cold allodynia and impaired temperature sense can be a manifestation of n-hexane neuropathy. Hence, abnormalities on nerve conduction studies can be detected in n-hexane neuropathy patients, even before clinical examination detects any such abnormalities. In the case of the patients presenting with sensory motor neuropathy, history of occupational exposure to n-hexane becomes important, as the sooner the disease is detected, the better the chances of recovery. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

Epalrestat, an aldose reductase inhibitor, in diabetic neuropathy: An Indian perspective

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Sharma S

2008-01-01

Full Text Available Background: A number of diabetic patients with diabetic neuropathy, in India, were treated with epalrestat, an aldose reductase inhibitor. In this study, more than 2000 patients with diabetic neuropathy, who were treated with epalrestat for 3-12 months, were analyzed to assess the efficacy and the adverse reactions of the drug. Method: We analyzed the subjective symptoms (spontaneous pain, numbness, coldness and hypoesthesia and the nerve function tests (motor nerve conduction velocity, sensory nerve conduction velocity and vibration threshold. Result: The improvement rate of the subjective symptoms was 75% (slightly improved or better and that of the nerve function tests 36%. Adverse drug reactions were encountered in 52 (2.5% of the 2190 patients, none of which was severe. Conclusion: Although data are limited, it is strongly suggested that epalrestat is a highly effective and safe agent for the treatment of diabetic neuropathy.

Suspected Perinatal Depression Revealed to be Hereditary Diffuse Leukoencephalopathy with Spheroids.

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Blume, Josefine; Weissert, Robert

2017-01-01

Early motor symptoms of neurodegenerative diseases often appear in combination with psychiatric symptoms, such as depression or personality changes, and are in danger of being misdiagnosed as psychogenic in young patients. We present the case of a 32-year-old woman who presented with rapid-onset depression, followed by a hypokinetic movement disorder and cognitive decline during pregnancy. Genetic testing revealed a mutation in the colony-stimulating factor 1 receptor gene, which led to the diagnosis of hereditary diffuse leukoencephalopathy with spheroids. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is probably an under-recognized disease. HDLS should be considered in patients with rapidly progressing parkinsonian symptoms and dementia accompanied by white matter lesions.

Suspected Perinatal Depression Revealed to be Hereditary Diffuse Leukoencephalopathy with Spheroids

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Josefine Blume

2017-01-01

Full Text Available Early motor symptoms of neurodegenerative diseases often appear in combination with psychiatric symptoms, such as depression or personality changes, and are in danger of being misdiagnosed as psychogenic in young patients. We present the case of a 32-year-old woman who presented with rapid-onset depression, followed by a hypokinetic movement disorder and cognitive decline during pregnancy. Genetic testing revealed a mutation in the colony-stimulating factor 1 receptor gene, which led to the diagnosis of hereditary diffuse leukoencephalopathy with spheroids. Hereditary diffuse leukoencephalopathy with spheroids (HDLS is probably an under-recognized disease. HDLS should be considered in patients with rapidly progressing parkinsonian symptoms and dementia accompanied by white matter lesions.

Taxane-induced peripheral neuropathy has good long-term prognosis: a 1- to 13-year evaluation.

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Osmani, Karima; Vignes, Stéphane; Aissi, Mouna; Wade, Fatou; Milani, Paolo; Lévy, Bernard I; Kubis, Nathalie

2012-09-01

Taxane-induced neuropathy is a frequent complication, in particular in women with breast cancer. The incidence can be variable and ranges from 11 to 87%, depending on the taxane used and identified risk factors, such as cumulative dose, additional neurotoxic chemotherapy agents and previous nerve fragility. However, little is known about long-term outcome and interference with daily life activities. The objective of this study was to assess clinical and electrophysiological neurological evaluation (ENMG) in a cohort of patients, 1-13 years (median 3 years) after the end of the last cure. Sixty-nine women were enrolled in the lymphology unit of Cognacq-Jay's Hospital. They were 58 ± 9 years old (mean age ± SD) and had been treated by docetexel (n = 56), paclitaxel (n = 10) or both (n = 3), 1-13 years before. Sensory neuropathy occurred in 64% and totally disappeared within months for only 14% after cessation of treatment. However, if symptoms were still present at the time of examination, they were considered as minor by almost all patients, with no interference with daily life activities (grade 2 CTCAE v.3.0). ENMG was accepted by 14 patients; it was normal in 7, and showed sensory axonal neuropathy in 5 and sensory-motor neuropathy in 2. The incidence of taxane-induced neuropathy is high, more frequent with paclitaxel than docetaxel, and is characterized by minor or moderate axonal sensory polyneuropathy. When persistent, it is extremely well tolerated by the patient. When clinical motor signs occur, the patient should be referred to a neurologist.

Effects of Semelil (ANGIPARSTM on diabetic peripheral neuropathy: A randomized, double-blind Placebo-controlled clinical trial

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S Bakhshayeshi

2011-03-01

Full Text Available "n Background and the purpose of the study: Diabetic neuropathy is the most common diabetic complication that often is accompanied by significant morbidity, mortality and economic burden. The purpose of this study was evaluation of effect of Semelil (ANGIPARSTM, a new herbal drug for treatment of diabetic foot ulcers or diabetic peripheral neuropathy. "nMethods: In this double blind clinical trial, 49 type 2 diabetes patients with different degrees of neuropathy were evaluated in two groups (ANGIPARSTM and placebo groups. All patients were assessed at the start and 12 weeks after treatment, with laboratory tests, United Kingdom screening test, Michigan neuropathy screening score, Michigan diabetic neuropathy score, vibration perception thresholds, nerve conduction study, monofilament test and visual analog scale. "nResults: Michigan diabetic neuropathy score was decreased notably in ANGIPARSTM group. In the nerve conduction study, appropriate meaningful changes were observed in the distal latency and amplitude in the motor Ulnar nerve in ANGIPARSTM group. Conclusion: The results showed limited evidence of efficacy of ANGIPARSTM in diabetic neuropathy treatment and more studies with a larger sample size and longer duration are required.

Hereditary Neuropathies

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... calf muscles (having the appearance of an inverted champagne glass) or scoliosis (curvature of the spine). The ... calf muscles (having the appearance of an inverted champagne glass) or scoliosis (curvature of the spine). The ...

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

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

2016-01-01

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. RESULTS: 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. CONCLUSIONS: Haplogroup distribution as well as mutational spectrum of the Danish LHON cohort do not deviate from those...

Hereditaer motorisk sensorisk neuropati (Charcot-Marie-Tooths sygdom). Molekyloergenetiske aspekter

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Hertz, M J; Børglum, Anders; Brandt, C A

1995-01-01

Hereditary motor and sensory neuropathy (HMSN) comprises a heterogenous group of peripheral neuropathies which are classified on the basis of symptoms, mode of inheritance and electrophysiological and neuropathological investigations. HMSN type I, or Charcot-Marie-Tooth disease (CMT) type 1...... be detected by DNA-analysis. The genes for HMSN type Ia, Ib and an X-linked dominant form have been identified as PMP22, MPZ and GJB1 respectively. Analysis for these molecular defects will become important in the differential diagnosis of peripheral neuropathies and will surely prove invaluable......, is a hypertrophic and demyelinating neuropathy with reduced nerve conduction velocity, and most often with dominant inheritance. HMSN type II (CMT type 2), the neuronal or axonal form, is dominantly inherited with normal or only moderately reduced nerve conduction velocity. HMSN type III, also called Déjérine...

Olesoxime (cholest-4-en-3-one, oxime): Analgesic and neuroprotective effects in a rat model of painful peripheral neuropathy produced by the chemotherapeutic agent, paclitaxel

OpenAIRE

Xiao, Wen Hua; Zheng, Felix Y.; Bennett, Gary J.; Bordet, Thierry; Pruss, Rebecca M.

2009-01-01

Olesoxime is a small cholesterol-like molecule that was discovered in a screening program aimed at finding treatment for amyotrophic lateral sclerosis and other diseases where motor neurons degenerate. In addition to its neuroprotective and pro-regenerative effects on motor neurons in vitro and in vivo, it has been shown to have analgesic effects in rat models of painful peripheral neuropathy due to vincristine and diabetes. We used a rat model of painful peripheral neuropathy produced by the...

Increased lipid droplet accumulation associated with a peripheral sensory neuropathy.

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Marshall, Lee L; Stimpson, Scott E; Hyland, Ryan; Coorssen, Jens R; Myers, Simon J

2014-04-01

Hereditary sensory neuropathy type 1 (HSN-1) is an autosomal dominant neurodegenerative disease caused by missense mutations in the SPTLC1 gene. The SPTLC1 protein is part of the SPT enzyme which is a ubiquitously expressed, critical and thus highly regulated endoplasmic reticulum bound membrane enzyme that maintains sphingolipid concentrations and thus contributes to lipid metabolism, signalling, and membrane structural functions. Lipid droplets are dynamic organelles containing sphingolipids and membrane bound proteins surrounding a core of neutral lipids, and thus mediate the intracellular transport of these specific molecules. Current literature suggests that there are increased numbers of lipid droplets and alterations of lipid metabolism in a variety of other autosomal dominant neurodegenerative diseases, including Alzheimer's and Parkinson's disease. This study establishes for the first time, a significant increase in the presence of lipid droplets in HSN-1 patient-derived lymphoblasts, indicating a potential connection between lipid droplets and the pathomechanism of HSN-1. However, the expression of adipophilin (ADFP), which has been implicated in the regulation of lipid metabolism, was not altered in lipid droplets from the HSN-1 patient-derived lymphoblasts. This appears to be the first report of increased lipid body accumulation in a peripheral neuropathy, suggesting a fundamental molecular linkage between a number of neurodegenerative diseases.

Upper Extremity Multifocal Neuropathy in a 10-Year-Old Boy Associated With NS6S Disaccharide Antibodies.

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Edelman, Frederick; Naddaf, Elie; Waclawik, Andrew J

2015-06-01

We present a 10-year-old boy with a predominantly motor multifocal neuropathy with demyelinating and axonal changes with sensory involvement, affecting only one upper extremity. Laboratory studies revealed an elevated titer of immunoglobulin M (IgM) antibodies against the NS6S antigen. He responded to treatment with high dose intravenous immunoglobulins. Focal or multifocal immune-mediated neuropathies are not common in children and may be underdiagnosed. © The Author(s) 2014.

Autonomic Neuropathy

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... risk of autonomic neuropathy. Other diseases. Amyloidosis, porphyria, hypothyroidism and cancer (usually due to side effects from treatment) may also increase the risk of autonomic neuropathy. ...

Peripheral neuropathy

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... peripheral; Neuritis - peripheral; Nerve disease; Polyneuropathy; Chronic pain - peripheral neuropathy ... Philadelphia, PA: Elsevier; 2016:chap 107. Shy ME. Peripheral neuropathies. In: Goldman L, Schafer AI, eds. Goldman's Cecil ...

L-3-n-Butylphthalide Protects HSPB8 K141N Mutation-Induced Oxidative Stress by Modulating the Mitochondrial Apoptotic and Nrf2 Pathways

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Xiao-Dong Yang

2017-07-01

Full Text Available Charcot–Marie–Tooth disease (CMT, also known as hereditary motor and sensory neuropathy, is the most common inherited peripheral nerve disorder. Missense mutations, such as K141N, in the small heat shock protein HSPB8 are known to cause distal hereditary motor neuropathy 2A (dHMN2A or Charcot-Marie-Tooth neuropathy type 2L (CMT2L. However, of critical clinical significance, very few specific therapies for this disease exist. In the present study, we investigated the impact of mutant K141N HSPB8 on mitochondrial distribution and function in a cellular model of CMT2L. Our results indicate that K141N HSPB8 induced mitochondrial aggregation and caused increased oxidative stress injury. As an extraction from Chinese celery Apium graveolens Linn seeds, L-3-n-Butylphthalide (NBP, has been reported to exert many neuroprotective effects, we interrogated whether NBP could elicit a protective effect on the cell injury typically caused by HSPB8 K141N mutations. We found NBP could reverse the pathological processes induced by HSPB8 K141N mutation via an antioxidant effect, modulation of the Bax/Bcl-2 mitochondrial apoptotic and Nrf2 pathways. We propose a novel function of HSPB8, highlighting the consequence of the K141N pathogenic mutation. Furthermore, we suggest NBP may have promising therapeutic potential in the treatment of CMT2L.

Association of peripheral neuropathy with sleep-related breathing disorders in myotonic dystrophies

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Banach M

2017-01-01

Full Text Available Marta Banach,1,* Jakub Antczak,1,* Rafał Rola21Department of Clinical Neurophysiology, 2First Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland *These authors contributed equally to this workBackground: Myotonic dystrophy (DM type 1 and type 2 are inherited diseases characterized by myotonia and myopathy. Additional symptoms include, among others, peripheral neuropathy and sleep-related breathing disorders (SRBDs. There is growing evidence for a complex association between DM1 and DM2, which was described in patients with diabetes mellitus and in the general population. In this study, we investigated whether there is an association between peripheral neuropathy and SRBDs also in the population of patients with DM.Methods: The study included 16 patients with DM1 (mean age, 37.9±14.1 years; 20–69 years and eight patients with DM2 (mean age, 47.6±14.1 years; 20–65 years, who underwent a sensory and motor nerve conduction study (NCS and diagnostic screening for SRBDs. In both groups, the NCS parameters were correlated with respiratory parameters.Results: In both groups, the amplitude of the ulnar sensory nerve action potential (SNAP correlated with the mean arterial oxygen saturation (SaO2. In addition, in the DM2 group, the median SNAP correlated with the mean SaO2. In the DM1 group, the median SNAP and the distal motor latency (DML of the ulnar nerve correlated with the apnea–hypopnea index, while the oxygen desaturation index correlated with the DML of the tibial nerve and with conduction velocity in the sural nerve.Conclusion: Our results indicate a complex association between neuropathy and SRBDs in DM1 and DM2. Axonal degeneration may contribute to nocturnal hypoxemia and vice versa. Neuropathy may contribute to muscle weakness, which in turn may cause respiratory events.Keywords: myotonic dystrophy, SRBD and neuropathy with AHI, SNAP, CMAP

[New trends in neuropathy practice: clinical approach to CIDP].

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Baba, M

2001-12-01

Our recent study showed that the overall prevalence of CIDP was estimated as 2.2 per 100,000 population in Aomori Prefecture, in Northan Honshu of Japan. In our series of more than 80 cases with CIDP, a chronic acquired inflammatory demyelinating polyneuropathy, nearly 30% showed clear laterality of weakness, and electrophysiologic laterality or multifocality was apparent in almost all cases. Nearly 90% of patients were able to walk without walking aids or other assistance. Sixty% showed distal dominant muscular weakness. In 12 patients with age of onset under 15, pes cavus deformity was seen in 5. Two thirds complained numbness in the extremities during progressive phase. Four cases initially showed severe sensory ataxia associated with motor conduction block. It should be, thus, reminded that clinical spectrum of CIDP is enormously wide: chronic acquired demyelinating multiple mononeuropathy showing asymmetric involvement (Lewis-Summer syndrome) should be put on one side of the clinical presentation of CIDP. Multifocal motor neuropathy (MMN) is, on the other hand, an unique syndrome mimicking amyotrophic lateral sclerosis (ALS). There may be, however, true association syndrome of CIDP and ALS presenting both peripheral nerve demyelination and pyramidal sign with progressive bulbar involvement. Recently, several atypical varieties of CIDP showing only one-limb involvement, upper limb weakness rather than lower limb power loss, or proximal weakness, etc ... have been reported in the literature. To realize such clinical variations of chronic acquired demyelinating neuropathy is important for early diagnosis and commencement of treatment of CIDP. Clinical guideline for suspicion of CIDP could be useful for general physicians and neurologists unfamiliar to peripheral neuropathies.

MR imaging of trigeminal neuropathy

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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.

Acquired neuropathies.

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Lozeron, Pierre; Trocello, Jean-Marc; Kubis, Nathalie

2013-09-01

Acquired neuropathies represent most of the neuropathies encountered in clinical practice. Hundreds of causes have been identified even though up to 41% of patients are still classified as idiopathic (Rajabally and Shah in J Neurol 258:1431-1436, 1). Routine evaluation relies on comprehensive medical history taking, clinical examination, nerve conduction studies and laboratory tests. Other investigations such as nerve biopsy or nerve or muscle imaging are performed in specific settings. This review focuses on recent advances in acquired neuropathies.

[Evidence of pudendal neuropathy in Proctalgia Fugax: perineal neurophysiological assessment in 55 patients].

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Damphousse, M; Jousse, M; Verollet, D; Guinet, A; Le Breton, F; Lacroix, P; Sheik Ismael, S; Amarenco, G

2012-04-01

Proctalgia fugax (PF) is a very common condition especially in women. Causes and pathophysiological mechanisms of PF are unknown. Recently, a pudendal neuropathy was clinically suspected in women with PF. The goal of our study was to demonstrate, or not, such abnormalities by means electrophysiological testing. Fifty-five patients with PF (45 female and 10 male, mean age 50.2 years) were evaluated. EMG testing with motor unit potential analysis of pelvic floor muscles (bulbocavernosus muscle and striated external anal sphincter), study of bulbocavernosus reflex and pudendal nerve terminal motor latencies (PNTML) were performed. EMG testing was altered in two males out of 10 (20%) and 29/45 females (64%). In women, denervation was found bilateral in 25/29 (86%). Sacral latency was delayed in eight out of 29 (bilateral in five cases, unilateral in three cases) and PNTML altered in 17 cases (13 bilateral alteration, four unilateral). A significant difference (P<0.002 Chi(2) test) was demonstrated between male and female concerning pelvic floor muscles denervation. Pelvic floor muscles denervation was a common feature in women suffering from PF, due to a stretch bilateral pudendal neuropathy. Distal lesions of the pudendal nerves, principally due to a stretch perineal neuropathy, can be imagined as a factor or co-factor of PF. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Optic neuropathies--importance of spatial distribution of mitochondria as well as function.

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Yu Wai Man, C Y; Chinnery, P F; Griffiths, P G

2005-01-01

Optic neuropathies such as Leber's hereditary optic neuropathy, dominant optic atrophy and toxic amblyopia are an important cause of irreversible visual failure. Although they are associated with a defect of mitochondrial energy production, their pathogenesis is poorly understood. A common feature to all these disorders is relatively selective degeneration of the papillomacular bundle of retinal ganglion cells resulting central or caecocentral visual field defects. The striking similarity in the pattern of clinical involvement seen with these disparate disorders suggests a common pathway in their aetiology. The existing hypothesis that the optic nerve head has higher energy demands than other tissues making it uniquely dependent on oxidative phosporylation is not satisfactory. First, other ocular tissues such as photoreceptors, which are more dependent on oxidative phosporylation are not affected. Second, other mitochondrial disorders, which have a greater impact on mitochondrial energy function, do not affect the optic nerve. The optic nerve head has certain unique ultra structural features. Ganglion cell axons exit the eye through a perforated collagen plate, the lamina cribrosa. There is a sharp discontinuity in the density of mitochondria at the optic nerve head, with a very high concentration in the prelaminar nerve fibre layer and low concentration behind the lamina. This has previously been attributed to a mechanical hold up of axoplasmic flow, which has itself been proposed as a factor in the pathogenesis of a number of optic neuropathies. More recent evidence shows that mitochondrial distribution reflects the different energy requirements of the unmyelinated prelaminar axons in comparison to the myelinated retrolaminar axons. The heterogeous distribution of mitochondria is actively maintained to support conduction through the optic nerve head. We propose that factors that disrupt the heterogeneous distribution of mitochondria can result in ganglion cell

An inversion disrupting FAM134B is associated with sensory neuropathy in the Border Collie dog breed

OpenAIRE

Forman, Oliver P.; Hitti, Rebekkah J.; Pettitt, Louise; Jenkins, Christopher A.; O'Brien, Dennis P.; Shelton, G. Diane; De Risio, Luisa; Gutierrez Quintana, Rodrigo; Beltran, Elsa; Mellersh, Cathryn

2016-01-01

Sensory neuropathy in the Border Collie is a severe neurological disorder caused by the degeneration of sensory and, to a lesser extent, motor nerve cells with clinical signs starting between 2 and 7 months of age. Using a genome-wide association study approach with three cases and 170 breed matched controls, a suggestive locus for sensory neuropathy was identified that was followed up using a genome sequencing approach. An inversion disrupting the candidate gene FAM134B was identified. Genot...

Aberrant signature methylome by DNMT1 hot spot mutation in hereditary sensory and autonomic neuropathy 1E.

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Sun, Zhifu; Wu, Yanhong; Ordog, Tamas; Baheti, Saurabh; Nie, Jinfu; Duan, Xiaohui; Hojo, Kaori; Kocher, Jean-Pierre; Dyck, Peter J; Klein, Christopher J

2014-08-01

DNA methyltransferase 1 (DNMT1) is essential for DNA methylation, gene regulation and chromatin stability. We previously discovered DNMT1 mutations cause hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss (HSAN1E; OMIM 614116). HSAN1E is the first adult-onset neurodegenerative disorder caused by a defect in a methyltransferase gene. HSAN1E patients appear clinically normal until young adulthood, then begin developing the characteristic symptoms involving central and peripheral nervous systems. Some HSAN1E patients also develop narcolepsy and it has recently been suggested that HSAN1E is allelic to autosomal dominant cerebellar ataxia, deafness, with narcolepsy (ADCA-DN; OMIM 604121), which is also caused by mutations in DNMT1. A hotspot mutation Y495C within the targeting sequence domain of DNMT1 has been identified among HSAN1E patients. The mutant DNMT1 protein shows premature degradation and reduced DNA methyltransferase activity. Herein, we investigate genome-wide DNA methylation at single-base resolution through whole-genome bisulfite sequencing of germline DNA in 3 pairs of HSAN1E patients and their gender- and age-matched siblings. Over 1 billion 75-bp single-end reads were generated for each sample. In the 3 affected siblings, overall methylation loss was consistently found in all chromosomes with X and 18 being most affected. Paired sample analysis identified 564,218 differentially methylated CpG sites (DMCs; P<0.05), of which 300 134 were intergenic and 264 084 genic CpGs. Hypomethylation was predominant in both genic and intergenic regions, including promoters, exons, most CpG islands, L1, L2, Alu, and satellite repeats and simple repeat sequences. In some CpG islands, hypermethylated CpGs outnumbered hypomethylated CpGs. In 201 imprinted genes, there were more DMCs than in non-imprinted genes and most were hypomethylated. Differentially methylated region (DMR) analysis identified 5649 hypomethylated and 1872

Converging cellular themes for the hereditary spastic paraplegias.

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Blackstone, Craig

2018-05-10

Hereditary spastic paraplegias (HSPs) are neurologic disorders characterized by prominent lower-extremity spasticity, resulting from a length-dependent axonopathy of corticospinal upper motor neurons. They are among the most genetically-diverse neurologic disorders, with >80 distinct genetic loci and over 60 identified genes. Studies investigating the molecular pathogenesis underlying HSPs have emphasized the importance of converging cellular pathogenic themes in the most common forms of HSP, providing compelling targets for therapy. Most notably, these include organelle shaping and biogenesis as well as membrane and cargo trafficking. Published by Elsevier Ltd.

Handwriting and fine motor problems after treatment for acute lymphoblastic leukemia

NARCIS (Netherlands)

Reinders-Messelink, H.A.; Schoemaker, M.M.; Goeken, L.N H; van den Briel, M.M.; Kamps, W.A; Simner, M L; Leedham, C G; Thomassen, A J W M

1996-01-01

Fine motor skills and handwriting performance were investigated in 17 children at least two years after treatment for acute lymphoblastic leukemia. It was hypothesized that as a late effect of vincristine neuropathy, children would still have fine motor and/or handwriting problems. Gross and fine

A Case of Paraneoplastic Demyelinating Motor Polyneuropathy

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Sohrab Mostoufizadeh

2012-04-01

Full Text Available Peripheral neuropathy is commonly accompanied by cancer but demyelinating ones are not commonly reported. We report the clinical, neurophysiological, and biological characteristics of an 82-year-old patient who presented with a demyelinating motor neuropathy and high titre of anti-ganglioside antibodies associated with oesophageal cancer. The neurological course worsened rapidly despite immunotherapy, leading to a bedridden status. We propose to suspect a paraneoplastic origin in older patients or when the clinical course progresses rapidly within a few weeks or months.

Niceritrol prevents the decrease in red blood cell 2,3-diphosphoglycerate and neuropathy in streptozotocin-induced diabetic rats.

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Hotta, N; Nakamura, J; Kakuta, H; Fukasawa, H; Koh, N; Sakakibara, F; Mori, K; Sakamoto, N

1995-01-01

Nerve ischemia/hypoxia has been linked to the pathogenesis of diabetic complications. Red blood cell 2,3-diphosphoglycerate is an important regulator of peripheral tissue oxygenation; however, the relationship between 2,3-diphosphoglycerate concentration and diabetic complications has not been studied in detail. This investigation focused on the relationship between red blood cell 2,3-diphosphoglycerate and diabetic neuropathy, by measuring motor nerve conduction velocity and sciatic nerve blood flow in streptozotocin-induced diabetic rats. The effect of treatment with niceritrol, a nicotinic acid derivative that acts as a vasodilator and reduces serum lipid concentrations, on 2,3-diphosphoglycerate concentration and diabetic neuropathy was also examined. Untreated diabetic rats had significantly lower concentrations of red blood cell 2,3-diphosphoglycerate, higher concentrations of serum total cholesterol and triglyceride, as well as reduced motor nerve conduction velocity and sciatic nerve blood flow, compared to untreated normal rats. Niceritrol prevented these abnormalities without correcting hyperglycemia in diabetic rats, but had no effect on these parameters in normal rats. Red blood cell 2,3-diphosphoglycerate concentration and motor nerve conduction velocity showed a positive correlation with sciatic nerve blood flow and 2,3-diphosphoglycerate, respectively. These observations suggest that ischemia/hypoxia plays an important role in the development of diabetic neuropathy, and that niceritrol has a therapeutic effect on this condition by improving endoneurial ischemia/hypoxia.

Follow-up of Thalidomide treatment in patients with Hereditary Haemorrhagic Telangiectasia.

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Hosman, A; Westermann, C J J; Snijder, R; Disch, F; Mummery, C L; Mager, J J

2015-12-01

Patients with a hereditary vascular disorder called Rendu-Osler-Weber syndrome (Hereditary Haemorrhagic Telangiectasia, HHT) haemorrhage easily due to weak-walled vessels. Haemorrhage in lungs or brain can be fatal but patients suffer most from chronic and prolonged nosebleeds (epistaxis), the frequency and intensity of which increases with age. Several years ago, it was discovered serendipitously that the drug Thalidomide had beneficial effects on the disease symptoms in several of a small group of HHT patients: epistaxis and the incidence of anaemia were reduced and patients required fewer blood transfusions. In addition, they reported a better quality of life. However, Thalidomide has significant negative side effects, including neuropathy and fatigue. We followed up all HHT patients in the Netherlands who had been taking Thalidomide at the time the original study was completed to find out (i) how many had continued taking Thalidomide and for how long (ii) the nature and severity of any side-effects and (iii) whether side-effects had influenced their decision to continue taking Thalidomide. Only a minority of patients had continued taking the drug despite its beneficial effects on their symptoms and that the side effects were the primary reason to stop. Despite symptom reduction, alternative treatments are still necessary for epistaxis in HHT patients and a large-scale clinical trial is not justified although incidental use in the most severely affected patients can be considered.

Does calf muscle spasticity contribute to postural imbalance? A study in persons with pure hereditary spastic paraparesis

NARCIS (Netherlands)

Niet, M. de; Weerdesteyn, V.G.M.; Bot, S.T. de; Warrenburg, B.P.C. van de; Geurts, A.C.H.

2013-01-01

OBJECTIVES: The contribution of spasticity to postural imbalance in patients with upper motor neuron syndrome is still unclear. This study aimed to evaluate the responses to support-surface perturbations in patients with hereditary spastic paraparesis (HSP). These patients typically suffer from

Genetics Home Reference: hereditary pancreatitis

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... Facebook Twitter Home Health Conditions Hereditary pancreatitis Hereditary pancreatitis Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Hereditary pancreatitis is a genetic condition characterized by recurrent episodes ...

Hereditary spastic paraplegia.

Science.gov (United States)

Blackstone, Craig

2018-01-01

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurologic disorders with the common feature of prominent lower-extremity spasticity, resulting from a length-dependent axonopathy of corticospinal upper motor neurons. The HSPs exist not only in "pure" forms but also in "complex" forms that are associated with additional neurologic and extraneurologic features. The HSPs are among the most genetically diverse neurologic disorders, with well over 70 distinct genetic loci, for which about 60 mutated genes have already been identified. Numerous studies elucidating the molecular pathogenesis underlying HSPs have highlighted the importance of basic cellular functions - especially membrane trafficking, mitochondrial function, organelle shaping and biogenesis, axon transport, and lipid/cholesterol metabolism - in axon development and maintenance. An encouragingly small number of converging cellular pathogenic themes have been identified for the most common HSPs, and some of these pathways present compelling targets for future therapies. Copyright © 2018 Elsevier B.V. All rights reserved.

A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.

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Hornemann, Thorsten; Penno, Anke; Richard, Stephane; Nicholson, Garth; van Dijk, Fleur S; Rotthier, Annelies; Timmerman, Vincent; von Eckardstein, Arnold

2009-04-01

Hereditary sensory neuropathy type 1 (HSAN I) is an autosomal dominant inherited neurodegenerative disorder of the peripheral nervous system associated with mutations in the SPTLC1 subunit of the serine palmitoyltransferase (SPT). Four missense mutations (C133W, C133Y, V144D and G387A) in SPTLC1 were reported to cause HSAN I. SPT catalyses the condensation of Serine and Palmitoyl-CoA, which is the first and rate-limiting step in the de novo synthesis of ceramides. Earlier studies showed that C133W and C133Y mutants have a reduced activity, whereas the impact of the V144D and G387A mutations on the human enzyme was not tested yet. In this paper, we show that none of the HSAN I mutations interferes with SPT complex formation. We demonstrate that also V144D has a reduced SPT activity, however to a lower extent than C133W and C133Y. In contrast, the G387A mutation showed no influence on SPT activity. Furthermore, the growth phenotype of LY-B cells--a SPTLC1 deficient CHO cell line--could be reversed by expressing either the wild-type SPTLC1 or the G387A mutant, but not the C133W mutant. This indicates that the G387A mutation is most likely not directly associated with HSAN I. These findings were genetically confirmed by the identification of a nuclear HSAN family which showed segregation of the G387A variant as a non-synonymous SNP.

PERIPHERAL NEUROPATHY ELECTROPHYSIOLOGICAL SCREENING IN CHILDREN WITH CELIAC DISEASE

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Şedat IŞIKAY

2015-06-01

Full Text Available Background The involvement of the peripheral nervous system in children with celiac disease is particularly rare. Objective The aim of this study was to assess the need for neurophysiological testing in celiac disease patients without neurological symptoms in order to detect early subclinical neuropathy and its possible correlations with clinical and demographic characteristics. Methods Two hundred and twenty consecutive children with celiac disease were screened for neurological symptoms and signs, and those without symptoms or signs were included. Also, patients with comorbidities associated with peripheral neuropathy or a history of neurological disease were excluded. The remaining 167 asymptomatic patients as well as 100 control cases were tested electro-physiologically for peripheral nervous system diseases. Motor nerve conduction studies, including F-waves, were performed for the median, ulnar, peroneal, and tibial nerves, and sensory nerve conduction studies were performed for the median, ulnar, and sural nerves with H reflex of the soleus muscle unilaterally. All studies were carried out using surface recording electrodes. Normative values established in our laboratory were used. Results Evidence for subclinical neuropathy was not determined with electrophysiological studies in any of the participants. Conclusion In this highly selective celiac disease group without any signs, symptoms as well as the predisposing factors for polyneuropathy, we did not determine any cases with neuropathy. With these results we can conclude that in asymptomatic cases with celiac disease electrophysiological studies are not necessary. However, larger studies with the electrophysiological studies performed at different stages of disease at follow-ups are warranted.

The vasculitic neuropathies: an update.

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Collins, Michael P

2012-10-01

Vasculitic neuropathy is a heterogeneous disorder that usually occurs in systemic diseases, but less commonly appears as nonsystemic vasculitic neuropathy (NSVN). This review is intended to highlight recent developments in the field of vasculitic neuropathies. A Peripheral Nerve Society guideline provides data-driven consensus recommendation on classification of vasculitic neuropathies and diagnosis/treatment of NSVN. NSVN is sometimes accompanied by subclinical inflammation of adjacent skin. Amyotrophic lateral sclerosis with sensory involvement can mimic NSVN. Systemic vasculitides with neuropathy include polyarteritis nodosa, microscopic polyangiitis (MPA), rheumatoid vasculitis, Churg-Strauss syndrome (CSS), and hepatitis C-related mixed cryoglobulinemic vasculitis (MCV). At autopsy, MPA affects limb nerves diffusely, with maximal damage in proximal/middle segments. CSS can be accompanied by antineutrophil cytoplasmic antibodies (ANCAs), but most patients with neuropathy lack ANCAs. Cryoglobulinemic neuropathies are usually caused by vasculitis, irrespective of phenotype. Two randomized trials revealed rituximab to be noninferior to cyclophosphamide for inducing remission in ANCA-associated vasculitis. Many reports also document efficacy of rituximab in MCV. Consensus guidelines on NSVN should be evaluated prospectively. MPA-associated vasculitic neuropathy results from vasculitic lesions distributed diffusely throughout peripheral extremity nerves. Rituximab is effective for ANCA-associated and cryoglobulinemic vasculitis with neuropathy.

Regulation of the neuropathy-associated Pmp22 gene by a distal super-enhancer.

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Pantera, Harrison; Moran, John J; Hung, Holly A; Pak, Evgenia; Dutra, Amalia; Svaren, John

2018-05-16

Peripheral nerve myelination is adversely affected in the most common form of the hereditary peripheral neuropathy called Charcot-Marie-Tooth Disease. This form, classified as CMT1A, is caused by a 1.4 Mb duplication on chromosome 17, which includes the abundantly expressed Schwann cell myelin gene, Peripheral Myelin Protein 22 (PMP22). This is one of the most common copy number variants causing neurological disease. Overexpression of Pmp22 in rodent models recapitulates several aspects of neuropathy, and reduction of Pmp22 in such models results in amelioration of the neuropathy phenotype. Recently we identified a potential super-enhancer approximately 90-130 kb upstream of the Pmp22 transcription start sites. This super-enhancer encompasses a cluster of individual enhancers that have the acetylated histone H3K27 active enhancer mark, and coincides with smaller duplications identified in patients with milder CMT1A-like symptoms, where the PMP22 coding region itself was not part of the duplication. In this study, we have utilized genome editing to create a deletion of this super-enhancer to determine its role in Pmp22 regulation. Our data show a significant decrease in Pmp22 transcript expression using allele-specific internal controls. Moreover, the P2 promoter of the Pmp22 gene, which is used in other cell types, is affected, but we find that the Schwann cell-specific P1 promoter is disproportionately more sensitive to loss of the super-enhancer. These data show for the first time the requirement of these upstream enhancers for full Pmp22 expression.

Multiple Cranial Neuropathies Without Limb Involvements: Guillain-Barre Syndrome Variant?

OpenAIRE

Yu, Ju Young; Jung, Han Young; Kim, Chang Hwan; Kim, Hyo Sang; Kim, Myeong Ok

2013-01-01

Acute multiple cranial neuropathies are considered as variant of Guillain-Barre syndrome, which are immune-mediated diseases triggered by various cases. It is a rare disease which is related to infectious, inflammatory or systemic diseases. According to previous case reports, those affected can exhibit almost bilateral facial nerve palsy, then followed by bulbar dysfunctions (cranial nerves IX and X) accompanied by limb weakness and walking difficulties due to motor and/or sensory dysfunction...

Alphabet soup: making sense of genetic testing in CMT.

Science.gov (United States)

Lawson, Victoria; Gharibshahi, Shahram

2010-09-01

The diagnosis of inherited neuropathies can be challenging in several ways. First, a hereditary neuropathy must be suspected. Although some family histories are clear with multiple members affected, other families require directed inquiry. Second, even when a hereditary neuropathy is clear, it can be difficult to make a genetic characterization. The field of genotyping is expanding so rapidly, it is difficult to know what tests to order. The authors share their guidelines for the diagnosis of inherited neuropathies. © Thieme Medical Publishers.

Demyelinating polyneuropathy with focally folded myelin sheaths in a family of Miniature Schnauzer dogs.

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Vanhaesebrouck, An E; Couturier, Jérôme; Cauzinille, Laurent; Mizisin, Andrew P; Shelton, G Diane; Granger, Nicolas

2008-12-15

A spontaneous demyelinating polyneuropathy in two young Miniature Schnauzer dogs was characterized clinically, electrophysiologically and histopathologically. Both dogs were related and a third dog, belonging to the same family, had similar clinical signs. On presentation, clinical signs were restricted to respiratory dysfunction. Electrophysiological tests showed a dramatic decrease in both motor and sensory nerve conduction velocities. Microscopic examination of peripheral nerve biopsies (light and electron microscopy, teased nerve fibers), showed that this neuropathy was characterized by segmental demyelination and focally folded myelin sheaths. Various clinical syndromes associated with tomacula or focal thickening of the myelin sheath of the peripheral nerves have been described in humans and shown to be caused by gene mutations affecting the myelin proteins, such as the hereditary neuropathy with liability to pressure palsies or the demyelinating forms of Charcot-Marie-Tooth disease. In animals, a tomaculous neuropathy has been reported in cattle and chickens but not in carnivores. Here we report a demyelinating peripheral neuropathy with tomacula in two Miniature Schnauzer dogs.

Genetic and phenotypic characterization of complex hereditary spastic paraplegia

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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

cases, next 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

Peripheral nerve disorder

Institute of Scientific and Technical Information of China (English)

1993-01-01

930185 Hereditary motor and sensory neu-ropathy.GUO Yupu(郭玉璞),et al.Dept Neu-rol,PUMC Hosp Beijing,100730.Chin J Neurol& Psychiat 1992;25(5):261-263.The report consisted of 10 cases of hereditarymotor and sensory neuropathy(HMSN).Therewere 7 males and 3 females.Their ages rangedfrom 11 to 42(average 24.6)years,and ages ofonset varied from 7 to 34(average 17.3)years.Hereditary history was showed in 4 cases.Theclinical features of all 10 cases had peronealmuscular atrophy 8 of 10 cases also had involve-ment of the upper limbs,and 7 of 10 cases hadpesarcuatus.The conduction velocity was obvi-ously slow in 5 cases and slightly slow in the

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...

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, pdifferential diagnosis of ALS/LMND and MMN. It might be superior to NCS in the diagnosis of MMN in hospital-admitted patients with this differential diagnosis.

iPSC-derived Insights into Motor Neuron Disease and Inflammatory Neuropathies

NARCIS (Netherlands)

Härschnitz, O.

2017-01-01

The proper function of the motor circuit is essential for normal interaction as a human being with external cues. While the motor circuit consists of a variety of cell types, one of its core components is the motor neuron itself. Dysfunction of motor neurons is a hallmark of many neuromuscular

Peripheral Neuropathy in Spinocerebellar Ataxia Type 1, 2, 3, and 6.

Science.gov (United States)

Linnemann, Christoph; Tezenas du Montcel, Sophie; Rakowicz, Maryla; Schmitz-Hübsch, Tanja; Szymanski, Sandra; Berciano, Jose; van de Warrenburg, Bart P; Pedersen, Karine; Depondt, Chantal; Rola, Rafal; Klockgether, Thomas; García, Antonio; Mutlu, Gurkan; Schöls, Ludger

2016-04-01

Spinocerebellar ataxias (SCAs) are characterized by autosomal dominantly inherited progressive ataxia but are clinically heterogeneous due to variable involvement of non-cerebellar parts of the nervous system. Non-cerebellar symptoms contribute significantly to the burden of SCAs, may guide the clinician to the underlying genetic subtype, and might be useful markers to monitor disease. Peripheral neuropathy is frequently observed in SCA, but subtype-specific features and subclinical manifestations have rarely been evaluated. We performed a multicenter nerve conduction study with 162 patients with genetically confirmed SCA1, SCA2, SCA3, and SCA6. The study proved peripheral nerves to be involved in the neurodegenerative process in 82 % of SCA1, 63 % of SCA2, 55 % of SCA3, and 22 % of SCA6 patients. Most patients of all subtypes revealed affection of both sensory and motor fibers. Neuropathy was most frequently of mixed type with axonal and demyelinating characteristics in all SCA subtypes. However, nerve conduction velocities of SCA1 patients were slower compared to other genotypes. SCA6 patients revealed less axonal damage than patients with other subtypes. No influence of CAG repeat length or biometric determinants on peripheral neuropathy could be identified in SCA1, SCA3, and SCA6. In SCA2, earlier onset and more severe ataxia were associated with peripheral neuropathy. We proved peripheral neuropathy to be a frequent site of the neurodegenerative process in all common SCA subtypes. Since damage to peripheral nerves is readily assessable by electrophysiological means, nerve conduction studies should be performed in a longitudinal approach to assess these parameters as potential progression markers.

Peripheral Neuropathy and Agent Orange

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... Enter ZIP code here Enter ZIP code here Peripheral Neuropathy and Agent Orange VA presumes Veterans' early-onset ... 10 percent disabling by VA's rating regulations. About peripheral neuropathy Peripheral neuropathy is a condition of the peripheral ...

Peripheral Neuropathy: Symptoms and Signs

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... Utah Research News Make a Difference Symptoms of Peripheral Neuropathy Print This Page Peripheral Neuropathy symptoms usually start ... more slowly over many years. The symptoms of peripheral neuropathy often include: A sensation of wearing an invisible “ ...

Biofeedback for foot offloading in diabetic patients with peripheral neuropathy.

Science.gov (United States)

Pataky, Z; de León Rodriguez, D; Allet, L; Golay, A; Assal, M; Assal, J-P; Hauert, C-A

2010-01-01

The reduction of high plantar pressure in diabetic patients with peripheral neuropathy is mandatory for prevention of foot ulcers and amputations. We used a new biofeedback-based method to reduce the plantar pressure at an at-risk area of foot in diabetic patients with peripheral neuropathy. Thirteen diabetic patients (age 60.8 +/- 12.3 years, body mass index 29.0 +/- 5.0 kg/m(2)) with peripheral neuropathy of the lower limbs were studied. Patients with memory impairment were excluded. The portable in-shoe foot pressure measurement system (PEDAR) was used for foot offloading training by biofeedback. The learning procedure consisted in sequences of walking (10 steps), each followed by a subjective estimation of performance and objective feedback. The goal was to achieve three consecutive walking cycles of 10 steps, with a minimum of seven steps inside the range of 40-80% of the baseline peak plantar pressure. The peak plantar pressure was assessed during the learning period and at retention tests. A significant difference in peak plantar pressure was recorded between the beginning and the end of the learning period (when the target for plantar pressure was achieved) (262 +/- 70 vs. 191 +/- 53 kPa; P = 0.002). The statistically significant difference between the beginning of learning and all retention tests persisted, even at the 10-day follow-up. Terminal augmented feedback training may positively affect motor learning in diabetic patients with peripheral neuropathy and could possibly lead to suitable foot offloading. Additional research is needed to confirm the maintenance of offloading in the long term.

Imaging of neuropathies about the hip

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Martinoli, Carlo, E-mail: carlo.martinoli@unige.it [Radiologia – DISC, Università di Genova, Largo Rosanna Benzi 8, I-16132 Genoa (Italy); Miguel-Perez, Maribel [Unit of Human Anatomy and Embryology, Department of Pathology and Experimental Therapy, Faculty of Medicine (C Bellvitge), University of Barcelona, Barcelona (Spain); Padua, Luca [Fondazione Don Gnocchi Onlus and Department of Neurology, Policlinico “A. Gemelli”, Università Cattolica del Sacro Cuore, Rome (Italy); Gandolfo, Nicola [IM2S – Institut Monégasque de Médecine and Chirurgie Sportive, Montecarlo (Monaco); Zicca, Anna [Radiologia – DISC, Università di Genova, Largo Rosanna Benzi 8, I-16132 Genoa (Italy); Tagliafico, Alberto [Radiologia – National Institute for Cancer Research, Genoa (Italy)

2013-01-15

Neuropathies about the hip may be cause of chronic pain and disability. In most cases, these conditions derive from mechanical or dynamic compression of a segment of a nerve within a narrow osteofibrous tunnel, an opening in a fibrous structure, or a passageway close to a ligament or a muscle. Although the evaluation of nerve disorders primarily relies on neurological examination and electrophysiology, diagnostic imaging is currently used as a complement to help define the site and aetiology of nerve compression and exclude other disease possibly underlying the patient’ symptoms. Diagnosis of entrapment neuropathies about the hip with US and MR imaging requires an in-depth knowledge of the normal imaging anatomy and awareness of the anatomic and pathologic factors that may predispose or cause a nerve injury. Accordingly, the aim of this article is to provide a comprehensive review of hip neuropathies with an emphasis on the relevant anatomy, aetiology, clinical presentation, and their imaging appearance. The lateral femoral cutaneous neuropathy (meiralgia paresthetica), femoral neuropathy, sciatic neuropathy, obturator neuropathy, superior and inferior gluteal neuropathies and pudendal neuropathy will be discussed.

Diagnostic value of combined magnetic resonance imaging examination of brachial plexus and electrophysiological studies in multifocal motor neuropathy

Directory of Open Access Journals (Sweden)

Basta Ivana

2014-01-01

Full Text Available Background/Aim. Multifocal motor neuropathy (MMN is an immune-mediated disorder characterized by slowly progressive asymetrical weakness of limbs without sensory loss. The objective of this study was to investigate the involvement of brachial plexus using combined cervical magnetic stimulation and magnetic resonance imaging (MRI of plexus brachialis in patients with MMN. We payed special attention to the nerve roots forming nerves inervating weak muscles, but without detectable conduction block (CB using conventional nerve conduction studies. Methods. Nine patients with proven MMN were included in the study. In all of them MRI of the cervical spine and brachial plexus was performed using a Siemens Avanto 1.5 T unit, applying T1 and turbo spinecho T1 sequence, axial turbo spin-echo T2 sequence and a coronal fat-saturated turbo spin-echo T2 sequence. Results. In all the patients severe asymmetric distal weakness of muscles inervated by radial, ulnar, median and peroneal nerves was observed and the most striking presentation was bilateral wrist and finger drop. Three of them had additional proximal weakness of muscles inervated by axillar and femoral nerves. The majority of the patients had slightly increased cerebrospinal fluid (CSF protein content. Six of the patients had positive serum polyclonal IgM anti-GM1 antibodies. Electromyoneurography (EMG showed neurogenic changes, the most severe in distal muscles inervated by radial nerves. All the patients had persistent partial CBs outside the usual sites of nerve compression in radial, ulnar, median and peroneal nerves. In three of the patients cervical magnetic stimulation suggested proximal CBs between cervical root emergence and Erb’s point (prolonged motor root conduction time. In all the patients T2-weighted MRI revealed increased signal intensity in at least one cervical root, truncus or fasciculus of brachial plexus. Conclusion. We found clinical correlation between muscle weakness

Genetics Home Reference: hereditary fructose intolerance

Science.gov (United States)

... Twitter Home Health Conditions Hereditary fructose intolerance Hereditary fructose intolerance Printable PDF Open All Close All Enable ... to view the expand/collapse boxes. Description Hereditary fructose intolerance is a condition that affects a person's ...

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....

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 peripheral...... 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...

Megaloblastic anemia with peripheral neuropathy, a misleading initial presentation in POEMS syndrome: A case report

Directory of Open Access Journals (Sweden)

Iadarilang Tiewsoh

2014-01-01

Full Text Available POEMS (peripheral neuropathy, organomegaly, endocrinopathy, M protein, skin changes syndrome is a rare multisystem paraneoplastic disorder that occurs in the setting of a plasma cell dyscrasia. A 57-year-old male with initial presentation of peripheral neuropathy of lower limbs and a peripheral blood picture of megaloblastic anemia, presented with progressive lower motor neuron weakness over few months; followed by additional features of skin hyperpigmentation, generalized lymphadenopathy, erectile dysfunction, weight loss, and an attack of cerebrovascular accident (stroke infarct which recovered. On further evaluation with time, there were presence of hepatosplenomegaly, Castleman′s disease of the lymph node on biopsy, serum electrophoresis suggestive of monoclonal gammopathy with light band lambda chain, and endocrinopathy (hypothyroidism and hypogonadism. His bone marrow was suggestive of plasmacytosis. This case report describes a patient who presented with initial picture of peripheral neuropathy with megaloblastic anemia, but when followed-up there were diverse clinical manifestations fulfilling the diagnostic clinical criteria of POEMS Syndrome.

Gasoline sniffing multifocal neuropathy.

Science.gov (United States)

Burns, T M; Shneker, B F; Juel, V C

2001-11-01

The polyneuropathy caused by chronic gasoline inhalation is reported to be a gradually progressive, symmetric, sensorimotor polyneuropathy. We report unleaded gasoline sniffing by a female 14 years of age that precipitated peripheral neuropathy. In contrast with the previously reported presentation of peripheral neuropathy in gasoline inhalation, our patient developed multiple mononeuropathies superimposed on a background of sensorimotor polyneuropathy. The patient illustrates that gasoline sniffing neuropathy may present with acute multiple mononeuropathies resembling mononeuritis multiplex, possibly related to increased peripheral nerve susceptibility to pressure in the setting of neurotoxic components of gasoline. The presence of tetraethyl lead, which is no longer present in modern gasoline mixtures, is apparently not a necessary factor in the development of gasoline sniffer's neuropathy.

Functional recovery of regenerating motor axons is delayed in mice heterozygously deficient for the myelin protein P(0) gene

DEFF Research Database (Denmark)

Rosberg, Mette Romer; Alvarez, Susana; Krarup, Christian

2013-01-01

Mice with a heterozygous knock-out of the myelin protein P0 gene (P0+/-) develop a neuropathy similar to human Charcot-Marie-Tooth disease. They are indistinguishable from wild-types (WT) at birth and develop a slowly progressing demyelinating neuropathy. The aim of this study was to investigate...... whether the regeneration capacity of early symptomatic P0+/- is impaired as compared to age matched WT. Right sciatic nerves were lesioned at the thigh in 7-8 months old mice. Tibial motor axons at ankle were investigated by conventional motor conduction studies and axon excitability studies using...... threshold tracking. To evaluate regeneration we monitored the recovery of motor function after crush, and then compared the fiber distribution by histology. The overall motor performance was investigated using Rotor-Rod. P0+/- had reduced compound motor action potential amplitudes and thinner myelinated...

Postural steadiness and ankle force variability in peripheral neuropathy

Science.gov (United States)

Paxton, Roger J.; Feldman-Kothe, Caitlin; Trabert, Megan K.; Hitchcock, Leah N.; Reiser, Raoul F.; Tracy, Brian L.

2015-01-01

Introduction The purpose was to determine the effect of peripheral neuropathy (PN) on motor output variability for ankle muscles of older adults, and the relation between ankle motor variability and postural stability in PN patients. Methods Older adults with (O-PN) and without PN (O), and young adults (Y) underwent assessment of standing postural stability and ankle muscle force steadiness. Results O-PN displayed impaired ankle muscle force control and postural stability compared with O and Y groups. For O-PN, the amplitude of plantarflexor force fluctuations was moderately correlated with postural stability under no-vision conditions (r = 0.54, P = 0.01). Discussion The correlation of variations in ankle force with postural stability in PN suggests a contribution of ankle muscle dyscontrol to the postural instability that impacts physical function for older adults with PN. PMID:26284897

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.

Phenotyping animal models of diabetic neuropathy

DEFF Research Database (Denmark)

Biessels, G J; Bril, V; Calcutt, N A

2014-01-01

NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy...... with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence...

Hereditary pancreatitis for the endoscopist

OpenAIRE

Patel, Milan R.; Eppolito, Amanda L.; Willingham, Field F.

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 trans...

Hereditary angioedema.

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Bracho, Francisco A

2005-11-01

Hereditary angioedema is an autosomal-dominant deficiency of C1 inhibitor--a serpin inhibitor of kallikrein, C1r, C1s, factor XII, and plasmin. Quantitative or qualitative deficiency of C1 inhibitor leads to the generation of vasoactive mediators, most likely bradykinin. The clinical syndrome is repeated bouts of nonpruritic, nonpitting edema of the face, larynx, extermities, and intestinal viscera. Recently, investigators, physicians, and industry have demonstrated a renewed interest in the biology and treatment of hereditary angioedema. Investigators have generated a C1INH-/- mouse model that has demonstrated the importance of the contact activation system for hereditary angioedema-related vascular permeability. An interactive database of mutations is available electronically. Investigators have continued exploration into mRNA/protein levels. The proceedings of a recent workshop have been impressive in the scope and depth. Clinicians have produced consensus documents and expert reviews. The pharmaceutical industry has initiated clinical trails with novel agents. Hereditary angioedema is often misdiagnosed and poorly treated. Diagnosis requires careful medical and family history and the measurement of functional C1 inhibitor and C4 levels. Attenuated androgens, anti-fibrinolytics, and C1 inhibitor concentrates are used for long-term and preprocedure prophylaxis, but have significant drawbacks. C1 inhibitor concentrates and fresh frozen plasma are available for acute intervention. The mainstays of supportive care are airway monitoring, pain relief, hydration, and control of nausea. New agents such as recombinant C1 inhibitor, kallikrein inhibitors, and bradykinin inhibitors may offer safer and more tolerable treatments.

HIV Associated Sensory Neuropathy.

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G, Amruth; S, Praveen-Kumar; B, Nataraju; Bs, Nagaraja

2014-07-01

In the era of highly active antiretroviral therapy, sensory neuropathies have increased in prevalence. We have documented the frequency and profile of the two most common forms of sensory neuropathies associated with Human Immunodeficiency Virus (HIV) infection and looked into clinicoelectrophysiological correlates to differentiate the two entities. The study population comprised of all consecutive patients detected to be HIV positive and attending the Neurology outpatient department (from March 2011 to March 2012) who were aged ≥ 18 years and were able to give informed consent. The data were collected from the patient records (including CD4 counts and treatment details) and questionnaire based interview with each patient. All patients underwent detailed clinical examination and nerve conduction studies (NCSs). Among the total study population of 50 patients, there were 31 men and 19 women. Thirty two patients were in age range of 21 - 40 years and rest were above 40 years. 25 were on antiretroviral therapy (18 on regimen containing zidovudine; seven on regimen containing stavudine). The mean duration of antiretroviral therapy was 16.6±8.4 months. Low CD4 counts ( 40 years. Subclinical neuropathy was common in those on antiretroviral therapy. Axonal neuropathy was the commonest pattern noted in patients who were receiving antiretroviral therapy and demyelinating neuropathy in patients not on antiretroviral therapy. Surprisingly no significant correlation was found between low CD4 counts and symptomatic neuropathy.

Pharmacological Modulation of the Mitochondrial Electron Transport Chain in Paclitaxel-Induced Painful Peripheral Neuropathy.

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Griffiths, Lisa A; Flatters, Sarah J L

2015-10-01

Paclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical hypersensitivity in adult male Sprague Dawley rats. The maximally tolerated dose (5 mg/kg) of rotenone inhibited established paclitaxel-induced mechanical hypersensitivity. However, some of these inhibitory effects coincided with decreased motor coordination; 3 mg/kg rotenone also significantly attenuated established paclitaxel-induced mechanical hypersensitivity without any motor impairment. The maximally tolerated dose (.6 mg/kg) of antimycin A reversed established paclitaxel-induced mechanical hypersensitivity without any motor impairment. Seven daily doses of systemic rotenone or antimycin A were given either after paclitaxel administration or before and during paclitaxel administration. Rotenone had no significant effect on the development of paclitaxel-induced mechanical hypersensitivity. However, antimycin A significantly inhibited the development of paclitaxel-induced mechanical hypersensitivity when given before and during paclitaxel administration but had no effect when given after paclitaxel administration. These studies provide further evidence of paclitaxel-evoked mitochondrial dysfunction in vivo, suggesting that complex III activity is instrumental in paclitaxel-induced pain. This study provides further in vivo evidence that mitochondrial dysfunction is a key contributor to the development and maintenance of chemotherapy-induced painful neuropathy. This work also indicates that selective modulation of the electron transport chain can induce antinociceptive

Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia.

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Martin, Elodie; Schüle, Rebecca; Smets, Katrien; Rastetter, Agnès; Boukhris, Amir; Loureiro, José L; Gonzalez, Michael A; Mundwiller, Emeline; Deconinck, Tine; Wessner, Marc; Jornea, Ludmila; Oteyza, Andrés Caballero; Durr, Alexandra; Martin, Jean-Jacques; Schöls, Ludger; Mhiri, Chokri; Lamari, Foudil; Züchner, Stephan; De Jonghe, Peter; Kabashi, Edor; Brice, Alexis; Stevanin, Giovanni

2013-02-07

Spastic paraplegia 46 refers to a locus mapped to chromosome 9 that accounts for a complicated autosomal-recessive form of hereditary spastic paraplegia (HSP). With next-generation sequencing in three independent families, we identified four different mutations in GBA2 (three truncating variants and one missense variant), which were found to cosegregate with the disease and were absent in controls. GBA2 encodes a microsomal nonlysosomal glucosylceramidase that catalyzes the conversion of glucosylceramide to free glucose and ceramide and the hydrolysis of bile acid 3-O-glucosides. The missense variant was also found at the homozygous state in a simplex subject in whom no residual glucocerebrosidase activity of GBA2 could be evidenced in blood cells, opening the way to a possible measurement of this enzyme activity in clinical practice. The overall phenotype was a complex HSP with mental impairment, cataract, and hypogonadism in males associated with various degrees of corpus callosum and cerebellar atrophy on brain imaging. Antisense morpholino oligonucleotides targeting the zebrafish GBA2 orthologous gene led to abnormal motor behavior and axonal shortening/branching of motoneurons that were rescued by the human wild-type mRNA but not by applying the same mRNA containing the missense mutation. This study highlights the role of ceramide metabolism in HSP pathology. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Prostaglandin E1 in conjunction with high doses of vitamin B12 improves nerve conduction velocity of patients with diabetic peripheral neuropathy

Institute of Scientific and Technical Information of China (English)

Jilai Li; Zhirong Wan

2008-01-01

BACKGROUND: Prostaglandin E1 improves diabetic peripheral neuropathy in symptoms and sensory threshold. Vitamin B1 and methyl-vitamin B12 improve microcirculation to peripheral nerve tissue and promote neurotrophy.OBJECTIVE: To observe motor nerve and sensory nerve conduction velocity in patients with diabetic peripheral neuropathy, prior to and after treatment with prostaglandin E1, vitamin B1 and different doses of vitamin B12.DESIGN, TIME AND SETTING: Randomized, controlled experiment, performed at the Department of Neurology. Beijing Hantian Central Hospital, between February 2002 and September 2007.PARTICIPANTS: A total of 122 patients with type 2 diabetic peripheral neuropathy; 73 males and 49 females were included. All patients met the diagnostic criteria of diabetes mellitus, as determined by the World Health Organization in 1999 and 2006, and also the diagnostic criteria of diabetic peripheral neuropathy. For each subject, conduction disorders in the median nerve and in the common peroneal nerve were observed using electromyogram. Also, after diet and drug treatment, the blood glucose level of subjects was observed to be at a satisfactory level for more than two weeks, and the symptoms of diabetic peripheral neuropathy were not alleviated.METHODS: All patients were randomly divided into the following three groups. A control group (n=40), in which, 100mg vitamin B1 and 500μg vitamin B12 were intramuscularly injected. A vitamin B12 low-dose treated group (n=42), in which 10μg prostaglandin E1 in 250mL physiological saline was intravenously injected once a day and 100mg vitamin B1 and 500μg vitamin B12 was intramuscularly injected once a day. Lastly, a vitamin B12 high-dose treated group (n=40), in which administration was the same as in the vitamin B12 low-dose treated group, except that 500μg vitamin B12 was replaced by 1mg vitamin B12. Administration was performed for four weeks for each group.MAIN OUTCOME MEASURES: The motor nerve and sensory nerve

Treatment strategies for inherited optic neuropathies: past, present and future

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Yu-Wai-Man, P; Votruba, M; Moore, A T; Chinnery, P F

2014-01-01

Bilateral visual loss secondary to inherited optic neuropathies is an important cause of registrable blindness among children and young adults. The two prototypal disorders seen in clinical practice are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 90% of LHON cases are due to one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A, and m.14484T>C, which affect critical complex I subunits of the mitochondrial respiratory chain. The majority of patients with DOA harbour pathogenic mutations within OPA1, a nuclear gene that codes for a multifunctional inner mitochondrial membrane protein. Despite their contrasting genetic basis, LHON and DOA share overlapping pathological and clinical features that serve to highlight the striking tissue-specific vulnerability of the retinal ganglion cell (RGC) layer to disturbed mitochondrial function. In addition to severe visual loss secondary to progressive optic nerve degeneration, a subgroup of patients will also develop a more aggressive syndromic phenotype marked by significant neurological deficits. The management of LHON and DOA remains largely supportive, but major advances in our understanding of the mechanisms underpinning RGC loss in these two disorders are paving the way for novel forms of treatment aimed at halting or reversing visual deterioration at different stages of the disease process. In addition to neuroprotective strategies for rescuing RGCs from irreversible cell death, innovative in vitro fertilisation techniques are providing the tantalising prospect of preventing the germline transmission of pathogenic mtDNA mutations, eradicating in so doing the risk of disease in future generations. PMID:24603424

Autophagy as an Emerging Common Pathomechanism in Inherited Peripheral Neuropathies

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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.

Treatment strategies for inherited optic neuropathies: past, present and future.

Science.gov (United States)

Yu-Wai-Man, P; Votruba, M; Moore, A T; Chinnery, P F

2014-05-01

Bilateral visual loss secondary to inherited optic neuropathies is an important cause of registrable blindness among children and young adults. The two prototypal disorders seen in clinical practice are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 90% of LHON cases are due to one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A, and m.14484T>C, which affect critical complex I subunits of the mitochondrial respiratory chain. The majority of patients with DOA harbour pathogenic mutations within OPA1, a nuclear gene that codes for a multifunctional inner mitochondrial membrane protein. Despite their contrasting genetic basis, LHON and DOA share overlapping pathological and clinical features that serve to highlight the striking tissue-specific vulnerability of the retinal ganglion cell (RGC) layer to disturbed mitochondrial function. In addition to severe visual loss secondary to progressive optic nerve degeneration, a subgroup of patients will also develop a more aggressive syndromic phenotype marked by significant neurological deficits. The management of LHON and DOA remains largely supportive, but major advances in our understanding of the mechanisms underpinning RGC loss in these two disorders are paving the way for novel forms of treatment aimed at halting or reversing visual deterioration at different stages of the disease process. In addition to neuroprotective strategies for rescuing RGCs from irreversible cell death, innovative in vitro fertilisation techniques are providing the tantalising prospect of preventing the germline transmission of pathogenic mtDNA mutations, eradicating in so doing the risk of disease in future generations.

Charcot Marie Tooth 2B Peripheral Sensory Neuropathy: How Rab7 Mutations Impact NGF Signaling?

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Harry Liu

2017-02-01

Full Text Available Charcot-Marie-Tooth 2B peripheral sensory neuropathy (CMT2B is a debilitating autosomal dominant hereditary sensory neuropathy. Patients with this disease lose pain sensation and frequently need amputation. Axonal dysfunction and degeneration of peripheral sensory neurons is a major clinical manifestation of CMT2B. However, the cellular and molecular pathogenic mechanisms remain undefined. CMT2B is caused by missense point mutations (L129F, K157N, N161T/I, V162M in Rab7 GTPase. Strong evidence suggests that the Rab7 mutation(s enhances the cellular levels of activated Rab7 proteins, thus resulting in increased lysosomal activity and autophagy. As a consequence, trafficking and signaling of neurotrophic factors such as nerve growth factor (NGF in the long axons of peripheral sensory neurons are particularly vulnerable to premature degradation. A “gain of toxicity” model has, thus, been proposed based on these observations. However, studies of fly photo-sensory neurons indicate that the Rab7 mutation(s causes a “loss of function”, resulting in haploinsufficiency. In the review, we summarize experimental evidence for both hypotheses. We argue that better models (rodent animals and human neurons of CMT2B are needed to precisely define the disease mechanisms.

Charcot Marie Tooth 2B Peripheral Sensory Neuropathy: How Rab7 Mutations Impact NGF Signaling?

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Liu, Harry; Wu, Chengbiao

2017-02-04

Charcot-Marie-Tooth 2B peripheral sensory neuropathy (CMT2B) is a debilitating autosomal dominant hereditary sensory neuropathy. Patients with this disease lose pain sensation and frequently need amputation. Axonal dysfunction and degeneration of peripheral sensory neurons is a major clinical manifestation of CMT2B. However, the cellular and molecular pathogenic mechanisms remain undefined. CMT2B is caused by missense point mutations (L129F, K157N, N161T/I, V162M) in Rab7 GTPase. Strong evidence suggests that the Rab7 mutation(s) enhances the cellular levels of activated Rab7 proteins, thus resulting in increased lysosomal activity and autophagy. As a consequence, trafficking and signaling of neurotrophic factors such as nerve growth factor (NGF) in the long axons of peripheral sensory neurons are particularly vulnerable to premature degradation. A "gain of toxicity" model has, thus, been proposed based on these observations. However, studies of fly photo-sensory neurons indicate that the Rab7 mutation(s) causes a "loss of function", resulting in haploinsufficiency. In the review, we summarize experimental evidence for both hypotheses. We argue that better models (rodent animals and human neurons) of CMT2B are needed to precisely define the disease mechanisms.

[Automatic analysis of the interference EMG of the brachioradial muscle in neuropathy of the radial nerve].

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Popelianskiĭ, Ia Iu; Bogdanov, E I; Khamidullina, V Z

1988-01-01

In 8 patients with radial neuropathy the authors studied histograms of distribution of potentials of motor units (PMU) by their duration, as well as of the number of intercrossings (T) and the mean amplitude of interference EMG of the musculus brachioradialis. The findings included a decrease in the T value and T/M ratio in the presence of an insignificant shift of the histograms and of the mean duration of PMU. With regard to the diagnosis of early neuropathies a reduction in the average value of T and T/M in the presence of ungraded voluntary tension of the muscle is diagnostically more important than changes in the duration of individual PMU.

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

Burn-related peripheral neuropathy: A systematic review.

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Tu, Yiji; Lineaweaver, William C; Zheng, Xianyou; Chen, Zenggan; Mullins, Fred; Zhang, Feng

2017-06-01

Peripheral neuropathy is the most frequent disabling neuromuscular complication of burns. However, the insidious and progressive onset of burn neuropathy makes it often undiagnosed or overlooked. In our study, we reviewed the current studies on the burn-related peripheral neuropathy to summarize the morbidity, mechanism, detecting method and management of peripheral neuropathy in burn patients. Of the 1533 burn patients included in our study, 98 cases (6.39%) were presented with peripheral neuropathy. Thermal and electrical burns were the most common etiologies. Surgical procedures, especially nerve decompression, showed good effect on functional recovery of both acute and delayed peripheral neuropathy in burn patients. It is noteworthy that, for early detection and prevention of peripheral neuropathy, electrodiagnostic examinations should be performed on burn patients independent of symptoms. Still, the underlying mechanisms of burn-related peripheral neuropathy remain to be clarified. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

Thalidomide for Epistaxis in Patients with Hereditary Hemorrhagic Telangiectasia: A Preliminary Study.

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Fang, Jia; Chen, Xiaomeng; Zhu, Bijun; Ye, Haibo; Zhang, Weitian; Guan, Jian; Su, Kaiming

2017-08-01

To evaluate the effectiveness of thalidomide for epistaxis in hereditary hemorrhagic telangiectasia (HHT), 7 HHT patients with recurrent epistaxis were treated with thalidomide at an initial dose of 50 mg/d, gradually increasing to 100 mg/d if needed. The Epistaxis Severity Score (ESS) was used to evaluate the treatment effects. Patients reported that epistaxis improved 1 to 3 weeks after starting thalidomide. The mean ESS before treatment, at the end of treatment, and 3 months after stopping treatment was 5.03 ± 2.05, 0.90 ± 0.84 ( P = .003), and 1.98 ± 1.33 ( P = .006), respectively. Four patients reported mild to moderate side effects, including drowsiness, dizziness, constipation, nausea, and peripheral neuropathy. Two patients stopped the treatment because of adverse effects. Those results showed that thalidomide may be a treatment choice for recurrent epistaxis in HHT patients, although the side effects should be considered. Further study should focus on guidelines for dosing and course and investigate how to reduce the adverse effects.

Hereditary forms of breast cancer

International Nuclear Information System (INIS)

Bella, V.

2009-01-01

Breast cancer is the most common oncologic disease in the female population. Besides the sporadic occurrence it occurs in the familial and hereditary form. Persons with the occurrence of positive family anamnesis of breast cancer should be actively investigated. In the indicated cases it is necessary to send the woman to genetic examination. In case that the hereditary form of breast cancer is affirmed it is necessary to examine her family relatives. Women with the hereditary form of breast cancer occur in about 5 – 10 % portion from all women diagnosed with breast cancer. Nowadays we already know that 80 % of hereditary breast cancers are due to germ mutations in BRCA 1 and BRCA 2 gene. Persons with detected gene mutations must be dispensarized in the centres intended for it. (author)

Proteomic analysis in giant axonal neuropathy: new insights into disease mechanisms.

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Mussche, Silke; De Paepe, Boel; Smet, Joél; Devreese, Katrien; Lissens, Willy; Rasic, Vedrana Milic; Murnane, Matthew; Devreese, Bart; Van Coster, Rudy

2012-08-01

Giant axonal neuropathy (GAN) is a progressive hereditary disease that affects the peripheral and central nervous systems. It is characterized morphologically by aggregates of intermediate filaments in different tissues. Mutations have been reported in the gene that codes for gigaxonin. Nevertheless, the underlying molecular mechanism remains obscure. Cell lines from 4 GAN patients and 4 controls were analyzed by iTRAQ. Among the dysregulated proteins were ribosomal protein L29, ribosomal protein L37, galectin-1, glia-derived nexin, and aminopeptidase N. Also, nuclear proteins linked to formin-binding proteins were found to be dysregulated. Although the major role of gigaxonin is reported to be degradation of cytoskeleton-associated proteins, the amount of 76 structural cytoskeletal proteins was unaltered. Several of the dysregulated proteins play a role in cytoskeletal reorganization. Based on these findings, we speculate that disturbed cytoskeletal regulation is responsible for formation of aggregates of intermediate filaments. Copyright © 2012 Wiley Periodicals, Inc.

Peripheral neuropathy associated with mitochondrial disease in children.

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Menezes, Manoj P; Ouvrier, Robert A

2012-05-01

Mitochondrial diseases in children are often associated with a peripheral neuropathy but the presence of the neuropathy is under-recognized because of the overwhelming involvement of the central nervous system (CNS). These mitochondrial neuropathies are heterogeneous in their clinical, neurophysiological, and histopathological characteristics. In this article, we provide a comprehensive review of childhood mitochondrial neuropathy. Early recognition of neuropathy may help with the identification of the mitochondrial syndrome. While it is not definite that the characteristics of the neuropathy would help in directing genetic testing without the requirement for invasive skin, muscle or liver biopsies, there appears to be some evidence for this hypothesis in Leigh syndrome, in which nuclear SURF1 mutations cause a demyelinating neuropathy and mitochondrial DNA MTATP6 mutations cause an axonal neuropathy. POLG1 mutations, especially when associated with late-onset phenotypes, appear to cause a predominantly sensory neuropathy with prominent ataxia. The identification of the peripheral neuropathy also helps to target genetic testing in the mitochondrial optic neuropathies. Although often subclinical, the peripheral neuropathy may occasionally be symptomatic and cause significant disability. Where it is symptomatic, recognition of the neuropathy will help the early institution of rehabilitative therapy. We therefore suggest that nerve conduction studies should be a part of the early evaluation of children with suspected mitochondrial disease. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.

Treatment options in painful diabetic neuropathy.

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Nash, T P

1999-01-01

Diabetic neuropathy is common in patients with diabetes mellitus, and 7.5% of diabetics experience pain from diabetic neuropathy. Complications of diabetes mellitus are more common where control of the disease is not optimal. By improving the control of the disease, both the neuropathy and the pain it can produce may be improved. The pain of diabetic neuropathy can frequently be controlled using analgesics, antidepressants, anticonvulsants, topical capsaicin, and neuromodulation, either alone or in any combination.

An Inversion Disrupting FAM134B Is Associated with Sensory Neuropathy in the Border Collie Dog Breed

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Oliver P. Forman

2016-09-01

Full Text Available Sensory neuropathy in the Border Collie is a severe neurological disorder caused by the degeneration of sensory and, to a lesser extent, motor nerve cells with clinical signs starting between 2 and 7 months of age. Using a genome-wide association study approach with three cases and 170 breed matched controls, a suggestive locus for sensory neuropathy was identified that was followed up using a genome sequencing approach. An inversion disrupting the candidate gene FAM134B was identified. Genotyping of additional cases and controls and RNAseq analysis provided strong evidence that the inversion is causal. Evidence of cryptic splicing resulting in novel exon transcription for FAM134B was identified by RNAseq experiments. This investigation demonstrates the identification of a novel sensory neuropathy associated mutation, by mapping using a minimal set of cases and subsequent genome sequencing. Through mutation screening, it should be possible to reduce the frequency of or completely eliminate this debilitating condition from the Border Collie breed population.

Neuropathy-specific alterations in a Mexican population of diabetic patients.

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Carbajal-Ramírez, Angélica; García-Macedo, Rebeca; Díaz-García, Carlos Manlio; Sanchez-Soto, Carmen; Padrón, Araceli Méndez; de la Peña, Jorge Escobedo; Cruz, Miguel; Hiriart, Marcia

2017-08-25

Neuropathy is one of the major complications of type 2 diabetes mellitus. Our first aim was to determine the clinical characteristics of a population of diabetic patients with different types of neuropathy. Our next goal was to characterize the cytokine profile (IL-6 and IL-10), nerve growth factor (NGF) and circulating cell-adhesion molecules in these patients. Finally, we aimed to compare the renal function among the groups of neuropathic patients. In a cross-sectional study, we included 217 diabetic patients classified in three groups: sensory polyneuropathy with hypoesthesia (DS h P) or hyperesthesia (DS H P), and motor neuropathy (DMN). Two control groups were included: one of 26 diabetic non-neuropathic patients (DNN), and the other of 375 non-diabetic (ND) healthy subjects. The participants were attending to the Mexican Institute of Social Security. The circulating levels of NGF were significantly lower in diabetic patients, compared to healthy subjects. The range of IL-6 and IL-10 levels in neuropathic patients was higher than the control groups; however, several samples yielded null measurements. Neuropathic patients also showed increased circulating levels of the adhesion molecules ICAM, VCAM, and E-Selectin, compared to the ND group. Moreover, neuropathic patients showed reduced glomerular filtration rates compared to healthy subjects (82-103 ml/min per 1.73 m 2 , data as range from 25th-75th percentiles), especially in the group with DMN (45-76 ml/min per 1.73 m 2 ). Some particular alterations in neuropathic patients included -but were not limited to- changes in circulating NGF, cell adhesion molecules, inflammation, and the worsening of the renal function. This study supports the need for further clinical surveillance and interventions considering a neuropathy-related basis.

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

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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.)

BRCA1/2 associated hereditary breast cancer

Institute of Scientific and Technical Information of China (English)

Li-song TENG; Yi ZHENG; Hao-hao WANG

2008-01-01

Breast cancer is one of the leading causes of death in women today. Some of the patients are hereditary, with a large proportion characterized by mutation in BRCA1 and/or BRCA2 genes. In this review, we provide an overview of these two genes,focusing on their relationship with hereditary breast cancers. BRCA1/2 associated hereditary breast cancers have unique features that differ from the general breast cancers, including alterations in cellular molecules, pathological bases, biological behavior, and a different prevention strategy. But the outcome of BRCA1/2 associated hereditary breast cancers still remains controversial;further studies are needed to elucidate the nature of BRCA1/2 associated hereditary breast cancers.

Electrochemical skin conductance to detect sudomotor dysfunction, peripheral neuropathy and the risk of foot ulceration among Saudi patients with diabetes mellitus.

Science.gov (United States)

Sheshah, Eman; Madanat, Amal; Al-Greesheh, Fahad; Al-Qaisi, Dalal; Al-Harbi, Mohammad; Aman, Reem; Al-Ghamdi, Abdul Aziz; Al-Madani, Khaled

2015-01-01

Sudomotor dysfunction is manifested clinically as abnormal sweating leading to dryness of feet skin and increased risk of foot ulceration. The aim of this study was to test the performance of foot electrochemical skin conductance (ESC) to detect diabetic peripheral neuropathy and the risk of foot ulceration against traditional methods in Saudi patients with diabetes mellitus. This cross-sectional study was conducted on 296 Saudi patients with diabetes mellitus. Painful neuropathic symptoms were evaluated using the neuropathy symptom score (NSS). The risk of foot ulceration and diabetic peripheral neuropathy were determined using the neuropathy disability score (NDS). Vibration perception threshold (VPT) was assessed using neurothesiometer. Neurophysiological assessment of the right and left sural, peroneal and tibial nerves was performed in 222 participants. Diabetic peripheral neuropathy was defined according to the definition of the American Academy of Neurology. ESC was measured with Sudoscan. Feet-ESC decreased as the scores of sensory and motor function tests increased. Feet-ESC decreased as the NSS, NDS and severity of diabetic peripheral neuropathy increased. Sensitivity of feet-ESC peripheral neuropathy assessed by VPT ≥ 25 V, NDS ≥ 3, NDS ≥ 6 was 90.1, 61 and 63.8 % respectively and specificity 77, 85 and 81.9 % respectively. Sensitivity of feet-ESC peripheral neuropathy assessed by VPT ≥ 25 V, NDS ≥ 3, NDS ≥ 6 was 100, 80.6 and 80.9 % respectively. Sensitivity and specificity of feet-ESC peripheral neuropathy were 67.5 and 58.9 % respectively. Sudoscan a simple and objective tool can be used to detect diabetic peripheral neuropathy and the risk of foot ulceration among patients with diabetes mellitus. Prospective studies to confirm our results are warranted.

Hyperacute peripheral neuropathy is a predictor of oxaliplatin-induced persistent peripheral neuropathy.

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Tanishima, Hiroyuki; Tominaga, Toshiji; Kimura, Masamichi; Maeda, Tsunehiro; Shirai, Yasutsugu; Horiuchi, Tetsuya

2017-05-01

Chronic peripheral neuropathy is a major adverse response to oxaliplatin-containing chemotherapy regimens, but there are no established risk factors pertaining to it. We investigated the efficacy of hyperacute peripheral neuropathy (HAPN) as a predictor of oxaliplatin-induced persistent peripheral neuropathy (PPN). Forty-seven cases of stage III colorectal cancer who received adjuvant chemotherapy with oxaliplatin after curative surgery between January 2010 and August 2014 were retrospectively reviewed. HAPN was defined as acute peripheral neuropathy (APN) occurring on day 1 (≤24 h after oxaliplatin infusion) of the first cycle. PPN was defined as neuropathy lasting >1 year after oxaliplatin discontinuation. The average total dose of oxaliplatin was 625.8 mg/m 2 , and the average relative dose intensity was 66.7%. Twenty-two of the 47 patients (46.8%) had PPN and 13 (27.7%) had HAPN. Male sex, treatment for neuropathy, HAPN, and APN were significantly more frequent in patients with PPN (p = 0.013, 0.02, <0.001, and 0.023, respectively). There was no significant difference in the total oxaliplatin dose between patients with and without PPN (p = 0.061). Multivariate analyses revealed total dose of oxaliplatin and HAPN as independent predictors of PPN [p = 0.015; odds ratio (OR) = 1.005, 95% confidence interval (CI), 1.001-1.009 and p = 0.001; OR = 75.307, 5.3-1070.123, respectively]. The total dose of oxaliplatin was relatively lower in patients with HAPN than that in those without HAPN in the PPN-positive group (not significant, p = 0.068). HAPN was found to be a predictor of oxaliplatin-induced PPN.

Gait rehabilitation in a patient affected with Charcot-Marie-Tooth disease associated with pyramidal and cerebellar features and blindness.

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Vinci, Paolo

2003-05-01

Charcot-Marie-Tooth (CMT) disease, an inherited neuropathy characterized by length-dependent degeneration of the motor and sensory nerve fibers with consequent distal muscle atrophy and sensory reduction, can be associated with symptoms and signs of involvement of the central nervous system and/or cranial nerves. We present a patient with relatively severe CMT, cerebellar ataxia, pyramidal involvement, and blindness due to Leber's hereditary optic neuropathy. The patient presented with poor standing and gait, with consequent severe disability. Factors responsible for the patient's functional impairment (plantarflexor failure, footdrop, foot rotation, knee flexor contracture, poor proprioception, cerebellar dysfunction, spastic paraparesis, blindness) were identified and addressed by a rehabilitation management, which included, as a main intervention, ankle stabilization by drop-foot boots instead of ankle-foot orthoses. Improved balance and independent ambulation resulted from rehabilitation.

Diabetic peripheral neuropathy, is it an autoimmune disease?

Science.gov (United States)

Janahi, Noor M; Santos, Derek; Blyth, Christine; Bakhiet, Moiz; Ellis, Mairghread

2015-11-01

Autoimmunity has been identified in a significant number of neuropathies, such as, proximal neuropathies, and autonomic neuropathies associated with diabetes mellitus. However, possible correlations between diabetic peripheral neuropathy and autoimmunity have not yet been fully investigated. This study was conducted to investigate whether autoimmunity is associated with the pathogenesis of human diabetic peripheral neuropathy. A case-control analysis included three groups: 30 patients with diabetic peripheral neuropathy, 30 diabetic control patients without neuropathy, and 30 healthy controls. Blood analysis was conducted to compare the percentages of positive antinuclear antibodies (ANA) between the three groups. Secondary analysis investigated the correlations between the presence of autoimmune antibodies and sample demographics and neurological manifestations. This research was considered as a pilot study encouraging further investigations to take place in the near future. Antinuclear antibodies were significantly present in the blood serum of patients with diabetic peripheral neuropathy in comparison to the control groups (pneuropathy group were 50 times higher when compared to control groups. Secondary analysis showed a significant correlation between the presence of ANA and the neurological manifestation of neuropathy (Neuropathy symptom score, Neuropathy disability score and Vibration Perception Threshold). The study demonstrated for the first time that human peripheral diabetic neuropathy may have an autoimmune aetiology. The new pathogenic factors may lead to the consideration of new management plans involving new therapeutic approaches and disease markers. Copyright © 2015 Elsevier B.V. All rights reserved.

Startle responses in hereditary hyperekplexia

NARCIS (Netherlands)

Tijssen, M. A.; Voorkamp, L. M.; Padberg, G. W.; van Dijk, J. G.

1997-01-01

BACKGROUND: Patients with hereditary hyperekplexia have excessive startle responses that are accompanied by transient stiffness and also continuous stiffness in infancy. A point of mutation has been identified for the major form of hereditary hyperekplexia in the gene encoding the alpha 1 subunit of

Startle responses in hereditary hyperekplexia

NARCIS (Netherlands)

Tijssen, MAJ; Voorkamp, LM; Padberg, GW; vanDijk, JG

Background: Patients with hereditary hyperekplexia have excessive startle responses that are accompanied by transient stiffness and also continuous stiffness in infancy. A point of mutation has been identified for the major form of hereditary hyperekplexia in the gene encoding the alpha 1 subunit of

Guideline of transthyretin-related hereditary amyloidosis for clinicians

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Ando Yukio

2013-02-01

Full Text Available Abstract Transthyretin amyloidosis is a progressive and eventually fatal disease primarily characterized by sensory, motor, and autonomic neuropathy and/or cardiomyopathy. Given its phenotypic unpredictability and variability, transthyretin amyloidosis can be difficult to recognize and manage. Misdiagnosis is common, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. This article aims to help physicians better understand transthyretin amyloidosis—and, specifically, familial amyloidotic polyneuropathy—so they can recognize and manage the disease more easily and discuss it with their patients. We provide guidance on making a definitive diagnosis, explain methods for disease staging and evaluation of disease progression, and discuss symptom mitigation and treatment strategies, including liver transplant and several pharmacotherapies that have shown promise in clinical trials.

Processing of nerve biopsies: a practical guide for neuropathologists.

NARCIS (Netherlands)

Weis, J.; Brandner, S.; Lammens, M.M.Y.; Sommer, C.; Vallat, J.M.

2012-01-01

Nerve biopsy is a valuable tool in the diagnostic work-up of peripheral neuropathies. Currently, major indications include interstitial pathologies such as suspected vasculitis and amyloidosis, atypical cases of inflammatory neuropathy and the differential diagnosis of hereditary neuropathies that

Nerve Regeneration Should Be Highly Valued in the Treatment of Diabetic Peripheral Neuropathy

Institute of Scientific and Technical Information of China (English)

LIANG Xiao-chun

2008-01-01

@@ Diabetic peripheral neuropathy (DPN) is the most common chronic complication of the long-term complications of diabetes, affecting up to 90% of patients during the progress of the disease. Many parts of the nerve system, including the sensory nerves, motor nerves and autonomic nerves, can be affected, leading to various clinical features. DPN leads not only to a great degree of mutilation and death but also to the occurrence and development of other long-term complications in diabetics.

Upper gastrointestinal sensory-motor dysfunction in diabetes mellitus

Science.gov (United States)

Zhao, Jing-Bo; Frøkjær, Jens Brøndum; Drewes, Asbjørn Mohr; Ejskjaer, Niels

2006-01-01

Gastrointestinal (GI) sensory-motor abnormalities are common in patients with diabetes mellitus and may involve any part of the GI tract. Abnormalities are frequently sub-clinical, and fortunately only rarely do severe and life-threatening problems occur. The pathogenesis of abnormal upper GI sensory-motor function in diabetes is incompletely understood and is most likely multi-factorial of origin. Diabetic autonomic neuropathy as well as acute suboptimal control of diabetes has been shown to impair GI motor and sensory function. Morphological and biomechanical remodeling of the GI wall develops during the duration of diabetes, and may contribute to motor and sensory dysfunction. In this review sensory and motility disorders of the upper GI tract in diabetes is discussed; and the morphological changes and biomechanical remodeling related to the sensory-motor dysfunction is also addressed. PMID:16718808

Stem Cell Ophthalmology Treatment Study II

Science.gov (United States)

2018-02-01

Retinal Disease; Age-Related Macular Degeneration; Retinitis Pigmentosa; Stargardt Disease; Optic Neuropathy; Nonarteritic Ischemic Optic Neuropathy; Optic Atrophy; Optic Nerve Disease; Glaucoma; Leber Hereditary Optic Neuropathy; Blindness; Vision Loss Night; Vision Loss Partial; Vision, Low; Retinopathy; Maculopathy; Macular Degeneration; Retina Atrophy

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

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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.

Sildenafil ameliorates long term peripheral neuropathy in type II diabetic mice.

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Lei Wang

Full Text Available Diabetic peripheral neuropathy is a common complication of long-standing diabetes mellitus. To mimic clinical trials in which patients with diabetes enrolled have advanced peripheral neuropathy, we investigated the effect of sildenafil, a specific inhibitor of phosphodiesterase type 5 enzyme, on long term peripheral neuropathy in middle aged male mice with type II diabetes. Treatment of diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db at age 36 weeks with sildenafil significantly increased functional blood vessels and regional blood flow in the sciatic nerve, concurrently with augmentation of intra-epidermal nerve fiber density in the skin and myelinated axons in the sciatic nerve. Functional analysis showed that the sildenafil treatment considerably improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal stimulus sensitivity compared with the saline treatment. In vitro studies showed that mouse dermal endothelial cells (MDE cultured under high glucose levels exhibited significant down regulation of angiopoietin 1 (Ang1 expression and reduction of capillary-like tube formation, which were completely reversed by sildenafil. In addition, incubation of dorsal root ganglia (DRG neurons with conditioned medium harvested from MDE under high glucose levels suppressed neurite outgrowth, where as conditional medium harvested from MDE treated with sildenafil under high glucose levels did not inhibit neurite outgrowth of DRG neurons. Moreover, blockage of the Ang1 receptor, Tie2, with a neutralized antibody against Tie2 abolished the beneficial effect of sildenafil on tube formation and neurite outgrowth. Collectively, our data indicate that sildenafil has a therapeutic effect on long term peripheral neuropathy of middle aged diabetic mice and that improvement of neurovascular dysfunction by sildenafil likely contributes to the amelioration of nerve function. The Ang1/Tie2 signaling pathway may play an important role in these

Protective effect of oryzanol isolated from crude rice bran oil in experimental model of diabetic neuropathy

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Somsuvra B. Ghatak

2012-09-01

Full Text Available Several studies have implicated the involvement of poor glycemic control and oxidative/nitrosative stress in the development of diabetic neuropathic pain, an important microvascular complication affecting more than 50% of diabetic patients. However, lack of understanding of the underlying etiology, development of tolerance, inadequate relief and possible toxicity associated with classical analgesics warrant the investigation of the novel agents. Therefore, the present study was carried out to investigate the effect of oryzanol (OZ, a commercially-important potent antioxidant component isolated from from crude rice bran oil (cRBO, in streptozotocin (STZ-induced diabetic neuropathy in rats. After eight weeks, diabetic rats developed neuropathy which was evident from decreased tail-flick latency (thermal hyperalgesia and increased nociceptive behavior during the formalin test. This was accompanied by decreased motor coordination based on the evaluation of neuromuscular strength. Na+ K+ ATPase, a biochemical marker associated with the development of diabetic neuropathy, was significantly inhibited in the sciatic nerve of diabetic animals. The activities of antioxidant enzymes and lipid peroxidation levels were significantly elevated in diabetic rats, indicating the involvement of oxidative stress in diabetic neuropathy. Chronic treatment with oryzanol (OZ (50 and 100 mg/kg per oral (p.o. and standard drug glibenclamide (Gl (10 mg/kg, p.o. significantly attenuated the behavioral as well as biochemical changes associated with diabetic neuropathy. The findings provide experimental evidence to the protective effects of OZ on hyperglycemia-induced thermal hyperalgesia and oxidative stress which might be responsible for diabetes induced nerve damage.

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.

Cellular characteristics of hereditary diseases of man

International Nuclear Information System (INIS)

Sasaki, Masao

1978-01-01

Hereditary diseases of which abnormal characters could be detected at cultured cell level were introduced, and tissue cultures of them were described. Characteristics such as reproduction, disorder, elimination, and repair of DNA in hereditary diseases with high cancer risk such as Bloom syndrome, etc. were investigated. Radiosensitivity of these hereditary diseases was also described, and factors of carcinogenesis were investigated. (Serizawa, K.)

An Inversion Disrupting FAM134B Is Associated with Sensory Neuropathy in the Border Collie Dog Breed.

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Forman, Oliver P; Hitti, Rebekkah J; Pettitt, Louise; Jenkins, Christopher A; O'Brien, Dennis P; Shelton, G Diane; De Risio, Luisa; Quintana, Rodrigo Gutierrez; Beltran, Elsa; Mellersh, Cathryn

2016-09-08

Sensory neuropathy in the Border Collie is a severe neurological disorder caused by the degeneration of sensory and, to a lesser extent, motor nerve cells with clinical signs starting between 2 and 7 months of age. Using a genome-wide association study approach with three cases and 170 breed matched controls, a suggestive locus for sensory neuropathy was identified that was followed up using a genome sequencing approach. An inversion disrupting the candidate gene FAM134B was identified. Genotyping of additional cases and controls and RNAseq analysis provided strong evidence that the inversion is causal. Evidence of cryptic splicing resulting in novel exon transcription for FAM134B was identified by RNAseq experiments. This investigation demonstrates the identification of a novel sensory neuropathy associated mutation, by mapping using a minimal set of cases and subsequent genome sequencing. Through mutation screening, it should be possible to reduce the frequency of or completely eliminate this debilitating condition from the Border Collie breed population. Copyright © 2016 Forman et al.

Peripheral neuropathy in HIV: prevalence and risk factors

Science.gov (United States)

Evans, Scott R.; Ellis, Ronald J.; Chen, Huichao; Yeh, Tzu-min; Lee, Anthony J.; Schifitto, Giovanni; Wu, Kunling; Bosch, Ronald J.; McArthur, Justin C.; Simpson, David M.; Clifford, David B.

2011-01-01

Objectives To estimate neuropathic sign/symptom rates with initiation of combination antiretroviral therapy (cART) in HIV-infected ART-naive patients, and to investigate risk factors for: peripheral neuropathy and symptomatic peripheral neuropathy (SPN), recovery from peripheral neuropathy/SPN after neurotoxic ART (nART) discontinuation, and the absence of peripheral neuropathy/SPN while on nART. Design AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trial participants who initiated cART in randomized trials for ART-naive patients were annually screened for symptoms/signs of peripheral neuropathy. ART use and disease characteristics were collected longitudinally. Methods Peripheral neuropathy was defined as at least mild loss of vibration sensation in both great toes or absent/hypoactive ankle reflexes bilaterally. SPN was defined as peripheral neuropathy and bilateral symptoms. Generalized estimating equation logistic regression was used to estimate associations. Results Two thousand, one hundred and forty-one participants were followed from January 2000 to June 2007. Rates of peripheral neuropathy/SPN at 3 years were 32.1/8.6% despite 87.1% with HIV-1RNA 400 copies/ml or less and 70.3% with CD4 greater than 350 cells/µl. Associations with higher odds of peripheral neuropathy included older patient age and current nART use. Associations with higher odds of SPN included older patient age, nART use, and history of diabetes mellitus. Associations with lower odds of recovery after nART discontinuation included older patient age. Associations with higher odds of peripheral neuropathy while on nART included older patient age and current protease inhibitor use. Associations with higher odds of SPN while on nART included older patient age, history of diabetes, taller height, and protease inhibitor use. Conclusion Signs of peripheral neuropathy remain despite virologic/immunologic control but frequently occurs without symptoms. Aging is a risk factor for

Hereditary angioedema

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... disease; HAE- Hereditary angioedema; Kallikrein inhibitor-HAE: bradykinin receptor antagonist-HAE; C1-inhibitors-HAE; Hives-HAE ... aunt, uncle, or grandparent. Dental procedures, sickness (including colds and the flu), and surgery may trigger HAE ...

The molecular classification of hereditary endocrine diseases.

Science.gov (United States)

Ye, Lei; Ning, Guang

2015-12-01

Hereditary endocrine diseases are an important group of diseases with great heterogeneity. The current classification for hereditary endocrine disease is mostly based upon anatomy, which is helpful for pathophysiological interpretation, but does not address the pathogenic variability associated with different underlying genetic causes. Identification of an endocrinopathy-associated genetic alteration provides evidence for differential diagnosis, discovery of non-classical disease, and the potential for earlier diagnosis and targeted therapy. Molecular diagnosis should be routinely applied when managing patients with suspicion of hereditary disease. To enhance the accurate diagnosis and treatment of patients with hereditary endocrine diseases, we propose categorization of endocrine diseases into three groups based upon the function of the mutant gene: cell differentiation, hormone synthesis and action, and tumorigenesis. Each category was further grouped according to the specific gene function. We believe that this format would facilitate practice of precision medicine in the field of hereditary endocrine diseases.

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....

Clinical diagnosis of diabetic polyneuropathy with the diabetic neuropathy symptom and diabetic neuropathy examination scores

NARCIS (Netherlands)

Meijer, J.W.; Lefrandt, J.D.; Links, T.P.; Smit, J.A.; Stewart, R.E.; van der Hoeven, J.H.; Hoogenberg, K.

OBJECTIVE - To evaluate the discriminative power of the Diabetic Neuropathy Symptom (DNS) and Diabetic Neuropathy Examination (DNE) scores for diagnosing diabetic polyneuropathy (PNP), as well as their relation with cardiovascular autonomic function testing (cAFT) and electro-diagnostic studies

Chapter 50: history of tropical neurology.

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Ogunniyi, Adesola

2010-01-01

Tropical neurology began less than two centuries ago. Consumption of dietary toxins predominated at the beginning and gave birth to the geographic entity. The story moved from lathyrism through Jamaican neuropathy to cassava-induced epidemic neuropathy, which was contrasted with Konzo, also associated with cassava. Other tropical diseases enumerated with chronological details include: Chaga's diseases, kwashiorkor, Madras type of motor neuron disease, atlanto-axial dislocation, Burkitt's lymphoma and Kuru, associated with cannibalism among the Fore linguistic group in New Guinea. More recent documentation includes the Cuban neuropathy in 1991 with an epidemic of visual loss and neuropathy, Anaphe venata entomophagy in Nigeria presenting as seasonal ataxia, and neurological aspects of the human immunodeficiency virus infection complete the picture. With time, professional associations were formed and the pioneers were given prominence. The World Federation of Neurology featured Geographic Neurology as a theme in 1977 and Tropical Neurology was given prominence at its 1989 meeting in New Delhi, India. The situation remains unchanged with regards to rare diseases like Meniere's, multiple sclerosis, hereditary disorders. However, with westernization and continued urbanization, changing disease patterns are being observed and tropical neurology may depart from dietary toxins to more western world-type disorders.

Cutaneous manifestations of diabetic peripheral neuropathy.

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Dogiparthi, S N; Muralidhar, K; Seshadri, K G; Rangarajan, S

2017-01-01

There is a rise in number of people diagnosed with Diabetes Mellitus. The incidence is rising in modern Indian society because of Industrial development and drastically changing lifestyles. Diabetic neuropathies are microvascular disorders that are usually associated with the duration of Diabetes. Among the various forms, the most common is Diabetic Peripheral Neuropathy. The disease if neglected leads to chronic ulcer formation leading to amputations frequently. Hence the aim of this study is to document the early cutaneous changes and create an early awareness in the importance of controlling Diabetes. The study consisted of 205 patients with Type 2 DM. Participant's neuropathy status was determined based on Neuropathy Disability Score and Diabetic Neuropathy Symptom Score. Among the Skin changes documented, the common changes seen were: Peripheral hair loss in 185 (90.2%), Xerosis in 168 (82%), Anhydrosis in 162 (79%), Plantar Fissures in 136 (66.3%), Plantar Ulcer in 80 (39%), common nail changes documented were Onychomycosis in 165 (80.5%) and Onychauxis in 53 (25.8%) patients in relation to the occupation and duration of Diabetes mellitus. In conclusion, it is important to control glycemic levels in the all stages of Diabetes and institute foot care measures to prevent the complications of neuropathy.

Treatment of painful diabetic peripheral neuropathy.

Science.gov (United States)

Rosenberg, Casandra J; Watson, James C

2015-02-01

Painful diabetic peripheral neuropathy impairs quality of life and can be difficult to treat. To discuss current treatment recommendations for painful diabetic peripheral neuropathy. Literature review. Systematic review of the literature discussing treatment of painful diabetic peripheral neuropathy. Existing treatment guidelines were studied and compared. Painful diabetic peripheral neuropathy occurs in about one in six people with diabetes. This condition impairs quality of life and increases healthcare costs. Treatment recommendations exist, but individual patient therapy can require a trial-and-error approach. Many treatment options have adjuvant benefits or side effects which should be considered prior to initiating therapy. Often, a combination of treatment modalities with various mechanisms of action is required for adequate pain control. Adequate medication titration and a reasonable trial period should be allowed. The treatment of painful diabetic peripheral neuropathy can be challenging, but effective management can improve patient's quality of life. Painful diabetic peripheral neuropathy impairs quality of life and can be difficult to treat. Many treatment options have adjuvant benefits or side effects which should be considered prior to initiating therapy. Often, a combination of treatment modalities with various mechanisms of action is required for adequate pain control. © The International Society for Prosthetics and Orthotics 2014.

Herpes Zoster Optic Neuropathy.

Science.gov (United States)

Kaufman, Aaron R; Myers, Eileen M; Moster, Mark L; Stanley, Jordan; Kline, Lanning B; Golnik, Karl C

2018-06-01

Herpes zoster optic neuropathy (HZON) is a rare manifestation of herpes zoster ophthalmicus (HZO). The aim of our study was to better characterize the clinical features, therapeutic choices, and visual outcomes in HZON. A retrospective chart review was performed at multiple academic eye centers with the inclusion criteria of all eyes presenting with optic neuropathy within 1 month of cutaneous zoster of the ipsilateral trigeminal dermatome. Data were collected regarding presenting features, treatment regimen, and visual acuity outcomes. Six patients meeting the HZON inclusion criteria were identified. Mean follow-up was 2.75 months (range 0.5-4 months). Herpes zoster optic neuropathy developed at a mean of 14.1 days after initial rash (range 6-30 days). Optic neuropathy was anterior in 2 eyes and retrobulbar in 4 eyes. Other manifestations of HZO included keratoconjunctivitis (3 eyes) and iritis (4 eyes). All patients were treated with systemic antiviral therapy in addition to topical and/or systemic corticosteroids. At the last follow-up, visual acuity in 3 eyes had improved relative to presentation, 2 eyes had worsened, and 1 eye remained the same. The 2 eyes that did not receive systemic corticosteroids had the best observed final visual acuity. Herpes zoster optic neuropathy is an unusual but distinctive complication of HZO. Visual recovery after HZON is variable. Identification of an optimal treatment regiment for HZON could not be identified from our patient cohort. Systemic antiviral agents are a component of HZON treatment regimens. Efficacy of systemic corticosteroids for HZON remains unclear and should be considered on a case-by-case basis.

Propylthiouracil and peripheral neuropathy

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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.

Splenic Involvement in Hereditary Hemorrhagic Telangiectasia

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Susumu Takamatsu

2016-01-01

Full Text Available A 33-year-old man who presented with prolonged epigastric pain was referred to our hospital. He had experienced recurrent epistaxis and had a family history of hereditary hemorrhagic telangiectasia. Computed tomography and magnetic resonance imaging revealed splenomegaly and a 9 cm hypervascular mass in his spleen. Computed tomography also showed a pulmonary arteriovenous malformation and heterogeneous enhancement of the liver parenchyma, suggesting the presence of arteriosystemic shunts and telangiectases. Based on these findings, the patient was definitely diagnosed with hereditary hemorrhagic telangiectasia according to Curaçao criteria. He underwent splenectomy, and his symptoms disappeared after surgery. Pathological examination of the resected specimen revealed that the hypervascular lesion of the spleen was not a tumor but was composed of abnormal vessels associated with hereditary hemorrhagic telangiectasia. Symptomatic splenic involvement may be a rare manifestation of hereditary hemorrhagic telangiectasia but can be revealed by imaging modalities.

Diagnosis and therapeutic options for peripheral vasculitic neuropathy

Science.gov (United States)

2015-01-01

Vasculitis can affect the peripheral nervous system alone (nonsystemic vasculitic neuropathy) or can be a part of primary or secondary systemic vasculitis. In cases of pre-existing systemic vasculitis, the diagnosis can easily be made, whereas suspected vasculitic neuropathy as initial or only manifestation of vasculitis requires careful clinical, neurophysiological, laboratory and histopathological workout. The typical clinical syndrome is mononeuropathia multiplex or asymmetric neuropathy, but distal-symmetric neuropathy can frequently be seen. Standard treatments include steroids, azathioprine, methotrexate and cyclophosphamide. More recently the B-cell antibody rituximab and intravenous immunoglobulins have shown to be effective in some vasculitic neuropathy types. PMID:25829955

Impact of presymptomatic genetic testing for hereditary ataxia and neuromuscular disorders.

Science.gov (United States)

Smith, Corrine O; Lipe, Hillary P; Bird, Thomas D

2004-06-01

With the exception of Huntington disease, the psychological and psychosocial impact of DNA testing for neurogenetic disorders has not been well studied. To evaluate the psychosocial impact of genetic testing for autosomal dominant forms of hereditary ataxia and neuromuscular disorders. Patients Fifty subjects at risk for autosomal dominant forms of spinocerebellar ataxia (n = 11), muscular dystrophy (n = 28), and hereditary neuropathy (n = 12). A prospective, descriptive, observational study in a university setting of individuals who underwent genetic counseling and DNA testing. Participants completed 3 questionnaires before testing and at regular intervals after testing. The questionnaire set included the Revised Impact of Event Scale, the Hospital Anxiety and Depression Scale, demographic information, and an assessment of attitudes and feelings about genetic testing. Thirty-nine subjects (78%) completed 6 months to 5 years of posttest follow-up. Common reasons for pursuing genetic testing were to provide an explanation for symptoms, emotional relief, and information for future planning. Thirty-four (68%) had positive and 16 (32%) had negative genetic results. In those with a positive result, 26 (76%) had nonspecific signs or symptoms of the relevant disorder. Forty-two participants (84%) felt genetic testing was beneficial. Groups with positive and negative test results coped well with results. However, 13 subjects (10 with positive and 3 with negative results) reported elevated anxiety levels, and 3 (1 with positive and 2 with negative results) expressed feelings of depression during the follow-up period. The test result was not predictive of anxiety or depression. Most individuals find neurogenetic testing to be beneficial, regardless of the result. Anxiety or depression may persist in some persons with positive or negative test results. Testing can have a demonstrable impact on family planning and interpersonal relationships. Further studies are needed to

Evaluation of PMI-5011, an ethanolic extract of Artemisia dracunculus L., on peripheral neuropathy in streptozotocin-diabetic mice.

Science.gov (United States)

Watcho, Pierre; Stavniichuk, Roman; Tane, Pierre; Shevalye, Hanna; Maksimchyk, Yury; Pacher, Pal; Obrosova, Irina G

2011-03-01

We previously reported that PMI-5011, an ethanolic extract of Artemisia dracunculus L., alleviates peripheral neuropathy in high fat diet-fed mice, a model of prediabetes and obesity developing oxidative stress and pro-inflammatory changes in the peripheral nervous system. This study evaluated PMI-5011 on established functional, structural, and biochemical changes associated with Type I diabetic peripheral neuropathy. C57Bl6/J mice with streptozotocin-induced diabetes of a 12-week duration, developed motor and sensory nerve conduction velocity deficits, thermal and mechanical hypoalgesia, tactile allodynia, and intra-epidermal nerve fiber loss. PMI-5011 (500 mg/kg/day for 7 weeks) alleviated diabetes-induced nerve conduction slowing, small sensory nerve fiber dysfunction, and increased intra-epidermal nerve fiber density. PMI-5011 blunted sciatic nerve and spinal cord 12/15-lipoxygenase activation and oxidative-nitrosative stress, without ameliorating hyperglycemia or reducing sciatic nerve sorbitol pathway intermediate accumulation. In conclusion, PMI-5011, a safe and non-toxic botanical extract, may find use in the treatment of diabetic peripheral neuropathy.

Genetics Home Reference: hereditary hemorrhagic telangiectasia

Science.gov (United States)

... Central OMIM: JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic ... 10.1097/GIM.0b013e3182136d32. Review. Citation on PubMed McDonald J, Wooderchak-Donahue W, VanSant Webb C, Whitehead ...

Multifocal visual evoked potential in optic neuritis, ischemic optic neuropathy and compressive optic neuropathy

Science.gov (United States)

Jayaraman, Manju; Gandhi, Rashmin Anilkumar; Ravi, Priya; Sen, Parveen

2014-01-01

Purpose: To investigate the effect of optic neuritis (ON), ischemic optic neuropathy (ION) and compressive optic neuropathy (CON) on multifocal visual evoked potential (mfVEP) amplitudes and latencies, and to compare the parameters among three optic nerve disorders. Materials and Methods: mfVEP was recorded for 71 eyes of controls and 48 eyes of optic nerve disorders with subgroups of optic neuritis (ON, n = 21 eyes), ischemic optic neuropathy (ION, n = 14 eyes), and compressive optic neuropathy (CON, n = 13 eyes). The size of defect in mfVEP amplitude probability plots and relative latency plots were analyzed. The pattern of the defect in amplitude probability plot was classified according to the visual field profile of optic neuritis treatment trail (ONTT). Results: Median of mfVEP amplitude (log SNR) averaged across 60 sectors were reduced in ON (0.17 (0.13-0.33)), ION (0.14 (0.12-0.21)) and CON (0.21 (0.14-0.30)) when compared to controls. The median mfVEP relative latencies compared to controls were significantly prolonged in ON and CON group of 10.53 (2.62-15.50) ms and 5.73 (2.67-14.14) ms respectively compared to ION group (2.06 (-4.09-13.02)). The common mfVEP amplitude defects observed in probability plots were diffuse pattern in ON, inferior altitudinal defect in ION and temporal hemianopia in CON eyes. Conclusions: Optic nerve disorders cause reduction in mfVEP amplitudes. The extent of delayed latency noted in ischemic optic neuropathy was significantly lesser compared to subjects with optic neuritis and compressive optic neuropathy. mfVEP amplitudes can be used to objectively assess the topography of the visual field defect. PMID:24088641

Peripheral Neuropathy, Sensory Processing, and Balance in Survivors of Acute Lymphoblastic Leukemia.

Science.gov (United States)

Varedi, Mitra; Lu, Lu; Howell, Carrie R; Partin, Robyn E; Hudson, Melissa M; Pui, Ching-Hon; Krull, Kevin R; Robison, Leslie L; Ness, Kirsten K; McKenna, Raymond F

2018-05-29

Purpose To compare peripheral nervous system function and balance between adult survivors of childhood acute lymphoblastic leukemia (ALL) and matched controls and to determine associations between peripheral neuropathy (PN) and limitations in static balance, mobility, walking endurance, and quality of life (QoL) among survivors. Patients and Methods Three hundred sixty-five adult survivors of childhood ALL and 365 controls with no cancer history completed assessments of PN (modified Total Neuropathy Score [mTNS]), static balance (Sensory Organization Test [SOT]), mobility (Timed Up and Go), walking endurance (6-minute walk test), QoL (Medical Outcomes Study 36-Item Short Form Survey), and visual-motor processing speed (Wechsler Adult Intelligence Scale). Results PN, but not impairments, in performance on SOT was more common in survivors than controls (41.4% v 9.5%, respectively; P general health). Processing speed (β = 1.69; 95% CI, 0.98 to 2.40; P balance. The association between processing speed and sway suggests that static balance impairment in ALL survivors may be influenced by problems with CNS function, including the processing of sensory information.

Polyol pathway, 2,3-diphosphoglycerate in erythrocytes and diabetic neuropathy in rats.

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Nakamura, J; Koh, N; Sakakibara, F; Hamada, Y; Wakao, T; Hara, T; Mori, K; Nakashima, E; Naruse, K; Hotta, N

1995-12-27

The relationship between the 2,3-diphosphoglycerate concentration in red blood cells as a biological indicator of tissue hypoxia and diabetic neuropathy, and the effect of a potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2'5'-dioxospiro [chroman-4,4'-imidazolidine]-2-carboxamide (SNK-860), on both were investigated in streptozotocin-induced diabetic rats. Diabetic rats demonstrated significantly delayed motor nerve conduction velocity and reduced sciatic nerve blood flow. Altered biochemical features in the sciatic nerves, including a marked accumulation of sorbitol and fructose, myo-inositol depletion and decreased Na+/K(+)-ATPase activity were also detected in diabetic rats. These defects were accompanied by a decrease in the red blood cell 2,3-diphosphoglycerate concentration. Treatment with SNK-860 partially or completely ameliorated these abnormalities. These observations suggest that a decrease in the red blood cell 2,3-diphosphoglycerate concentration is one of the factors contributing to tissue hypoxia, which results in diabetic neuropathy, and that this decrease is mediated through an aldose reductase inhibitor-sensitive pathway.

Hypothyroidism: Can It Cause Peripheral Neuropathy?

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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 ...

Diabetic cachectic neuropathy: An uncommon neurological ...

African Journals Online (AJOL)

Diabetic cachectic neuropathy, also called diabetic neuropathic cachexia, is a very rare ... type 1 and type 2 diabetics and occurs irrespective of the duration of diabetes. .... distal symmetrical peripheral neuropathy in pregnancy. However,.

Finger extension weakness and downbeat nystagmus motor neuron disease syndrome: A novel motor neuron disorder?

Science.gov (United States)

Delva, Aline; Thakore, Nimish; Pioro, Erik P; Poesen, Koen; Saunders-Pullman, Rachel; Meijer, Inge A; Rucker, Janet C; Kissel, John T; Van Damme, Philip

2017-12-01

Disturbances of eye movements are infrequently encountered in motor neuron diseases (MNDs) or motor neuropathies, and there is no known syndrome that combines progressive muscle weakness with downbeat nystagmus. To describe the core clinical features of a syndrome of MND associated with downbeat nystagmus, clinical features were collected from 6 patients. All patients had slowly progressive muscle weakness and wasting in combination with downbeat nystagmus, which was clinically most obvious in downward and lateral gaze. Onset was in the second to fourth decade with finger extension weakness, progressing to other distal and sometimes more proximal muscles. Visual complaints were not always present. Electrodiagnostic testing showed signs of regional motor axonal loss in all patients. The etiology of this syndrome remains elusive. Because finger extension weakness and downbeat nystagmus are the discriminating clinical features of this MND, we propose the name FEWDON-MND syndrome. Muscle Nerve 56: 1164-1168, 2017. © 2017 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.

New Treatments for Nonarteritic Anterior Ischemic Optic Neuropathy.

Science.gov (United States)

Foroozan, Rod

2017-02-01

Despite increasing knowledge about the risk factors and clinical findings of nonarteritic anterior ischemic optic neuropathy (NAION), the treatment of this optic neuropathy has remained limited and without clear evidence-based benefit. Historical treatments of NAION are reviewed, beginning with the Ischemic Optic Neuropathy Decompression Trial. More recent treatments are placed within the historical context and illustrate the need for evidence-based therapy for ischemic optic neuropathy. Copyright © 2016 Elsevier Inc. All rights reserved.

Docetaxel-induced neuropathy

DEFF Research Database (Denmark)

Eckhoff, Lise; Feddersen, Søren; Knoop, Ann

2015-01-01

Background. Docetaxel is a highly effective treatment of a wide range of malignancies but is often associated with peripheral neuropathy. The genetic variability of genes involved in the transportation or metabolism of docetaxel may be responsible for the variation in docetaxel-induced peripheral...... neuropathy (DIPN). The main purpose of this study was to investigate the impact of genetic variants in GSTP1 and ABCB1 on DIPN. Material and methods. DNA was extracted from whole blood from 150 patients with early-stage breast cancer who had received adjuvant docetaxel from February 2011 to May 2012. Two...

Spectrum of peripheral neuropathies associated with surgical interventions; A neurophysiological assessment

LENUS (Irish Health Repository)

Saidha, Shiv

2010-04-19

Abstract Background We hypothesized that a wide range of surgical procedures may be complicated by neuropathies, not just in close proximity but also remote from procedural sites. The aim of this study was to classify post-operative neuropathies and the procedures associated with them. Methods We retrospectively identified 66 patients diagnosed with post-procedure neuropathies between January 2005 and June 2008. We reviewed their referral cards and medical records for patient demographics, information on procedures, symptoms, as well as clinical and neurophysiological findings. Results Thirty patients (45.4%) had neuropathies remote from procedural sites and 36 patients (54.5%) had neuropathies in close proximity to procedural sites. Half of the remote neuropathies (15\\/30) developed following relatively short procedures. In 27% of cases (8\\/30) remote neuropathies were bilateral. Seven patients developed neuropathies remote from operative sites following hip arthroplasties (7\\/30: 23.3%), making hip arthroplasty the most common procedure associated with remote neuropathies. Sciatic neuropathies due to hip arthroplasty (12\\/36, 33.3%) accounted for the majority of neuropathies occurring in close proximity to operative sites. Five medial cutaneous nerve of forearm neuropathies occurred following arterio-venous fistula (AVF) formation. Conclusions An array of surgical procedures may be complicated by neuropathy. Almost half of post-procedure neuropathies occur remote from the site of procedure, emphasizing the need to try to prevent not just local, but also remote neuropathies. Mechanical factors and patient positioning should be considered in the prevention of post-operative neuropathies. There is a possible association between AVF formation and medial cutaneous nerve of forearm neuropathy, which requires further study for validation.

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 ... Diffuse Gastric Cancer MedlinePlus Encyclopedia: Gastric Cancer National Cancer ... Option Overview General Information from MedlinePlus ( ...

Corneal markers of diabetic neuropathy.

Science.gov (United States)

Pritchard, Nicola; Edwards, Katie; Shahidi, Ayda M; Sampson, Geoff P; Russell, Anthony W; Malik, Rayaz A; Efron, Nathan

2011-01-01

Diabetic neuropathy is a significant clinical problem that currently has no effective therapy, and in advanced cases, leads to foot ulceration and lower limb amputation. The accurate detection, characterization and quantification of this condition are important in order to define at-risk patients, anticipate deterioration, monitor progression, and assess new therapies. This review evaluates novel corneal methods of assessing diabetic neuropathy. Two new noninvasive corneal markers have emerged, and in cross-sectional studies have demonstrated their ability to stratify the severity of this disease. Corneal confocal microscopy allows quantification of corneal nerve parameters and noncontact corneal esthesiometry, the functional correlate of corneal structure, assesses the sensitivity of the cornea. Both these techniques are quick to perform, produce little or no discomfort for the patient, and are suitable for clinical settings. Each has advantages and disadvantages over traditional techniques for assessing diabetic neuropathy. Application of these new corneal markers for longitudinal evaluation of diabetic neuropathy has the potential to reduce dependence on more invasive, costly, and time-consuming assessments, such as skin biopsy.

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.

Peripheral neuropathy in prediabetes and the metabolic syndrome.

Science.gov (United States)

Stino, Amro M; Smith, Albert G

2017-09-01

Peripheral neuropathy is a major cause of disability worldwide. Diabetes is the most common cause of neuropathy, accounting for 50% of cases. Over half of people with diabetes develop neuropathy, and diabetic peripheral neuropathy (DPN) is a major cause of reduced quality of life due to pain, sensory loss, gait instability, fall-related injury, and foot ulceration and amputation. Most patients with non-diabetic neuropathy have cryptogenic sensory peripheral neuropathy (CSPN). A growing body of literature links prediabetes, obesity and metabolic syndrome to the risk of both DPN and CSPN. This association might be particularly strong in type 2 diabetes patients. There are no effective medical treatments for CSPN or DPN, and aggressive glycemic control is an effective approach to neuropathy risk reduction only in type 1 diabetes. Several studies suggest lifestyle-based treatments that integrate dietary counseling with exercise might be a promising therapeutic approach to early DPN in type 2 diabetes and CSPN associated with prediabetes, obesity and metabolic syndrome. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Genetic profiles distinguish different types of hereditary ovarian cancer

DEFF Research Database (Denmark)

Domanska, Katarina; Malander, Susanne; Staaf, Johan

2010-01-01

(HBOC) syndrome and the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Genome-wide array comparative genomic hybridization was applied to 12 HBOC associated tumors with BRCA1 mutations and 8 HNPCC associated tumors with mismatch repair gene mutations with 24 sporadic ovarian cancers......Heredity represents the strongest risk factor for ovarian cancer with disease predisposing mutations identified in 15% of the tumors. With the aim to identify genetic classifiers for hereditary ovarian cancer, we profiled hereditary ovarian cancers linked to the hereditary breast and ovarian cancer...... that HBOC and HNPCC associated ovarian cancer develop along distinct genetic pathways and genetic profiles can thus be applied to distinguish between different types of hereditary ovarian cancer....

Peripheral Neuropathy

Science.gov (United States)

... wasting. Various dietary strategies can improve gastrointestinal symptoms. Timely treatment of injuries can help prevent permanent damage. ... diabetic neuropathy is more limited. Transcutaneous electrical nerve stimulation (TENS) is a non-invasive intervention used for ...

Auditory Neuropathy

Science.gov (United States)

... children and adults with auditory neuropathy. Cochlear implants (electronic devices that compensate for damaged or nonworking parts ... and Drug Administration: Information on Cochlear Implants Telecommunications Relay Services Your Baby's Hearing Screening News Deaf health ...

Hereditary haemorrhagic telangiectasia

DEFF Research Database (Denmark)

Kjeldsen, A D; Vase, P; Green, A

1999-01-01

Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease characterized by telangiectatic lesions. The disease manifestations are variable and include epistaxis, gastrointestinal bleeding, pulmonary arteriovenous malformations and cerebral arteriovenous malformations. Early...

Hereditary spherocytosis: Consequences of delayed diagnosis

Directory of Open Access Journals (Sweden)

Sarah C Steward

2014-08-01

Full Text Available Objective: To determine whether patients with undiagnosed hereditary spherocytosis hospitalized for transfusions might have avoided hospitalization via earlier diagnosis. Study design: Charts of all (N = 30 patients with hereditary spherocytosis seen in pediatric hematology at West Virginia University-Charleston were reviewed. Family and transfusion history and presence of neonatal jaundice were recorded. Complete blood count and reticulocyte values during infancy were available for 20 of 30 patients, while baseline steady-state values were available for all 30. Results: Transfusions were given to 22 patients; 12 of 14 with an aplastic crisis were undiagnosed. In 10 of 12, the severity of anemia led to hospitalization (3 to intensive care. All 10 had prior mean corpuscular hemoglobin concentration and/or red cell distribution width elevations and a history of neonatal jaundice; 7 of 10 had a positive family history. Conclusions: Undiagnosed hereditary spherocytosis may lead to inpatient transfusions for severe anemia. Earlier detection of hereditary spherocytosis is easily achievable and may reduce hospitalizations via closer monitoring.

Effectiveness of gabapentin pharmacotherapy in chemotherapy-induced peripheral neuropathy.

Science.gov (United States)

Magnowska, Magdalena; Iżycka, Natalia; Kapoła-Czyż, Joanna; Romała, Anna; Lorek, Jakub; Spaczyński, Marek; Nowak-Markwitz, Ewa

2018-01-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a common chemotherapy side effect, but its prevention and treatment remains a challenge. Neurotoxicity may lead to dose limitation or even treatment discontinuation, and therefore potentially affect the efficacy of anticancer treatment and long term outcomes. The practice to administer gabapentin for neuropathy may be applicable, but is limited by insufficient studies. The aim of our study was to assess the presence of chemotherapy-induced peripheral neuropathy in ovarian cancer patients treated with first-line paclitaxel and carboplatin chemotherapy and evaluate the effectiveness of gabapentin in treatment of this condition. 61 ovarian cancer patients treated with first line chemotherapy were included in the study. The first phase of the study was to assess neurological condition of each patient by: neuropathy symptoms scale, McGill's scale, neurological deficit and quality of life, during the chemotherapy. In the second phase of the study we evaluated the response to gabapentin treatment in a group of patients who developed neuropathy. 78.7% of the patients developed chemotherapy related neuropathy. During the course of chemotherapy these patients experienced significant exacerbation of neuropathy symptoms (p peripheral neuropathy.

Peripheral neuropathy in HIV: an analysis of evidence-based approaches.

Science.gov (United States)

Nicholas, Patrice K; Corless, Inge B; Evans, Linda A

2014-01-01

Peripheral neuropathy is a common and vexing symptom for people living with HIV infection (PLWH). Neuropathy occurs in several different syndromes and is identified in the literature as distal sensory polyneuropathy or distal sensory peripheral neuropathy. More recently, the HIV literature has focused on the syndrome as painful HIV-associated sensory neuropathy, addressing the symptom rather than the underlying pathophysiology. Assessment of neuropathy in PLWH is critical and must be incorporated into nursing practice for each visit. Neuropathy has been attributed to the direct effects of HIV, exposure to antiretroviral medications (particularly the nucleoside reverse transcriptase inhibitors), advanced immune suppression, and comorbid tuberculosis infection and exposure to antituberculosis medications. Evidence supports the importance of addressing neuropathy in PLWH with pharmacologic treatment regimens and complementary/alternative approaches. This paper examines the pathophysiology, evidence, and approaches to managing peripheral neuropathy. A case study has been included to illustrate a patient's experience with neuropathy symptoms. Copyright © 2014 Association of Nurses in AIDS Care. Published by Elsevier Inc. All rights reserved.

Modeling neurodevelopment and cortical dysfunction in SPG11-linked hereditary spastic paraplegia using human induced pluripotent stem cells

OpenAIRE

Mishra, Himanshu Kumar

2016-01-01

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of inherited motor neuron diseases characterized by progressive spasticity and weakness of the lower limbs. Mutations in the Spastic Paraplegia Gene11 (SPG11), encoding spatacsin, cause the most frequent form of autosomal recessive HSP. SPG11 patients are clinically distinguishable from most other HSPs, by severe cortical atrophy and presence of a thin corpus callosum (TCC), associated with cognitive deficits. Partly due to l...

Sensorimotor polyneuropathy

Science.gov (United States)

... neuropathy , including chemotherapy Guillain-Barré syndrome Hereditary neuropathy HIV/AIDS Low thyroid Parkinson disease Vitamin deficiency ( vitamins B12 , B1 , and E) Zika virus infection Symptoms Symptoms may include any of the following: Decreased ...

Vasculopathic Cranial Ocular Motor Neuropathy Following Sudden Emotional Stress

OpenAIRE

Purvin, Valerie

2010-01-01

We describe three patients who experienced onset of a microvascular ocular motor nerve palsy in the setting of sudden emotional stress. Such emotional states are accompanied by a marked increase in sympathetic tone in some individuals. Mechanisms by which these autonomic changes might produce an ischemic cranial nerve palsy include intra-cranial vasoconstriction and transient systemic hypotension due to alterations in cardiac function.

Chronic obstructive pulmonary disease and peripheral neuropathy

Directory of Open Access Journals (Sweden)

Gupta Prem

2006-01-01

Full Text Available Chronic obstructive pulmonary disease (COPD is the fourth leading cause of death world-wide and a further increase in the prevalence as well as mortality of the disease is predicted for coming decades. There is now an increased appreciation for the need to build awareness regarding COPD and to help the thousands of people who suffer from this disease and die prematurely from COPD or its associated complication(s. Peripheral neuropathy in COPD has received scanty attention despite the fact that very often clinicians come across COPD patients having clinical features suggestive of peripheral neuropathy. Electrophysiological tests like nerve conduction studies are required to distinguish between axonal and demyelinating type of disorder that cannot be analyzed by clinical examination alone. However, various studies addressing peripheral neuropathy in COPD carried out so far have included patients with COPD having markedly varying baseline characteristics like severe hypoxemia, elderly patients, those with long duration of illness, etc. that are not uniform across the studies and make it difficult to interpret the results to a consistent conclusion. Almost one-third of COPD patients have clinical evidence of peripheral neuropathy and two-thirds have electrophysiological abnormalities. Some patients with no clinical indication of peripheral neuropathy do have electrophysiological deficit suggestive of peripheral neuropathy. The more frequent presentation consists of a polyneuropathy that is subclinical or with predominantly sensory signs, and the neurophysiological and pathological features of predominantly axonal neuropathy. The presumed etiopathogenic factors are multiple: chronic hypoxia, tobacco smoke, alcoholism, malnutrition and adverse effects of certain drugs.

Paralyse af nervus peroneus hos patient med Ehlers-Danlos syndrom

DEFF Research Database (Denmark)

Al-Aubaidi, Zaid; Skov, Ole

2011-01-01

Ehlers-Danlos syndrome (EDS) is a hereditary generalized connective tissue disorder characterized by skin hyperextensibility, joint hypermobility and tissue fragility. Peripheral neuropathy is described sporadically. Although the exact mechanism of the neuropathy is not well-known, excessive...

Peripheral Neuropathy: A Practical Approach to Diagnosis and Symptom Management.

Science.gov (United States)

Watson, James C; Dyck, P James B

2015-07-01

Peripheral neuropathy is one of the most prevalent neurologic conditions encountered by physicians of all specialties. Physicians are faced with 3 distinct challenges in caring for patients with peripheral neuropathy: (1) how to efficiently and effectively screen (in less than 2 minutes) an asymptomatic patient for peripheral neuropathy when they have a disorder in which peripheral neuropathy is highly prevalent (eg, diabetes mellitus), (2) how to clinically stratify patients presenting with symptoms of neuropathy to determine who would benefit from specialty consultation and what testing is appropriate for those who do not need consultation, and (3) how to treat the symptoms of painful peripheral neuropathy. In this concise review, we address these 3 common clinical scenarios. Easily defined clinical patterns of involvement are used to identify patients in need of neurologic consultation, the yield of laboratory and other diagnostic testing is reviewed for the evaluation of length-dependent, sensorimotor peripheral neuropathies (the most common form of neuropathy), and an algorithmic approach with dosing recommendations is provided for the treatment of neuropathic pain associated with peripheral neuropathy. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Unipedal stance testing in the assessment of peripheral neuropathy.

Science.gov (United States)

Hurvitz, E A; Richardson, J K; Werner, R A

2001-02-01

To define further the relation between unipedal stance testing and peripheral neuropathy. Prospective cohort. Electroneuromyography laboratory of a Veterans Affairs medical center and a university hospital. Ninety-two patients referred for lower extremity electrodiagnostic studies. A standardized history and physical examination designed to detect peripheral neuropathy, 3 trials of unipedal stance, and electrodiagnostic studies. Peripheral neuropathy was identified by electrodiagnostic testing in 32%. These subjects had a significantly shorter (p unipedal stance time (15.7s, longest of 3 trials) than the patients without peripheral neuropathy (37.1s). Abnormal unipedal stance time (unipedal stance time had a negative predictive value of 90%. Abnormal unipedal stance time was associated with an increased risk of having peripheral neuropathy on univariate analysis (odds ratio = 8.8, 95% confidence interval = 2.5--31), and was the only significant predictor of peripheral neuropathy in the regression model. Aspects of the neurologic examination did not add to the regression model compared with abnormal unipedal stance time. Unipedal stance testing is useful in the clinical setting both to identify and to exclude the presence of peripheral neuropathy.

Ethambutol/Linezolid Toxic Optic Neuropathy.

Science.gov (United States)

Libershteyn, Yevgeniya

2016-02-01

To report a rare toxic optic neuropathy after long-term use of two medications: ethambutol and linezolid. A 65-year-old man presented to the Miami Veterans Affairs Medical Center in December 2014 for evaluation of progressive vision decrease in both eyes. The patient presented with best-corrected visual acuities of 20/400 in the right eye and counting fingers at 5 feet in the left eye. Color vision was significantly reduced in both eyes. Visual fields revealed a cecocentral defect in both eyes. His fundus and optic nerve examination was unremarkable. Because vision continued to decline after discontinuation of ethambutol, linezolid was also discontinued, after which vision, color vision, and visual fields improved. Because of these findings, the final diagnosis was toxic optic neuropathy. Final visual outcome was 20/30 in the right eye and 20/40 in the left eye. Drug-associated toxic optic neuropathy is a rare but vision-threatening condition. Diagnosis is made based on an extensive case history and careful clinical examination. The examination findings include varying decrease in vision, normal pupils and extraocular muscles, and unremarkable fundoscopy, with the possibility of swollen optic discs in the acute stage of the optic neuropathy. Other important findings descriptive of toxic optic neuropathy include decreased color vision and cecocentral visual field defects. This case illustrates the importance of knowledge of all medications and/or substances a patient consumes that may cause a toxic reaction and discontinuing them immediately if the visual functions are worsening or not improving.

Hereditary & familial colorectal cancer : Identification, characteristics, surveillance

NARCIS (Netherlands)

Kallenberg, F.G.J.

2017-01-01

Of all colorectal cancer (CRC) cases, 15-20% is related to familial or hereditary factors. Diagnosing familial and hereditary CRC syndromes is important for several reasons. One of these is that surveillance colonoscopies can reduce CRC incidence and mortality importantly. A complete family history

Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

Science.gov (United States)

Giavina-Bianchi, Pedro; França, Alfeu T; Grumach, Anete S; Motta, Abílio A; Fernandes, Fátima R; Campos, Regis A; Valle, Solange O; Rosário, Nelson A; Sole, Dirceu

2011-01-01

Hereditary angioedema is an autosomal dominant disease characterized by edema attacks with multiple organ involvement. It is caused by a quantitative or functional deficiency of the C1 inhibitor, which is a member of the serine protease inhibitor family. Hereditary angioedema is unknown to many health professionals and is therefore an underdiagnosed disease. The causes of death from hereditary angioedema include laryngeal edema with asphyxia. The estimated mortality rate in patients in whom the disease goes undetected and who are therefore incorrectly treated is 25-40%. In addition to edema of the glottis, hereditary angioedema often results in edema of the gastrointestinal tract, which can be incapacitating. Patients with hereditary angioedema may undergo unnecessary surgical interventions because the digestive tract can be the primary or only organ system involved, thus mimicking acute surgical abdomen. It is estimated that patients with hereditary angioedema experience some degree of disability 20-100 days per year. The Experts in Clinical Immunology and Allergy of the "Associação Brasileira de Alergia e Imunopatologia -ASBAI" developed these guidelines for the diagnosis, therapy, and management of hereditary angioedema.

Peripheral neuropathy in HIV-infected and uninfected patients in Rakai, Uganda.

Science.gov (United States)

Saylor, Deanna; Nakigozi, Gertrude; Nakasujja, Noeline; Robertson, Kevin; Gray, Ronald H; Wawer, Maria J; Sacktor, Ned

2017-08-01

To determine the prevalence, risk factors, and functional impairment associated with peripheral neuropathy in a prospective cohort of adults in rural Uganda. Eight hundred participants (400 HIV- and 400 antiretroviral-naive HIV+) in the Rakai Community Cohort Study underwent detailed neurologic evaluations including assessment of neuropathy symptoms, functional measures (Patient Assessment of Own Functioning Inventory and Karnofsky Performance Status scores), and neurologic evaluation by a trained medical officer. Neuropathy was defined as ≥1 subjective symptom and ≥1 sign of neuropathy on examination. Neuropathy risk factors were assessed using log binomial regression. Fifty-three percent of participants were men, with a mean (SD) age of 35 (8) years. Neuropathy was present in 13% of the cohort and was more common in HIV+ vs HIV- participants (19% vs 7%, p neuropathy in the overall cohort. Only older age was associated with neuropathy risk in the HIV+ (RR 1.03, 95% CI 1.01-1.05) and HIV- (RR 1.06, 95% CI 1.02-1.10) cohorts. Neuropathy was associated with impaired functional status on multiple measures across all participant groups. Peripheral neuropathy is relatively common and associated with impaired functional status among adults in rural Uganda. Older age, female sex, and HIV infection significantly increase the risk of neuropathy. Neuropathy may be an underrecognized but important condition in rural Uganda and warrants further study. © 2017 American Academy of Neurology.

Diagnostic capability of retinal thickness measures in diabetic peripheral neuropathy

Directory of Open Access Journals (Sweden)

Sangeetha Srinivasan

2017-10-01

Conclusions: The GCC FLV can differentiate individuals with diabetic neuropathy from healthy controls, while the inferior RNFL thickness is able to differentiate those with greater degrees of neuropathy from those with mild or no neuropathy, both with an acceptable level of accuracy. Optical coherence tomography represents a non-invasive technology that aids in detection of retinal structural changes in patients with established diabetic neuropathy. Further refinement of the technique and the analytical approaches may be required to identify patients with minimal neuropathy.

Extracellular Matrix Remodeling and Modulation of Inflammation and Oxidative Stress by Sulforaphane in Experimental Diabetic Peripheral Neuropathy.

Science.gov (United States)

Moustafa, Passant E; Abdelkader, Noha F; El Awdan, Sally A; El-Shabrawy, Osama A; Zaki, Hala F

2018-04-27

The peripheral nervous system is one of many organ systems that can be profoundly impacted in diabetes mellitus. Diabetic peripheral neuropathy has a significant negative effect on patients' quality of life as it begins with loss of limbs' sensation and may result in lower limb amputation. This investigation aimed at exploring the effect of sulforaphane on peripheral neuropathy in diabetic rats. Experimental diabetes was induced through single intraperitoneal injections of nicotinamide (50 mg/kg) and streptozotocin (52.5 mg/kg). Rats were divided into five groups. Two groups were treated with saline or sulforaphane (1 mg/kg, p.o.). Three diabetic groups were either untreated or given sulforaphane (1 mg/kg, p.o.) or pregabalin (10 mg/kg, i.p.). Two weeks after drugs' administration, biochemical, behavioral, histopathological, and immunohistochemical investigations were carried out. Treatment with sulforaphane restored animals' body weight, reduced blood glucose, glycated hemoglobin, and increased insulin levels. In parallel, it normalized motor coordination and the latency withdrawal time of tail flick test, increased the latency withdrawal time of cold allodynia test, and ameliorated histopathological changes. Treatment of sulforaphane, likewise, decreased sciatic nerve malondialdehyde, nitric oxide, interleukin-6, and matrix metalloproteinase-2 and -9 contents. Similarly, it reduced sciatic nerve DNA fragmentation and expression of cyclooxygenase-2 and nuclear factor kappa-B p65. Meanwhile, it increased sciatic nerve superoxide dismutase and interleukin-10 contents. These results reveal the neuroprotective effect of sulforaphane against peripheral neuropathy in diabetic rats possibly through modulating oxidative stress, inflammation, and extracellular matrix remodeling. Graphical Abstract Diagram that illustrates the effects of sulforaphane in treating experimental diabetic peripheral neuropathy. In NA-STZ model of diabetes mellitus, sulforaphane, restored

Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy

Science.gov (United States)

Kramer, Rita; Bielawski, Jacek; Kistner-Griffin, Emily; Othman, Alaa; Alecu, Irina; Ernst, Daniela; Kornhauser, Drew; Hornemann, Thorsten; Spassieva, Stefka

2015-01-01

Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and cisplatin chemotherapy. In the current study, we tested the involvement of a novel class of neurotoxic sphingolipids, the 1-deoxysphingolipids. 1-Deoxysphingolipids are produced when the enzyme serine palmitoyltransferase uses l-alanine instead of l-serine as its amino acid substrate. We tested whether treatment of cells with paclitaxel (250 nM, 1 µM) and cisplatin (250 nM, 1 µM) would result in elevated cellular levels of 1-deoxysphingolipids. Our results revealed that paclitaxel, but not cisplatin treatment, caused a dose-dependent elevation of 1-deoxysphingolipids levels and an increase in the message and activity of serine palmitoyltransferase (P peripheral neuropathy symptoms [evaluated by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-chemotherapy-induced peripheral neuropathy-20 (CIPN20) instrument] and the 1-deoxysphingolipid plasma levels (measured by mass spectrometry) in 27 patients with breast cancer who were treated with paclitaxel chemotherapy. Our results showed that there was an association between the incidence and severity of neuropathy and the levels of very-long-chain 1-deoxyceramides such as C24 (P neuropathy (P peripheral neuropathy.—Kramer, R., Bielawski, J., Kistner-Griffin, E., Othman, A., Alecu, I., Ernst, D., Kornhauser, D., Hornemann, T., Spassieva, S. Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy. PMID:26198449

Pure neuritic leprosy presenting as ulnar nerve neuropathy: a case report of electrodiagnostic, radiographic, and histopathological findings.

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Payne, Russell; Baccon, Jennifer; Dossett, John; Scollard, David; Byler, Debra; Patel, Akshal; Harbaugh, Kimberly

2015-11-01

Hansen's disease, or leprosy, is a chronic infectious disease with many manifestations. Though still a major health concern and leading cause of peripheral neuropathy in the developing world, it is rare in the United States, with only about 150 cases reported each year. Nevertheless, it is imperative that neurosurgeons consider it in the differential diagnosis of neuropathy. The causative organism is Mycobacterium leprae, which infects and damages Schwann cells in the peripheral nervous system, leading first to sensory and then to motor deficits. A rare presentation of Hansen's disease is pure neuritic leprosy. It is characterized by nerve involvement without the characteristic cutaneous stigmata. The authors of this report describe a case of pure neuritic leprosy presenting as ulnar nerve neuropathy with corresponding radiographic, electrodiagnostic, and histopathological data. This 11-year-old, otherwise healthy male presented with progressive right-hand weakness and numbness with no cutaneous abnormalities. Physical examination and electrodiagnostic testing revealed findings consistent with a severe ulnar neuropathy at the elbow. Magnetic resonance imaging revealed diffuse thickening and enhancement of the ulnar nerve and narrowing at the cubital tunnel. The patient underwent ulnar nerve decompression with biopsy. Pathology revealed acid-fast organisms within the nerve, which was pathognomonic for Hansen's disease. He was started on antibiotic therapy, and on follow-up he had improved strength and sensation in the ulnar nerve distribution. Pure neuritic leprosy, though rare in the United States, should be considered in the differential diagnosis of those presenting with peripheral neuropathy and a history of travel to leprosy-endemic areas. The long incubation period of M. leprae, the ability of leprosy to mimic other conditions, and the low sensitivity of serological tests make clinical, electrodiagnostic, and radiographic evaluation necessary for diagnosis

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......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...

Transcorneal Electrical Stimulation Therapy for Retinal Disease

Science.gov (United States)

2012-05-03

Retinitis Pigmentosa; Macula Off; Primary Open Angle Glaucoma; Hereditary Macular Degeneration; Treated Retina Detachment; Retinal Artery Occlusion; Retinal Vein Occlusion; Non-Arthritic-Anterior-Ischemic Optic-Neuropathy; Hereditary Autosomal Dominant Optic Atrophy; Dry Age Related Macular Degeneration; Ischemic Macula Edema

Immune mediated neuropathy following checkpoint immunotherapy.

Science.gov (United States)

Gu, Yufan; Menzies, Alexander M; Long, Georgina V; Fernando, S L; Herkes, G

2017-11-01

Checkpoint immunotherapy has revolutionised cancer therapy and is now standard treatment for many malignancies including metastatic melanoma. Acute inflammatory neuropathies, often labelled as Guillain-Barre syndrome, are an uncommon but potentially severe complication of checkpoint immunotherapy with individual cases described but never characterised as a group. We describe a case of acute sensorimotor and autonomic neuropathy following a single dose of combination ipilimumab and nivolumab for metastatic melanoma. A literature search was performed, identifying 14 other cases of acute neuropathy following checkpoint immunotherapy, with the clinical, electrophysiological and laboratory features summarised. Most cases described an acute sensorimotor neuropathy (92%) with hyporeflexia (92%) that could occur from induction up till many weeks after the final dose of therapy. In contrast to Guillain-Barre syndrome, the cerebrospinal fluid (CSF) analysis often shows a lymphocytic picture (50%) and the electrophysiology showed an axonal pattern (55%). Treatment was variable and often in combination. 11 cases received steroid therapy with only 1 death within this group, whereas of the 4 patients who did not receive steroid therapy there were 3 deaths. In conclusion checkpoint immunotherapy - induced acute neuropathies are distinct from and progress differently to Guillain-Barre syndrome. As with other immunotherapy related adverse events corticosteroid therapy should be initiated in addition to usual therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Screening for Electrophysiological Abnormalities in Chronic Hepatitis C Infection: Peripheral Neuropathy and Optic Neuropathy.

Science.gov (United States)

Köşkderelioğlu, Aslı; Ortan, Pınar; Ari, Alpay; Gedizlioğlu, Muhteşem

2016-03-01

To investigate the existence of peripheral and optic neuropathies in asymptomatic individuals with hepatitis C infection. Thirty consecutive patients who were followed in a hepatitis C outpatient clinic were recruited for electrophysiological evaluation together with 30 age- and gender-compatible healthy controls. All patients had a detailed neurological examination. The information regarding the disease duration and management with interferons were collected. Nerve conduction studies and visual evoked potentials (VEP) were recorded in all subjects. The results of the patient and control groups were statistically compared. Of the patients with hepatitis C infection, 16 were females and 14 males. The mean age was 57.5 years, and the average disease duration was 6.43 years. The P100 latencies in the patient group were within normal limits, while the amplitudes were meaningfully small by comparison with the controls. There were some abnormalities in the nerve conduction studies of 15 patients. Sensorial neuropathy was detected in two patients, sensorimotor polyneuropathy in four, carpal tunnel syndrome in seven, and carpal tunnel syndrome and sensorimotor polyneuropathy as comorbid states in another two patients. The nerve conduction studies and VEP parameters were entirely normal in the control group. Hepatitis C-related neurological abnormalities may occur both in the central and peripheral nervous system. Mononeuritis multiplex, sensorial axonal neuropathy, and multiple mononeuropathies are some of the presentations of the peripheral nervous system involvement. The mode of infection is considered to be via vasculitic mechanisms. In addition, optic neuropathy is a known complication of interferon treatment. Autoantibodies, cytokines, chemokines, and cryoglobulins are accused to play roles in the pathogenesis. In this study, we investigated the involvement of the peripheral nervous system and optic nerves in a group of patients with hepatitis C. The results were in

AUTOSOMAL RECESSIVE PERIPHERAL NEUROPATHY WITH NEUROMYOTONIA (ARAN-NM: DESCRIPTION OF A CLINICAL CASE CONFIRMED BY A MUTATION IN THE HINT1 GENE

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Olga A. Klochkova

2017-01-01

Full Text Available Autosomal recessive  peripheral neuropathy with neuromyotonia  (ARAN-NM  is a relatively newly described  disease associated  with mutations  in the HINT1 gene.  It accounts  for a significant  part of the poorly  differentiated  forms  of axonal polyneuropathies.  We present the first in Russia description of the genetically confirmed case of ARAN-NM in a boy aged 14 years and 11 months without the hereditary-tainted anamnesis. On presentation,  the patient experienced  progressive  distal muscular weakness, asymmetric foot deformity,  gait disorders  and minimal manifestations  of neuromyotonia  (stiffness  in the fingers.  During examination,  we detected an increase in the level of creatine phosphokinase up to 635 U/l, a disturbance of conduction of motor and, to a lesser extent, sensory fibers  of  the  peripheral  nerves  (according  to  the  stimulation  electromyography,  EMG,  denervation-reinnervation  changes,  single positive acute waves, fibrillation potentials, complex repeated discharge (according to the data of needle EMG. In the study of exome, a homozygous mutation c.110G>C, p.R37P was determined in exon 01 of the HINT1 gene, which confirmed the presence of ARAN-NM. A molecular-genetic  examination of the patient's immediate relatives was carried out. The described case is compared with literature data. An overview of currently available information on ARAN-NM is provided. Diagnostic criteria of the disease are presented.

Assessment of Motor Units in Neuromuscular Disease.

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Henderson, Robert D; McCombe, Pamela A

2017-01-01

The motor unit comprises the anterior horn cell, its axon, and the muscle fibers that it innervates. Although the true number of motor units is unknown, the number of motor units appears to vary greatly between different muscles and between different individuals. Assessment of the number and function of motor units is needed in diseases of the anterior horn cell and other motor nerve disorders. Amyotrophic lateral sclerosis is the most important disease of anterior horn cells. The need for an effective biomarker for assessing disease progression and for use in clinical trials in amyotrophic lateral sclerosis has stimulated the study of methods to measure the number of motor units. Since 1970 a number of different methods, including the incremental, F-wave, multipoint, and statistical methods, have been developed but none has achieved widespread applicability. Two methods (MUNIX and the multipoint incremental method) are in current use across multiple centres and are discussed in detail in this review, together with other recently published methods. Imaging with magnetic resonance and ultrasound is increasingly being applied to this area. Motor unit number estimates have also been applied to other neuromuscular diseases such as spinal muscular atrophy, compression neuropathies, and prior poliomyelitis. The need for an objective measure for the assessment of motor units remains tantalizingly close but unfulfilled in 2016.

Peripheral Neuropathy and Nerve Compression Syndromes in Burns.

Science.gov (United States)

Strong, Amy L; Agarwal, Shailesh; Cederna, Paul S; Levi, Benjamin

2017-10-01

Peripheral neuropathy and nerve compression syndromes lead to substantial morbidity following burn injury. Patients present with pain, paresthesias, or weakness along a specific nerve distribution or experience generalized peripheral neuropathy. The symptoms manifest at various times from within one week of hospitalization to many months after wound closure. Peripheral neuropathy may be caused by vascular occlusion of vasa nervorum, inflammation, neurotoxin production leading to apoptosis, and direct destruction of nerves from the burn injury. This article discusses the natural history, diagnosis, current treatments, and future directions for potential interventions for peripheral neuropathy and nerve compression syndromes related to burn injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Brazilian guidelines for the diagnosis and treatment of hereditary angioedema

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Pedro Giavina-Bianchi

2011-01-01

Full Text Available Hereditary angioedema is an autosomal dominant disease characterized by edema attacks with multiple organ involvement. It is caused by a quantitative or functional deficiency of the C1 inhibitor, which is a member of the serine protease inhibitor family. Hereditary angioedema is unknown to many health professionals and is therefore an underdiagnosed disease. The causes of death from hereditary angioedema include laryngeal edema with asphyxia. The estimated mortality rate in patients in whom the disease goes undetected and who are therefore incorrectly treated is 25-40%. In addition to edema of the glottis, hereditary angioedema often results in edema of the gastrointestinal tract, which can be incapacitating. Patients with hereditary angioedema may undergo unnecessary surgical interventions because the digestive tract can be the primary or only organ system involved, thus mimicking acute surgical abdomen. It is estimated that patients with hereditary angioedema experience some degree of disability 20-100 days per year. The Experts in Clinical Immunology and Allergy of the "Associação Brasileira de Alergia e Imunopatologia -ASBAI" developed these guidelines for the diagnosis, therapy, and management of hereditary angioedema.

Carcinomatous versus radiation-induced brachial plexus neuropathy in breast cancer

International Nuclear Information System (INIS)

Bagley, F.H.; Walsh, J.W.; Cady, B.; Salzman, F.A.; Oberfield, R.A.; Pazianos, A.G.

1978-01-01

A retrospective study was performed of 18 women in whom ipsilateral brachial plexus neuropathy developed after treatment for carcinoma of the breast. In the absence of metastatic tumor elsewhere, the only distinguishing feature between carcinomatous neuropathy and radiation-induced neuropathy was the symptom-free interval after mastectomy and radiation therapy. Women with an interval of less than a year have radiation-induced neuropathy. Brachial plexus exploration in difficult diagnostic situations will permit early treatment and avoid debilitating loss of function. Brachial plexus exploration for biopsy is safe and free of complications if performed carefully. Treatment of carcinomatous neuropathy is most likely to succeed if the tumor is hormonally sensitive, but radiotherapy may also be effective. Treatment of radiation-induced neuropathy remains largely ineffective

Concurrent targeting of nitrosative stress-PARP pathway corrects functional, behavioral and biochemical deficits in experimental diabetic neuropathy

Energy Technology Data Exchange (ETDEWEB)

Negi, Geeta; Kumar, Ashutosh [Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160062 (India); Sharma, Shyam S., E-mail: sssharma@niper.ac.in [Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160062 (India)

2010-01-01

Peroxynitrite mediated nitrosative stress, an indisputable initiator of DNA damage and overactivation of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated after sensing DNA damage, are two crucial pathogenetic mechanisms in diabetic neuropathy. The intent of the present study was to investigate the effect of combination of a peroxynitrite decomposition catalyst (PDC), FeTMPyP and a PARP inhibitor, 4-ANI against diabetic peripheral neuropathy. The end points of evaluation of the study included motor nerve conduction velocity (MNCV) and nerve blood flow (NBF) for evaluating nerve functions; thermal hyperalgesia and mechanical allodynia for assessing nociceptive alterations, malondialdehyde and peroxynitrite levels to detect oxidative stress-nitrosative stress; NAD concentration in sciatic nerve to assess overactivation of PARP. Additionally immunohistochemical studies for nitrotyrosine and Poly(ADP-ribose) (PAR) was also performed. Treatment with the combination of FeTMPyP and 4-ANI led to significant improvement in nerve functions and pain parameters and also attenuated the oxidative-nitrosative stress markers. Further, the combination also reduced the overactivation of PARP as evident from increased NAD levels and decreased PAR immunopositivity in sciatic nerve microsections. Thus, it can be concluded that treatment with the combination of a PDC and PARP inhibitor attenuates alteration in peripheral nerves in diabetic neuropathy (DN).

Peripheral neuropathy in thalassemia

International Nuclear Information System (INIS)

Sawaya, Raja A.; Tahir, A.; Zahad, L.

2006-01-01

Patients with thalassemia may complain of numbness and weakness of lower extremities. The aim of the study was to determine whether these patients suffer from a polyneuropathy and to determine any contributing factors for the development of neuropathy. We examined 30 patients with thalasemia major and intermedia, clinically and electrophysiologically. We correlated these findings with demographics, blood status and treatment and compared electrophysiologic data with 30 age and sex matched normal subjects or historical controls. We found that 78% of thalassemia patients suffer from a mild sensory polyneuropathy. The neuropathy seemed to be worse in the intermedia type. Thalassemia patients who received blood transfusions and deferoaximine had better nerve faction than those who did not, irrespective of the dose of the deferoxamine. The neuropathy was worse for the older patients, irrespective of the sex. The hemoglobin level, and the fact that some patients underwent spleenctomy, did not affect the status of the patient's nerves. Patients with thalassemia may suffer from a sensor polyneuropathy especially as they grow older and they are not optimally treated. (author)

Properties of pattern standard deviation in open-angle glaucoma patients with hemi-optic neuropathy and bi-optic neuropathy.

Science.gov (United States)

Heo, Dong Won; Kim, Kyoung Nam; Lee, Min Woo; Lee, Sung Bok; Kim, Chang-Sik

2017-01-01

To evaluate the properties of pattern standard deviation (PSD) according to localization of the glaucomatous optic neuropathy. We enrolled 242 eyes of 242 patients with primary open-angle glaucoma, with a best-corrected visual acuity ≥ 20/25, and no media opacity. Patients were examined via dilated fundus photography, spectral-domain optical coherence tomography, and Humphrey visual field examination, and divided into those with hemi-optic neuropathy (superior or inferior) and bi-optic neuropathy (both superior and inferior). We assessed the relationship between mean deviation (MD) and PSD. Using broken stick regression analysis, the tipping point was identified, i.e., the point at which MD became significantly associated with a paradoxical reversal of PSD. In 91 patients with hemi-optic neuropathy, PSD showed a strong correlation with MD (r = -0.973, β = -0.965, p < 0.001). The difference between MD and PSD ("-MD-PSD") was constant (mean, -0.32 dB; 95% confidence interval, -2.48~1.84 dB) regardless of visual field defect severity. However, in 151 patients with bi-optic neuropathy, a negative correlation was evident between "-MD-PSD" and MD (r2 = 0.907, p < 0.001). Overall, the MD tipping point was -14.0 dB, which was close to approximately 50% damage of the entire visual field (p < 0.001). Although a false decrease of PSD usually begins at approximately 50% visual field damage, in patients with hemi-optic neuropathy, the PSD shows no paradoxical decrease and shows a linear correlation with MD.

Autonomic Neuropathy in Diabetes Mellitus

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