WorldWideScience

Sample records for charcot-marie-tooth disease type

  1. Charcot-Marie-Tooth disease complicating type 2 diabetes.

    LENUS (Irish Health Repository)

    Win, Htet Htet Ne

    2012-02-01

    Although both conditions are relatively common, there are very few descriptions of type 2 diabetes mellitus coexisting with Charcot-Marie-Tooth disease (CMT). This case report and literature review describes a 53-year-old Irish man who presented with type 2 diabetes and significant neuropathy, and who was subsequently diagnosed with CMT type 1A. This case report will also discuss how to differentiate diabetic neuropathy from a progressive hereditary neuropathy and how coexistence aggravates the progression of neuropathy thus necessitating early diagnosis.

  2. Charcot-marie-tooth disease complicating type 2 diabetes.

    LENUS (Irish Health Repository)

    Win, Htet Htet Ne

    2011-07-01

    Although both conditions are relatively common, there are very few descriptions of type 2 diabetes mellitus coexisting with Charcot-Marie-Tooth disease (CMT). This case report and literature review describes a 53-year-old Irish man who presented with type 2 diabetes and significant neuropathy, and who was subsequently diagnosed with CMT type 1A. This case report will also discuss how to differentiate diabetic neuropathy from a progressive hereditary neuropathy and how coexistence aggravates the progression of neuropathy thus necessitating early diagnosis.

  3. Charcot-Marie-Tooth disease type 1A

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Børglum, A D; Brandt, C A

    1994-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant peripheral neuropathy associated with a DNA duplication on chromosome 17p11.2-p12 in the majority of cases. Most of the sporadic cases are due to a de novo duplication. We have screened for this duplication in 11 Danish patients...... with CMT type 1, using four different techniques, and identified a de novo duplication in a sporadic case. Analysis of the fully informative pVAW409R3a alleles in this family showed the duplication to be of paternal origin....

  4. De novo PMP2 mutations in families with type 1 Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Motley, William W; Palaima, Paulius; Yum, Sabrina W; Gonzalez, Michael A; Tao, Feifei; Wanschitz, Julia V; Strickland, Alleene V; Löscher, Wolfgang N; De Vriendt, Els; Koppi, Stefan; Medne, Livija; Janecke, Andreas R; Jordanova, Albena; Zuchner, Stephan; Scherer, Steven S

    2016-06-01

    We performed whole exome sequencing on a patient with Charcot-Marie-Tooth disease type 1 and identified a de novo mutation in PMP2, the gene that encodes the myelin P2 protein. This mutation (p.Ile52Thr) was passed from the proband to his one affected son, and segregates with clinical and electrophysiological evidence of demyelinating neuropathy. We then screened a cohort of 136 European probands with uncharacterized genetic cause of Charcot-Marie-Tooth disease and identified another family with Charcot-Marie-Tooth disease type 1 that has a mutation affecting an adjacent amino acid (p.Thr51Pro), which segregates with disease. Our genetic and clinical findings in these kindred demonstrate that dominant PMP2 mutations cause Charcot-Marie-Tooth disease type 1.

  5. A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease.

    Science.gov (United States)

    Gonzalez, Michael A; Feely, Shawna M; Speziani, Fiorella; Strickland, Alleene V; Danzi, Matt; Bacon, Chelsea; Lee, Youjin; Chou, Tsui-Fen; Blanton, Susan H; Weihl, Conrad C; Zuchner, Stephan; Shy, Michael E

    2014-11-01

    Mutations in VCP have been reported to account for a spectrum of phenotypes that include inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia, hereditary spastic paraplegia, and 1-2% of familial amyotrophic lateral sclerosis. We identified a novel VCP mutation (p.Glu185Lys) segregating in an autosomal dominant Charcot-Marie-Tooth disease type 2 family. Functional studies showed that the Glu185Lys variant impaired autophagic function leading to the accumulation of immature autophagosomes. VCP mutations should thus be considered for genetically undefined Charcot-Marie-Tooth disease type 2.

  6. Nerve Excitability Properties in Charcot-Marie-Tooth Disease Type 1A

    Science.gov (United States)

    Nodera, Hiroyuki; Bostock, Hugh; Kuwabara, Satoshi; Sakamoto, Takashi; Asanuma, Kotaro; Jia-Ying, Sung; Ogawara, Kazue; Hattori, Naoki; Hirayama, Masaaki; Kaji, Ryuji

    2004-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is commonly considered a prototype of a hereditary demyelinating polyneuropathy. Apart from the myelin involvement, there has been little information on axonal membrane properties in this condition. Taking advantage of the uniform nature of the disease process, we undertook the "in vivo" assessment of…

  7. Neuromuscular Hip Dysplasia in Charcot-Marie-Tooth Disease Type 1A

    Science.gov (United States)

    Bamford, Nigel S.; White, Klane K.; Robinett, Stephanie A.; Otto, Randolph K.; Gospe, Sidney M., Jr.

    2009-01-01

    Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders, affecting 36 in 100,000 people. CMT type 1A (hereditary motor and sensory neuropathy) is the most frequent form of this disease, affecting 60 to 80% of the CMT population, but its diagnosis may be delayed because of inconsistent clinical signs and…

  8. Hand involvement in children with Charcot-Marie-Tooth disease type 1A

    NARCIS (Netherlands)

    Burns, Joshua; Bray, Paula; Cross, Lauren A.; North, Kathryn N.; Ryan, Monique M.; Ouvrier, Robert A.

    2008-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A), a demyelinating neuropathy characterised by progressive length-dependent muscle weakness and atrophy, is thought to affect the foot and leg first followed some time later by hand weakness and dysfunction. We aimed to characterise hand Strength, function a

  9. Charcot-Marie-Tooth disease.

    LENUS (Irish Health Repository)

    Reilly, Mary M

    2011-03-01

    Charcot-Marie-Tooth (CMT) disease is the commonest inherited neuromuscular disorder affecting at least 1 in 2,500. Over the last two decades, there have been rapid advances in understanding the molecular basis for many forms of CMT with more than 30 causative genes now described. This has made obtaining an accurate genetic diagnosis possible but at times challenging for clinicians. This review aims to provide a simple, pragmatic approach to diagnosing CMT from a clinician\\'s perspective.

  10. Laparoscopic appendectomy in a pediatric patient with type 1 Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Heller, Joshua A; Marn, Richard Y

    2015-12-01

    A pediatric patient with type 1 Charcot-Marie-Tooth disease-a disorder associated with a demyelinating polyneuropathy-presented for laparoscopic appendectomy in the setting of acute appendicitis. Induction and maintenance of anesthesia were successfully managed without the use of any depolarizing or nondepolarizing neuromuscular blocking agents. The patient was successfully extubated at the completion of the procedure without any respiratory or neuromuscular sequelae, with excellent pain control and no postoperative nausea or vomiting.

  11. A novel transgenic mouse model of Chinese Charcot-Marie-Tooth disease type 2L

    Institute of Scientific and Technical Information of China (English)

    Ruxu Zhang; Qian Pan; Beisha Tang; Fufeng Zhang; Xiaobo Li; Shunxiang Huang; Xiaohong Zi; Ting Liu; Sanmei Liu; Xuning Li; Kun Xia

    2014-01-01

    We previously found that the K141N mutation in heat shock protein B8 (HSPB8) was respon-sible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a transgenic mouse model bearing the K141N mutation in the human HSPB8 gene, and to determine whether this K141NHSPB8 transgenic mouse model would manifest the clinical phenotype of Charcot-Marie-Tooth disease type 2L, and consequently be suitable for use in studies of disease pathogenesis. Transgenic mice overexpressing K141NHSPB8 were generated using K141N mutant HSPB8 cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. PCR and western blot analysis conifrmed integra-tion of the K141NHSPB8 gene and widespread expression in tissues of the transgenic mice. The K141NHSPB8 transgenic mice exhibited decreased muscle strength in the hind limbs and impaired motor coordination, but no obvious sensory disturbance at 6 months of age by behavioral assess-ment. Electrophysiological analysis showed that the compound motor action potential amplitude in the sciatic nerve was signiifcantly decreased, but motor nerve conduction velocity remained normal at 6 months of age. Pathological analysis of the sciatic nerve showed reduced myelinated ifber density, notable axonal edema and vacuolar degeneration in K141NHSPB8 transgenic mice, suggesting axonal involvement in the peripheral nerve damage in these animals. These ifndings indicate that the K141NHSPB8 transgenic mouse successfully models Charcot-Marie-Tooth disease type 2L and can be used to study the pathogenesis of the disease.

  12. Charcot-Marie-Tooth Disease Type 2B

    Directory of Open Access Journals (Sweden)

    Şenay Durdu

    2009-06-01

    Full Text Available Chatcot-Marie-Tooth (CMT is also known as peroneal muscular atrophy and hereditary motor-sensory neuropathy (HMSN. It is the most commonly encountered inherited peripheral neuropathy. Actually, CMT is not a single disease, but is a group of disorders with similar symptoms. CMT type 2 is the second most common form after CMT type1. Symptoms usually begin in childhood or early adulthood. Mostly the peripheral nerves of the lower extremities and occasionaly upper extremities may be affected. Motor nerve involvoment induces distal muscle weakness and atrophy in the lower extremities that may result in foot deformities known as foot drop, pes cavus, pes planus, hammer toe etc. As a result of sensorial nevre degeneration, callus, recurrent foot ulcers, osteonecrosis, osteolysis and spontaneous amputation may accompany the disease. The speed of nerve conduction is not changed in the EMG, but axonal type sensorymotor semptoms that lead to a decrease of amplitude. We report here a 55 year old man with recurrent foot ulcers for 33 years and self amputations, whose EMG findings suggest acsonal neuropathy and who also has a 20 year - old son with similar complaints.

  13. A family with Charcot-Marie-Tooth disease (type 1: evaluating diagnostic role of nerve conduction studies

    Directory of Open Access Journals (Sweden)

    Sangeeta Gupta

    2014-06-01

    Full Text Available We aimed to report a case history of a family with Charcot-Marie-Tooth disease and to assess the role of nerve conduction studies in the diagnosis. A 10-year-old girl presented with difficulty in walking with a history of delayed motor milestones and slowly progressive weakness in distal muscles of both the lower limbs, with similar group of complaints in her father and a younger brother. Clinical examination of the patients was done and nerve conduction studies were performed. Clinical features and nerve conduction studies suggested the diagnosis as Charcot-Marie-Tooth disease with characteristic electro-diagnostic findings of Charcot-Marie-Tooth disease type-1. Charcot-Marie-Tooth disease is a rare disorder found in India. Although genetic tests form the basis of accurate diagnosis, yet nerve conduction studies, to a great extent, prove to be remarkable in approaching the diagnosis and distinguishing the common subtypes of this rare condition. [Int J Res Med Sci 2014; 2(3.000: 1147-1150

  14. Early Onset Charcot-Marie-Tooth Disease

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-06-01

    Full Text Available The clinical signs and genetic analysis of early-onset Charcot-Marie-Tooth disease (CMT in a 2-year-old boy and members of his family are reported from the Academic Medical Center, Amsterdam, and Sophia Children’s Hospital, Rotterdam, the Netherlands.

  15. Factors associated with foot and ankle strength in healthy preschool-age children and age-matched cases of Charcot-Marie-Tooth disease type 1A.

    Science.gov (United States)

    Rose, Kristy J; Burns, Joshua; North, Kathryn N

    2010-04-01

    Charcot-Marie-Tooth disease affects foot and ankle strength from the earliest stages of the disease; however, little is known about factors influencing normal strength development or the pathogenesis of foot weakness and deformity in Charcot-Marie-Tooth disease. The authors investigated factors associated with foot and ankle strength in healthy preschool-age children and compared to age-matched cases of Charcot-Marie-Tooth disease type 1A. In healthy children, ankle dorsiflexion range of motion was one of the strongest independent correlates of foot and ankle strength. Compared with healthy children, those with Charcot-Marie-Tooth disease type 1A had significantly less dorsiflexion strength and range as well as imbalance in inversion-to-eversion and plantarflexion-to-dorsiflexion strength ratios. Given the association between ankle dorsiflexion strength and range in the healthy children, and the abnormality of these parameters in Charcot-Marie-Tooth disease, investigation of the cause-effect relationship is warranted to identify more targeted therapy and further understand the pathogenesis of foot deformity in Charcot-Marie-Tooth disease.

  16. Charcot-Marie-Tooth type 4F disease caused by S399fsx410 mutation in the PRX gene.

    Science.gov (United States)

    Kabzinska, D; Drac, H; Sherman, D L; Kostera-Pruszczyk, A; Brophy, P J; Kochanski, A; Hausmanowa-Petrusewicz, I

    2006-03-14

    Charcot-Marie-Tooth type 4F disease (CMT4F) is an autosomal recessive neuropathy caused by mutations in the PRX gene. To date, only seven mutations have been identified in the PRX gene. In this study, the authors report a novel S399fsX410 mutation in the PRX gene and its effects at the protein level, which was identified in an 8-year-old patient with early-onset CMT disease.

  17. Charcot-Marie-Tooth type 1A disease from patient to laboratory.

    Science.gov (United States)

    Perveen, Shazia; Mannan, Shazia; Hussain, Abrar; Kanwal, Sumaira

    2015-02-01

    Charcot-Marie-Tooth (CMT) disease is a well-known neural or spinal type of muscular atrophy. It is the most familiar disease within a group of conditions called Hereditary Motor and Sensory Neuropathies (HMSN). The disease was discovered by three scientists several years ago. Several genes are involved as the causative agents for the disease. Hundreds of causative mutations have been found and research work for the identification of a novel locus and for the treatment of CMT1A is going on. This review article was planned to gather information on CMT disease and updates on its treatment.National Center for Biotechnology Information (NCBI) and PubMed were searched for data retrieval. Molgen database, which is the exclusive site for CMT mutation, was the other source of articles. Different aspects of the CMT disease were compared.Advancements in the finding of the causative gene, discovery of the novel Loci are the current issues in this regard.CMT disease is incurable, but researchers are trying to get some benefits from different natural compounds and several therapeutic agents.Various groups are working on the treatment projects of CMT1A. Major step forward in CMT research was taken in 2004 when ascorbic acid was used for transgenic mice treatment. Gene therapy for constant neurotrophin-3 (NT- 3) delivery by secretion by muscle cells for the CMT1A is also one of the possible treatments under trial.

  18. Myelin protein zero gene sequencing diagnoses Charcot-Marie-Tooth Type 1B disease

    Energy Technology Data Exchange (ETDEWEB)

    Su, Y.; Zhang, H.; Madrid, R. [Univ. of California, San Francisco, CA (United States)] [and others

    1994-09-01

    Charcot-Marie-Tooth disease (CMT), the most common genetic neuropathy, affects about 1 in 2600 people in Norway and is found worldwide. CMT Type 1 (CMT1) has slow nerve conduction with demyelinated Schwann cells. Autosomal dominant CMT Type 1B (CMT1B) results from mutations in the myelin protein zero gene which directs the synthesis of more than half of all Schwann cell protein. This gene was mapped to the chromosome 1q22-1q23.1 borderline by fluorescence in situ hybridization. The first 7 of 7 reported CMT1B mutations are unique. Thus the most effective means to identify CMT1B mutations in at-risk family members and fetuses is to sequence the entire coding sequence in dominant or sporadic CMT patients without the CMT1A duplication. Of the 19 primers used in 16 pars to uniquely amplify the entire MPZ coding sequence, 6 primer pairs were used to amplify and sequence the 6 exons. The DyeDeoxy Terminator cycle sequencing method used with four different color fluorescent lables was superior to manual sequencing because it sequences more bases unambiguously from extracted genomic DNA samples within 24 hours. This protocol was used to test 28 CMT and Dejerine-Sottas patients without CMT1A gene duplication. Sequencing MPZ gene-specific amplified fragments identified 9 polymorphic sites within the 6 exons that encode the 248 amino acid MPZ protein. The large number of major CMT1B mutations identified by single strand sequencing are being verified by reverse strand sequencing and when possible, by restriction enzyme analysis. This protocol can be used to distringuish CMT1B patients from othre CMT phenotypes and to determine the CMT1B status of relatives both presymptomatically and prenatally.

  19. Quality-of-life in Charcot-Marie-Tooth disease: the patient's perspective.

    Science.gov (United States)

    Johnson, Nicholas E; Heatwole, Chad R; Dilek, Nuran; Sowden, Janet; Kirk, Callyn A; Shereff, Denise; Shy, Michael E; Herrmann, David N

    2014-11-01

    This study determines the impact of symptoms associated with Charcot-Marie-Tooth disease on quality-of-life. Charcot-Marie-Tooth patients in the Inherited Neuropathies Consortium Rare Diseases Clinical Research Network Contact Registry were surveyed. The survey inquired about 214 symptoms and 20 themes previously identified as important to Charcot-Marie-Tooth patients through patient interviews. Symptom population impact was calculated as the prevalence multiplied by the relative importance of each symptom identified. Prevalence and symptom impact were analyzed by age, symptom duration, gender, Charcot-Marie-Tooth type, and employment status. 407 participants returned the survey, identifying foot and ankle weakness (99.7%) and impaired balance (98.6%) as the most prevalent themes. Foot and ankle weakness and limitations with mobility were the themes with the highest impact. Both symptom prevalence and impact gradually increased with age and symptom duration. Several themes were more prevalent in women with Charcot-Marie-Tooth, including activity limitations, pain, fatigue, hip-thigh weakness, and gastrointestinal issues. All of the themes, except emotional or body image issues, were more prevalent among unemployed individuals. There were minimal differences in symptom prevalence between Charcot-Marie-Tooth types. There are multiple symptoms that impact Charcot-Marie-Tooth quality-of-life in adults. These symptoms have different levels of importance, are readily recognized by patients, and represent critical areas of Charcot-Marie-Tooth health.

  20. Pediatric Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Jani-Acsadi, Agnes; Ounpuu, Sylvia; Pierz, Kristan; Acsadi, Gyula

    2015-06-01

    Heritable diseases of the peripheral nerves (Charcot-Marie-Tooth disease [CMT]) affect the motor units and sensory nerves, and they are among the most prevalent genetic conditions in the pediatric patient population. The typical clinical presentation includes distal muscle weakness and atrophy, but the severity and progression are largely variable. Improvements in supportive treatment have led to better preservation of patients' motor functions. More than 80 genes have been associated with CMT. These genetic discoveries, along with the developments of cellular and transgenic disease models, have allowed clinicians to better understand the disease mechanisms, which should lead to more specific treatments.

  1. Charcot-Marie-Tooth Disease

    Science.gov (United States)

    ... as the hormone androgen, to prevent nerve degeneration. Vitamin C has been studied in CMT1A and the ... Complications of AIDS Information Page Neurological Complications of Lyme Disease Information Page Neuromyelitis Optica Information Page Neuronal Migration ...

  2. Rapid genetic screening of Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies patients

    Institute of Scientific and Technical Information of China (English)

    Xiaobo Li; Kun Xia; Beisha Tang; Ruxu Zhang; Xiaohong Zi; Lin Li; Yajing Zhan; Shunxiang Huang; Jin Li; Xuning Li; Xigui Li; Zhengmao Hu

    2012-01-01

    We used the allele-specific PCR-double digestion method on peripheral myelin protein 22 (PMP22) to determine duplication and deletion mutations in the proband and family members of one family with Charcot-Marie-Tooth disease type 1 and one family with hereditary neuropathy with liability to pressure palsies. The proband and one subclinical family member from the Charcot-Marie-Tooth disease type 1 family had a PMP22 gene duplication; one patient from the hereditary neuropathy with liability to pressure palsies family had a PMP22 gene deletion. Electron microscopic analysis of ultrathin sections of the superficial peroneal nerve from the two probands demonstrated demyelination and myelin sheath hyperplasia, as well as an ‘onion-like’ structure in the Charcot-Marie-Tooth disease type 1A patient. We observed an irregular thickened myelin sheath and ‘mouse-nibbled’-like changes in the patient with hereditary neuropathy with liability to pressure palsies. In the Charcot-Marie-Tooth disease type 1A patient, nerve electrophysiological examination revealed moderate-to-severe reductions in the motor and sensory conduction velocities of the bilateral median nerve, ulnar nerve, tibial nerve, and sural nerve. Moreover, the compound muscle action potential amplitude was decreased. In the patient with hereditary neuropathy with liability to pressure palsies, the nerve conduction velocity of the bilateral tibial nerve and sural nerve was moderately reduced, and the nerve conduction velocity of the median nerve and ulnar nerve of both upper extremities was slightly reduced.

  3. Tripod pinch strength and thumb opposition are the major determinants of manual dexterity in Charcot-Marie-Tooth disease type 1A

    NARCIS (Netherlands)

    Videler, A.J.; Beelen, A.; van Schaik, I.N.; Verhamme, C.; van den Berg, L.H.; Visser, M.; Nollet, F.

    2010-01-01

    BACKGROUND: Clinical features of Charcot-Marie-Tooth disease type 1A (CMT1A) include slowly progressive distal muscle weakness, atrophy and sensory loss. Upper-limb involvement results in reduced manual dexterity interfering with the execution of daily activities. OBJECTIVE: To identify which hand f

  4. Mild phenotype of Charcot-Marie-Tooth disease type 4B1.

    Science.gov (United States)

    Murakami, Tatsufumi; Kutoku, Yumiko; Nishimura, Hirotake; Hayashi, Makiko; Abe, Akiko; Hayasaka, Kiyoshi; Sunada, Yoshihide

    2013-11-15

    Charcot-Marie-Tooth type 4B1 (CMT4B1) is a rare autosomal recessive demyelinating neuropathy caused by mutation of the myotubularin-related 2 (MTMR2) gene. It is characterized by a severe early-onset motor and sensory neuropathy, and myelin outfoldings on nerve biopsy. We describe a mild phenotype of CMT4B1 in a Japanese patient. She noticed difficulty in walking as an initial symptom at age 13. Her symptoms progressed slowly, and she could still walk at age 34. There was no cranial neuropathy. A nerve conduction study demonstrated demyelinating neuropathy. Sural nerve biopsy revealed a moderate-to-severe loss of myelinated fibers, and many focally folded myelin sheaths. Electron micrographs showed myelin outfoldings and infoldings. DNA tests for CMT showed that she is a homozygote for the MTMR2 p.R628PfsX18 mutation. The mild phenotype in our patient is probably due to the C-terminal position of the frame-shift mutation in MTMR2.

  5. Effective cauda equina decompression in two siblings with Charcot-Marie-Tooth disease type 1B

    NARCIS (Netherlands)

    van Doormaal, Tristan P C; van Ruissen, Fred; Miller, Kai J; Hoogendijk, Jessica E

    2016-01-01

    Two siblings with Charcot-Marie-Tooth (CMT) 1B due to a c.517G>C (p.Gly173Arg) mutation in the MPZ gene both developed an acute cauda syndrome with unbearable back pain radiating to both legs, progressive muscle weakness of the legs, and saddle hypesthesia with fecal and urinary incontinence. MRI sh

  6. Diagnosis of Charcot-Marie-Tooth Disease

    Directory of Open Access Journals (Sweden)

    Isabel Banchs

    2009-01-01

    Full Text Available Charcot-Marie-Tooth (CMT disease or hereditary motor and sensory neuropathy (HMSN is a genetically heterogeneous group of conditions that affect the peripheral nervous system. The disease is characterized by degeneration or abnormal development of peripheral nerves and exhibits a range of patterns of genetic transmission. In the majority of cases, CMT first appears in infancy, and its manifestations include clumsiness of gait, predominantly distal muscular atrophy of the limbs, and deformity of the feet in the form of foot drop. It can be classified according to the pattern of transmission (autosomal dominant, autosomal recessive, or X linked, according to electrophysiological findings (demyelinating or axonal, or according to the causative mutant gene. The classification of CMT is complex and undergoes constant revision as new genes and mutations are discovered. In this paper, we review the most efficient diagnostic algorithms for the molecular diagnosis of CMT, which are based on clinical and electrophysiological data.

  7. A novel mitofusin 2 gene mutation causing Charcot-Marie-Tooth type 2A disease in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    CHEING Chor Kwan; LAU Kwok Kwong; YU Kwok Wai; CHAN Yan Wo Albert; MAK Miu Chloe

    2010-01-01

    @@ Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathies, comprises a genetically heterogeneous group of inherited peripheral neuropathies. Clinically it is characterized by progressive distal weakness, muscle atrophy, distal sensory loss and loss of deep tendon reflexes. Following electrophysiological criteria, CMT is divided into two main forms: the primarily demyelinating neuropathy CMT1 with severely decreased nerve conduction velocity (NCV) (38 m/s) but decreased amplitudes.1 CMT2A, an autosomal dominant disease caused by mitofusin 2 gene (MFN2) mutations, is the most common type of CMT2, accounting for up to 33% of familial CMT2 cases.2 We reported a patient with clinical diagnosis of CMT2 caused by a novel MFN2 mutation. To our knowledge, this is a relatively early report of genetically confirmed CMT2A in Chinese.

  8. Analysis of the benefits of vitamin cocktails in treating Charcot-Marie-Tooth disease type 1A.

    Science.gov (United States)

    Kaya, Ferdinand; Belin, Sophie; Micallef, Joelle; Blin, Olivier; Fontés, Michel

    2008-08-01

    We recently proposed that the use of high doses of ascorbic acid (AA) could constitute the first potential treatment for Charcot-Marie-Tooth disease type 1A (CMT1A).4 We investigated the potential benefits of using cocktails of vitamins for CMT1A therapy. We used transient transfection of Schwann cells with a construction placing the expression of a reporter gene under the control of the Schwann cell-specific promoter of PMP22. Transfected cells were cultured with or without addition of ascorbic acid, vitamin A, vitamin E, or a cocktail of these vitamins. Adding vitamin A or E counteracts the effect of ascorbic acid in inhibiting PMP22 expression. We thus recommend that vitamins A and E should not be included in combination with AA in clinical trials.

  9. [Case of Charcot-Marie-Tooth disease type 1A with increased cerebrospinal fluid proteins and nerve root hypertrophy].

    Science.gov (United States)

    Ishigami, Noriko; Kondo, Masaki; Nakagawa, Masanori

    2008-06-01

    We report herein a 54-year-old man who first noticed muscle weakness of the hands and legs and hypesthesia of the legs at 20-years-old. Symptoms gradually worsened. Charcot-Marie-Tooth disease type 1A (CMT 1A) was diagnosed on the basis of a nerve conduction study and PMP22 gene duplication. Increased levels of cerebrospinal fluid proteins were identified and cervical and lumbosacral nerve root hypertrophy was evident on magnetic resonance imaging (MRI). CMT 1A with increased CSF proteins and nerve root hypertrophy was carefully evaluated clinically and electrophysiologically to rule out other motor sensory neuropathies such as CIDP. Increased levels of CSF proteins in this case might have resulted from circulatory disturbance of CSF in hypertrophic nerve roots.

  10. [Pathology of Charcot-Marie-Tooth Disease].

    Science.gov (United States)

    Oka, Nobuyuki

    2016-01-01

    Although genetic testing is available, nerve biopsy is useful in selected patients for the diagnosis of Charcot-Marie-Tooth disease (CMT). These are sporadic cases of hereditary neuropathy, or familial cases in which genetic testing is negative. CMT is caused by mutations of various genes. The pathological features of CMT have mostly been investigated using nerve biopsy, which may shed light on the presumed functions of mutated gene products. PMP22 duplication in CMT1A induces numerous large onion bulb lesions (OB). Compared to chronic inflammatory demyelinating polyradiculoneuropathy, the differential features of CMT1A are patchy distribution of OB and non-inflammatory lesions. CMT1B also manifests as OB, but presents abnormal compaction of myelin sheaths caused by uncompacted myelin or excessive myelin folding. CMT2 includes axonal neuropathies and many causative genes have been found. CMT2A (MFN2 mutation) shows abnormal mitochondria with a spherical morphology instead of tubular in the longitudinal direction. CMT4 consists of autosomal recessive forms with demyelinating pathology. Most subtypes have mutations of genes relating to myelin maintenance, and pathologically, they show abnormal folding of the myelin structure.

  11. Charcot-Marie-Tooth disease: genetic and rehabilitation aspects

    Directory of Open Access Journals (Sweden)

    Mariana CEVEI

    2008-05-01

    Full Text Available Charcot-Marie-Tooth hereditary motor and sensory neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy. Typical cases have distal muscle weakness and peroneal atrophy often associated with mild to moderate sensory loss, depressed tendon reflexes, and pes cavus. Hereditary neuropathies are categorized by mode of inheritance and chromosomal locus. The diagnosis is based on family history, characteristic findings on physical examination, EMG, nerve conduction velocity testing, and occasionally on nerve biopsy. The disorder shows allelic and non-allelic genetic heterogeneity, thus mutations of different genes leading to the same clinical features. Also, different mutations of the same gene may lead to different phenotypes. Molecular genetic testing is available in clinical laboratories for diagnosis of 7 subtypes of the disease. Genetic counseling and risk assessment depend on the inheritance. We present two cases with Charcot-Marie-Tooth type 1 and type 2 respectively. There is no cure for the disorder, although physical therapy and moderate activity are often recommended to maintain muscle strength and endurance.

  12. ANESTHESIA FOR CHARCOT-MARIE-TOOTH DISEASE: CASE REPORT.

    Science.gov (United States)

    Alzaben, Khalid R; Samarah, Omar Q; Obeidat, Salameh S; Halhouli, Oday; Al Kharabsheh, Murad

    2016-06-01

    Charcot-Marie-Tooth disease comprises a group of disorders characterized by progressive muscle weakness and wasting. Reviewing the anaesthetic literature produced conflicting reports about the best anaesthetic options for patients with CMTD; as they are at increased risk of prolonged response to muscle relaxants, malignant hyperthermia and risks of regional anaesthesia. We present a case of the successful use of total intravenous anaesthesia with dexmedetomidine and propofol combined with caudal block using bupivacaine mixed with dexmedetomidine without any complications, for a 17 year old male patient with Charcot Marie-Tooth disease who underwent a lower limb orthopedic surgery.

  13. Occurrence of Optic Neuritis and Cervical Cord Schwannoma with Charcot-Marie-Tooth Type 4B1 Disease.

    Science.gov (United States)

    Scott, Patrick; Bruwer, Zandre; Al-Kharusi, Khalsa; Meftah, Douja; Al-Murshedi, Fathiya

    2016-05-01

    Charcot-Marie-Tooth neuropathy type 4B1 (CMT4B1) disease is a rare subtype of CMT4 with reported association of facial weakness, vocal cord paresis, chest deformities, and claw hands. We report the unusual occurrence of optic neuritis and cervical cord schwannoma in a male individual with confirmed CMT4B1 disease. Sequencing of the MTMR2 gene revealed a novel nonsense homozygous mutation c.1768C>T (p.Gln590*). The mutation was identified in affected relatives of the proband and a second, apparently unrelated, family. The rare association of optic neuritis or schwannoma with genetically confirmed CMT1A has been individually observed, but never with recessive CMT. To the best of our knowledge, the occurrence of optic neuritis and cervical cord schwannoma in the same patient has never been reported with any form of CMT including CMT4B1. In similar cases, we recommend immediate medical attention to rule out the possibility of schwannomas in patients with all demyelinating CMT subtypes in case of the development of focal neurological signs or acute worsening of clinical status.

  14. Charcot-Marie-Tooth Disease Type 4H Resulting from Compound Heterozygous Mutations in FGD4 from Nonconsanguineous Korean Families.

    Science.gov (United States)

    Hyun, Young Se; Lee, Jinho; Kim, Hye Jin; Hong, Young Bin; Koo, Heasoo; Smith, Alec S T; Kim, Deok-Ho; Choi, Byung-Ok; Chung, Ki Wha

    2015-11-01

    Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive demyelinating subtype of peripheral enuropathies caused by mutations in the FGD4 gene. Most CMT4H patients are in consanguineous Mediterranean families characterized by early onset and slow progression. We identified two CMT4H patients from a Korean CMT cohort, and performed a detailed genetic and clinical analysis in both cases. Both patients from nonconsanguineous families showed characteristic clinical manifestations of CMT4H including early onset, scoliosis, areflexia, and slow disease progression. Exome sequencing revealed novel compound heterozygous mutations in FGD4 as the underlying cause in both families (p.Arg468Gln and c.1512-2A>C in FC73, p.Met345Thr and c.2043+1G>A (p.Trp663Trpfs*30) in FC646). The missense mutations were located in highly conserved RhoGEF and PH domains which were predicted to be pathogenic in nature by in silico modeling. The CMT4H occurrence frequency was calculated to 0.7% in the Korean demyelinating CMT patients. This study is the first report of CMT4H in Korea. FGD4 assay could be considered as a means of molecular diagnosis for sporadic cases of demyelinating CMT with slow progression.

  15. Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice.

    Science.gov (United States)

    D'Antonio, Maurizio; Musner, Nicolò; Scapin, Cristina; Ungaro, Daniela; Del Carro, Ubaldo; Ron, David; Feltri, M Laura; Wrabetz, Lawrence

    2013-04-01

    P0 glycoprotein is an abundant product of terminal differentiation in myelinating Schwann cells. The mutant P0S63del causes Charcot-Marie-Tooth 1B neuropathy in humans, and a very similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum of Schwann cells, where it promotes unfolded protein stress and elicits an unfolded protein response (UPR) associated with translational attenuation. Ablation of Chop, a UPR mediator, from S63del mice completely rescues their motor deficit and reduces active demyelination by half. Here, we show that Gadd34 is a detrimental effector of CHOP that reactivates translation too aggressively in myelinating Schwann cells. Genetic or pharmacological limitation of Gadd34 function moderates translational reactivation, improves myelination in S63del nerves, and reduces accumulation of P0S63del in the ER. Resetting translational homeostasis may provide a therapeutic strategy in tissues impaired by misfolded proteins that are synthesized during terminal differentiation.

  16. Quality of life in patients with Charcot-Marie-Tooth disease type 1A

    Directory of Open Access Journals (Sweden)

    Juliana B. Taniguchi

    2013-06-01

    Full Text Available We assessed the functional impairment in Charcot-Marie-Tooth resulting from 17p11.2-p12 duplication (CMT1A patients using the Short-Form Health Survey (SF-36, which is a quality of life questionnaire. Twenty-five patients of both genders aged ≥10 years with a positive molecular diagnosis of CMT1A were selected. Age- and gender-matched Control Group (without family history of neuropathy, and the sociodemographic and professional conditions similar to the patients' group were selected to compare the SF-36 results between them. The results showed that the majority quality of life impairments in CMT1A patients occurred in the social and emotional domains. Functional capacity also tended to be significantly affected; other indicators of physical impairment were preserved. In conclusion, social and emotional aspects are mostly neglected in the assistance provided to CMT1A Brazilian patients, and they should be better understood in order to offer global health assistance with adequate quality of life as a result.

  17. Molecular Diagnosis of Charcot-Marie Tooth Disease

    Directory of Open Access Journals (Sweden)

    J. Gordon Millichap

    2002-02-01

    Full Text Available The frequency of mutations in certain genes in 153 unrelated patients with Charcot-Marie-Tooth disease (CMT was determined by DNA sequencing before clinical testing at the Departments of Molecular and Human Genetics and Pediatrics, Baylor College of Medicine, Houston, TX, and other centers.

  18. Muscle pathology without severe nerve pathology in a new mouse model of Charcot-Marie-Tooth disease type 2E.

    Science.gov (United States)

    Shen, Hailian; Barry, Devin M; Dale, Jeffrey M; Garcia, Virginia B; Calcutt, Nigel A; Garcia, Michael L

    2011-07-01

    Mutations in neurofilament light (NF-L) have been linked to Charcot-Marie-Tooth disease type 2E (CMT2E) in humans. To provide insight into disease pathogenesis, we developed a novel line of CMT2E mice that constitutively express human NF-L (hNF-L) with a glutamic acid to lysine mutation at position 397 (hNF-L(E397K)). This new line of mice developed signs consistent with CMT2E patients. Disease signs were first observed at 4 months in hNF-L(E397K) mice, and consisted of aberrant hind limb posture, digit deformities, reduced voluntary locomotor activity, reduced motor nerve conduction velocities (MNCVs) and muscle atrophy. Reduced voluntary locomotor activity and muscle pathology occurred without significant denervation, and hNF-L(E397K) mice showed relatively mild signs of nerve pathology. Nerve pathology in hNF-L(E397K) mice was characterized by ectopic accumulations of phosphorylated NFs in motor neuron cell bodies as early as 1 month. Moreover, NF organization was altered in motor and sensory roots, with small motor axons being most affected. Peak axonal diameter was reduced for small motor axons prior to and after the onset of overt phenotypes, whereas large motor axons were affected only after onset, which correlated with reduced MNCVs. Additionally, there was a small reduction in the number of sensory axons in symptomatic hNF-L(E397K) mice. hNF-L(E397K) mice are a novel line of CMT2E mice that recapitulate many of the overt phenotypes observed in CMT2E patients and hNF-L(P22S) mice. The cellular pathology observed in hNF-L(E397K) mice differed from that recently reported in hNF-L(P22S) mice, suggesting that overt CMT2E phenotypes may arise through different cellular mechanisms.

  19. 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.

  20. First reported case of Charcot Marie Tooth disease type 4C in a child from India with SH3TC2 mutation but absent spinal deformities

    Directory of Open Access Journals (Sweden)

    Umesh Dinkar Kalane

    2015-01-01

    Full Text Available Charcot Marie Tooth (CMT disease is a group of hereditary motor sensory neuropathies with significant genetic heterogeneity. This disorder has been scarcely reported in the Indian literature. Here, we report a case of the rare but relatively more severe autosomal recessive CMT type 4C disease with a few features that are distinct from its regular presentation. Our patient was proven to have one of the common mutations in the SH3TC2 gene, which has so far not been described in Indian patients.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Misclassification and linkage of hereditary sensory and autonomic neuropathy type 1 as Charcot-Marie-Tooth disease, Type 2B

    Energy Technology Data Exchange (ETDEWEB)

    Vance, J.M.; Speer, M.C.; Stajich, J.M. [Duke Univ. Medical Center, Durham, NC (United States)

    1996-07-01

    Recently Kwon et al. published in the Journal their work describing linkage of a single large family with an inherited axonal neuropathy to chromosome 3, which they suggest is a second locus for Charcot-Marie-Tooth (CMT) type 2 and subsequently named {open_quotes}CMT2B.{close_quotes} We think that the diagnostic classification of this family as CMT2 is incorrect, since the subjects have a severe sensory neuropathy that fits within the hereditary sensory and autonomic neuropathy (HSAN) type 1 classification of Dyck (1993). Abnormal sensory findings in CMT2 separate it from distal spinal muscular atrophy but are a minor component of clinical symptoms in most CMT patients, as CMT is primarily a motor neuropathy. When Kwon et al. state that {open_quotes}all [patients] had characteristic findings in their physical examinations, including... evidence of foot sores that were slow to heal, or amputated limbs related to the poorly healing foot ulcers,{close_quotes} it suggests that a different diagnosis is more appropriate. In our experience collecting data on >950 individuals in >60 CMT1, CMT2, CMTX and CMT4 families, we have not seen foot ulcers, osteomyelitis, or amputations. Ulcerations leading to osteomyelitis and amputations are usually associated with severe sensory neuropathies. 16 refs., 1 tab.

  3. A Rasch Analysis of the Charcot-Marie-Tooth Neuropathy Score (CMTNS) in a Cohort of Charcot-Marie-Tooth Type 1A Patients

    Science.gov (United States)

    Guedj, Mickaël; Bertrand, Viviane; Foucquier, Julie; Jouve, Elisabeth; Commenges, Daniel; Proust-Lima, Cécile; Murphy, Niall P.; Blin, Olivier; Magy, Laurent; Cohen, Daniel; Attarian, Shahram

    2017-01-01

    The Charcot-Marie-Tooth Neuropathy Score (CMTNS) was developed as a main efficacy endpoint for application in clinical trials of Charcot-Marie-Tooth disease type 1A (CMT1A). However, the sensitivity of the CMTNS for measuring disease severity and progression in CMT1A patients has been questioned. Here, we applied a Rasch analysis in a French cohort of patients to evaluate the psychometrical properties of the CMTNS. Overall, our analysis supports the validity of the CMTNS for application to CMT1A patients though with some limitations such as certain items of the CMTNS being more suitable for moderate to severe forms of the disease, and some items being disordered. We suggest that additional items and/or categories be considered to better assess mild-to-moderate patients. PMID:28095456

  4. Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Sevilla, Teresa; Lupo, Vincenzo; Martínez-Rubio, Dolores; Sancho, Paula; Sivera, Rafael; Chumillas, María J; García-Romero, Mar; Pascual-Pascual, Samuel I; Muelas, Nuria; Dopazo, Joaquín; Vílchez, Juan J; Palau, Francesc; Espinós, Carmen

    2016-01-01

    Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a

  5. Mapping of the chromosome 1p36 region surrounding the Charcot-Marie-Tooth disease type 2A locus

    Energy Technology Data Exchange (ETDEWEB)

    Denton, P.; Gere, S.; Wolpert, C. [Duke Univ., Durham, NC (United States)] [and others

    1994-09-01

    Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy. Although CMT2 is clinically indistinguishable from CMT1, the two forms can be differentiated by pathological and neurophysiological methods. We have established one locus, CMT2A on chromosome 1p36, and have established genetic heterogeneity. This locus maps to the region of the deletions associated with neuroblastoma. We have now identified an additional 11 CMT2 families. Three families are linked to chromosome 1p36 while six families are excluded from this region. Another six families are currently under analysis and collection. To date the CMT2A families represent one third of those CMT2 families examined. We have established a microdissection library of the 1p36 region which is currently being characterized for microsatellite repeats and STSs using standard hybridization techniques and a modified degenerate primer method. In addition, new markers (D1S253, D1S450, D1S489, D1S503, GATA27E04, and GATA4H04) placed in this region are being mapped using critical recombinants in the CEPH reference pedigrees. Fluorescent in situ hybridization (FISH) has been used to confirm mapping. A YAC contig is being assembled from the CEPH megabase library using STSs to isolate key YACs which are extended by vectorette end clone and Alu-PCR. These findings suggest that the CMT2 phenotype is secondary to at least two different genes and demonstrates further heterogeneity in the CMT phenotype.

  6. Charcot-Marie-Tooth disease and intracellular traffic.

    Science.gov (United States)

    Bucci, Cecilia; Bakke, Oddmund; Progida, Cinzia

    2012-12-01

    Mutations of genes whose primary function is the regulation of membrane traffic are increasingly being identified as the underlying causes of various important human disorders. Intriguingly, mutations in ubiquitously expressed membrane traffic genes often lead to cell type- or organ-specific disorders. This is particularly true for neuronal diseases, identifying the nervous system as the most sensitive tissue to alterations of membrane traffic. Charcot-Marie-Tooth (CMT) disease is one of the most common inherited peripheral neuropathies. It is also known as hereditary motor and sensory neuropathy (HMSN), which comprises a group of disorders specifically affecting peripheral nerves. This peripheral neuropathy, highly heterogeneous both clinically and genetically, is characterized by a slowly progressive degeneration of the muscle of the foot, lower leg, hand and forearm, accompanied by sensory loss in the toes, fingers and limbs. More than 30 genes have been identified as targets of mutations that cause CMT neuropathy. A number of these genes encode proteins directly or indirectly involved in the regulation of intracellular traffic. Indeed, the list of genes linked to CMT disease includes genes important for vesicle formation, phosphoinositide metabolism, lysosomal degradation, mitochondrial fission and fusion, and also genes encoding endosomal and cytoskeletal proteins. This review focuses on the link between intracellular transport and CMT disease, highlighting the molecular mechanisms that underlie the different forms of this peripheral neuropathy and discussing the pathophysiological impact of membrane transport genetic defects as well as possible future ways to counteract these defects.

  7. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H; Barsottini, Orlando G P; Kawarai, Toshitaka; Orlacchio, Antonio

    2016-01-01

    Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth

  8. Systematic review of exercise for Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Sman, Amy D; Hackett, Daniel; Fiatarone Singh, Maria; Fornusek, Ché; Menezes, Manoj P; Burns, Joshua

    2015-12-01

    Charcot-Marie-Tooth disease (CMT) is a slowly progressive hereditary degenerative disease and one of the most common neuromuscular disorders. Exercise may be beneficial to maintain strength and function for people with CMT, however, no comprehensive evaluation of the benefits and risks of exercise have been conducted. A systematic review was completed searching numerous electronic databases from earliest records to February 2015. Studies of any design including participants of any age with confirmed diagnosis of CMT that investigated the effects of exercise were eligible for inclusion. Of 13,301 articles identified following removal of duplicates, 11 articles including 9 unique studies met the criteria. Methodological quality of studies was moderate, sample sizes were small, and interventions and outcome measures used varied widely. Although the majority of the studies identified changes in one or more outcome measurements across exercise modalities, the majority were non-significant, possibly due to Type II errors. Significant effects described included improvements in strength, functional activities, and physiological adaptations following exercise. Despite many studies showing changes in strength and function following exercise, findings of this review should be met with caution due to the few studies available and moderate quality of evidence. Well-powered studies, harmonisation of outcome measures, and clearly described interventions across studies would improve the quality and comparability of the evidence base. The optimal exercise modality and intensity for people with CMT as well as the long-term safety of exercise remain unclear.

  9. Spinal and bulbar muscular atrophy and Charcot-Marie-Tooth type 1A: Co-existence of two rare neuromuscular genetic diseases in the same patient.

    Science.gov (United States)

    Sagnelli, Anna; Scaioli, Vidmer; Piscosquito, Giuseppe; Salsano, Ettore; Dalla Bella, Eleonora; Gellera, Cinzia; Pareyson, Davide

    2015-10-01

    Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by a trinucleotide CAG repeat expansion in the androgen receptor gene; it is clinically characterized by adult-onset, slowly progressive weakness and atrophy mainly affecting proximal limb and bulbar muscles. Charcot-Marie-Tooth disease type 1A is an autosomal dominant polyneuropathy due to peripheral myelin protein 22 gene duplication and characterized by slowly progressive distal limb muscle weakness, atrophy and sensory loss with foot deformities. Here we report the co-occurrence of both neuromuscular genetic diseases in the same male patient. Difficulties in climbing stairs and jaw weakness were presenting symptoms consistent with SBMA. However, predominant distal weakness and bilateral pes cavus were rather suggestive of a hereditary polyneuropathy. The combination of two diseases, even if extremely rare, should be considered in the presence of atypical symptoms; in the case of genetic diseases this event may have important implications on family members' counseling.

  10. Metabolite profile of a mouse model of Charcot-Marie-Tooth type 2D neuropathy: implications for disease mechanisms and interventions.

    Science.gov (United States)

    Bais, Preeti; Beebe, Kirk; Morelli, Kathryn H; Currie, Meagan E; Norberg, Sara N; Evsikov, Alexei V; Miers, Kathy E; Seburn, Kevin L; Guergueltcheva, Velina; Kremensky, Ivo; Jordanova, Albena; Bult, Carol J; Burgess, Robert W

    2016-01-01

    Charcot-Marie-Tooth disease encompasses a genetically heterogeneous class of heritable polyneuropathies that result in axonal degeneration in the peripheral nervous system. Charcot-Marie-Tooth type 2D neuropathy (CMT2D) is caused by dominant mutations in glycyl tRNA synthetase (GARS). Mutations in the mouse Gars gene result in a genetically and phenotypically valid animal model of CMT2D. How mutations in GARS lead to peripheral neuropathy remains controversial. To identify putative disease mechanisms, we compared metabolites isolated from the spinal cord of Gars mutant mice and their littermate controls. A profile of altered metabolites that distinguish the affected and unaffected tissue was determined. Ascorbic acid was decreased fourfold in the spinal cord of CMT2D mice, but was not altered in serum. Carnitine and its derivatives were also significantly reduced in spinal cord tissue of mutant mice, whereas glycine was elevated. Dietary supplementation with acetyl-L-carnitine improved gross motor performance of CMT2D mice, but neither acetyl-L-carnitine nor glycine supplementation altered the parameters directly assessing neuropathy. Other metabolite changes suggestive of liver and kidney dysfunction in the CMT2D mice were validated using clinical blood chemistry. These effects were not secondary to the neuromuscular phenotype, as determined by comparison with another, genetically unrelated mouse strain with similar neuromuscular dysfunction. However, these changes do not seem to be causative or consistent metabolites of CMT2D, because they were not observed in a second mouse Gars allele or in serum samples from CMT2D patients. Therefore, the metabolite 'fingerprint' we have identified for CMT2D improves our understanding of cellular biochemical changes associated with GARS mutations, but identification of efficacious treatment strategies and elucidation of the disease mechanism will require additional studies.

  11. De Novo duplication in Charcot-Marie-Tooth Type 1A

    Energy Technology Data Exchange (ETDEWEB)

    Mandich, P.; Bellone, E.; Ajmar, F. [and others

    1996-09-01

    We read with interest the paper on {open_quotes}Prevalence and Origin of De Novo Duplications in Charcot-Marie-Tooth Disease Type 1A: First Report of a De Novo Duplication with a Maternal Origin,{close_quotes}. They reported their experience with 10 sporadic cases of Charcot-Marie-Tooth type 1A (CMT1A) in which it was demonstrated that the disease had arisen as the result of a de novo duplication. They analyzed the de novo-duplication families by using microsatellite markers and identified the parental origin of the duplication in eight cases. In one family the duplication was of maternal origin, whereas in the remaining seven cases it was of paternal origin. The authors concluded that their report was the first evidence of a de novo duplication of maternal origin, suggesting that this is not a phenomenon associated solely with male meiosis. 7 refs.

  12. Surgical Treatment of Scoliosis in Patients with Charcot-Marie-Tooth Disease

    Institute of Scientific and Technical Information of China (English)

    Farzad Omidi Kashani; Ibrahim Ghayem Hasankhani; Mahdi Banaii

    2009-01-01

    Objective: Apparently, scoliosis occurs in approximately one-third of patients with Charcot-Marie-Tooth disease. Little is known about the response of these curves to treatment. The purpose of this study was to evaluate the results of spinal surgery in these peculiar patients. Methods: We retrospectively evaluated the results of spinal surgery in eight patients who had scoliosis due to clinically and electrophysiologically proven Charcot-Marie-Tooth disease. Radiographs were reviewed. The location and direction of the curve pattern, the age at the time of surgery, type of surgery, number of levels fused, instrumentations used, intra or postoperative complications, and results and need for reoperation were recorded. Results: Eight patients associated with Charcot-Marie-Tooth disease who underwent scoliotic surgery were identified. The average age and curve at the time of surgery were 21.1 years and 56.4° respectively. 62.5% of the curves had left thoracic component and more than one third was associated with thoracic hyperkyphosis. Long posterior spinal fusion was performed most often, with an average of 11.5 spinal segments fused. Instrumentation was used in all posterior fusions. At an average of 39 months (range, 24 to 72 months) postoperatively, the fusion appeared to be solid in all patients. Conclusion: Scoliosis in patients with Charcot-Marie-Tooth disease differs from that in patients with idiopathic scoliosis in regarding to the etiology and the prevalence of thoracic hyperkyphosis, but the surgical management appears to be similar. Spondylodesis does not appear to be associated with a high rate of complications.

  13. Noncompaction Cardiomyopathy with Charcot-Marie-Tooth Disease

    Directory of Open Access Journals (Sweden)

    Sherif Ali Eltawansy

    2015-01-01

    Full Text Available We report a case of a 53-year-old female presenting with a new-onset heart failure that was contributed secondary to noncompaction cardiomyopathy. The diagnosis was made by echocardiogram and confirmed by cardiac MRI. Noncompaction cardiomyopathy (also known as ventricular hypertrabeculation is a newly discovered disease. It is considered to be congenital (genetic cardiomyopathy. It is usually associated with genetic disorders and that could explain the genetic pathogenesis of the non-compaction cardiomyopathy. Our case had a history of Charcot-Marie-Tooth disease. There is a high incidence of arrhythmia and embolic complications. The treatment usually consists of the medical management, defibrillator placement, and lifelong anticoagulation. Heart transplantation will be the last resort.

  14. Therapeutic options in Charcot-Marie-Tooth diseases.

    Science.gov (United States)

    Mathis, Stéphane; Magy, Laurent; Vallat, Jean-Michel

    2015-04-01

    Charcot-Marie-Tooth (CMT) diseases represent a heterogeneous genetic disorder (more than 80 genes are implicated in these inherited neuropathies), but sharing a similar phenotype. In recent years, advances in molecular genetics and molecular biology, and also the development of various animal models of CMT, have led to a better understanding. Taken together, this knowledge represents a prerequisite for the development of future therapies in CMT, and in peripheral nervous system disorders in general. The efficacy of various substances has been shown in vitro and also in vivo (in animal models); but, no significant positive effect has yet been confirmed in humans. However, some of these trials are still in development, and we may expect positive results in the future. Although CMT is still an incurable disease, symptomatic treatments (physiotherapy, surgery, analgesic, etc.) are crucial to improve the quality of life of CMT patients.

  15. Hand weakness in Charcot-Marie-Tooth disease 1X.

    LENUS (Irish Health Repository)

    Arthur-Farraj, P J

    2012-07-01

    There have been suggestions from previous studies that patients with Charcot-Marie-Tooth disease (CMT) have weaker dominant hand muscles. Since all studies to date have included a heterogeneous group of CMT patients we decided to analyse hand strength in 43 patients with CMT1X. We recorded handedness and the MRC scores for the first dorsal interosseous and abductor pollicis brevis muscles, median and ulnar nerve compound motor action potentials and conduction velocities in dominant and non-dominant hands. Twenty-two CMT1X patients (51%) had a weaker dominant hand; none had a stronger dominant hand. Mean MRC scores were significantly higher for first dorsal interosseous and abductor pollicis brevis in non-dominant hands compared to dominant hands. Median nerve compound motor action potentials were significantly reduced in dominant compared to non-dominant hands. We conclude that the dominant hand is weaker than the non-dominant hand in patients with CMT1X.

  16. MRI findings, patterns of disease distribution, and muscle fat fraction calculation in five patients with Charcot-Marie-Tooth type 2 F disease

    Energy Technology Data Exchange (ETDEWEB)

    Gaeta, Michele; Mileto, Achille; Minutoli, Fabio; Settineri, Nicola; Donato, Rocco; Ascenti, Giorgio; Blandino, Alfredo [Policlinico ' ' G. Martino' ' , Dipartimento di Scienze Radiologiche, Messina (Italy); Mazzeo, Anna; Di Leo, Rita [Policlinico ' ' G. Martino' ' , Dipartimento di Neuroscienze, Scienze Psichiatriche ed Anestesiologiche, Messina (Italy)

    2012-05-15

    To describe the magnetic resonance imaging (MRI) pattern of muscle involvement and disease progression in five patients with late-onset Charcot-Marie-Tooth (CMT) disease type 2 F, due to a previously unknown mutation. Five patients (three males, two females) underwent MRI of the lower limbs to define the pattern of muscle involvement and evaluate the muscle fat fraction (MFF) of residual thigh muscle with gradient-echo (GRE) dual-echo dual-flip angle technique. Evaluation of fatty infiltration both by visual inspection and MFF calculation was performed. A proximal-to-distal gradient of muscle involvement was depicted in male patients with extensive muscle wasting of lower legs, less severe impairment of distal thigh muscles, and sparing of proximal thigh muscles. A peculiar phenotype finding was that no or only slight muscle abnormalities could be found in the two female patients. We described the pattern of muscle involvement and disease progression in a family with CMT disease type 2 F. GRE dual-echo dual-flip angle MRI technique is a valuable technique to obtain a rapid quantification of MFF. (orig.)

  17. [Autopsy case of a patient with Charcot-Marie-Tooth disease type 1A and suspected chronic inflammatory demyelinating polyradiculoneuropathy, which was later diagnosed as amyotrophic lateral sclerosis].

    Science.gov (United States)

    Higuchi, Yujiro; Sakiyama, Yusuke; Nishihira, Yasushi; Endo, Kazuhiro; Suwazono, Shugo; Suehara, Masahito

    2012-01-01

    We report an autopsy case of a 74-year-old man with late onset Charcot-Marie-Tooth disease type 1A (CMT1A) diagnosed by genetic screening, later associated with amyotrophic lateral sclerosis (ALS). At the age of 70 years, the patient was admitted to our hospital because of progressive weakness and dysesthesia in the right upper limb. In the early stages of the illness, he was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and transient improvement was achieved with intravenous immunoglobulin. However, the symptoms progressively worsened and became refractory. Gene analysis revealed PMP22 gene duplication, which confirmed CMT1A. On sural nerve biopsy, severe demyelinating neuropathy and abundant onion-bulb formations with endoneurial infiltration of inflammatory cells were observed. Thereafter, pseudo-bulbar palsy and respiratory muscle weakness developed insidiously and progressed rapidly along with muscle weakness in the limbs and trunk. The patient died about four years after the onset of this disease. Postmortem examination showed moderate neuronal cell loss, Bunina bodies, and TDP-43-positive inclusions in the anterior horn cells. The spinal cord revealed axonal loss and extensive macrophage permeation in the corticospinal tracts. On the basis of these findings, the final neuropathological diagnosis was ALS. This is the first report of an autopsy case of CMT1A complicated with ALS. We here discuss the significant clinical and neuropathological findings of this case.

  18. Identification of a novel SBF2 frameshift mutation in charcot-marie-tooth disease type 4B2 using whole-exome sequencing.

    Science.gov (United States)

    Chen, Meiyan; Wu, Jing; Liang, Ning; Tang, Lihui; Chen, Yanhua; Chen, Huishuang; Wei, Wei; Wei, Tianying; Huang, Hui; Yi, Xin; Qi, Ming

    2014-10-01

    Charcot-Marie-Tooth disease type 4B2 with early-onset glaucoma (CMT4B2, OMIM 604563) is a genetically-heterogeneous childhood-onset neuromuscular disorder. Here, we report the case of a 15-year-old male adolescent with lower extremity weakness, gait abnormalities, foot deformities and early-onset glaucoma. Since clinical diagnosis alone was insufficient for providing pathogenetic evidence to indicate that the condition belonged to a consanguineous family, we applied whole-exome sequencing to samples from the patient, his parents and his younger brother, assuming that the patient's condition is transmitted in an autosomal recessive pattern. A frame-shift mutation, c.4571delG (P.Gly1524Glufs∗42), was revealed in the CMT4B2-related gene SBF2 (also known as MTMR13, MIM 607697), and this mutation was found to be homozygous in the proband and heterozygous in his parents and younger brother. Together with the results of clinical diagnosis, this case was diagnosed as CMT4B2. Our finding further demonstrates the use of whole-exome sequencing in the diagnosis and treatment of rare diseases.

  19. The influence of somatosensory and muscular deficits on postural stabilization: Insights from an instrumented analysis of subjects affected by different types of Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Lencioni, Tiziana; Piscosquito, Giuseppe; Rabuffetti, Marco; Bovi, Gabriele; Calabrese, Daniela; Aiello, Alessia; Di Sipio, Enrica; Padua, Luca; Diverio, Manuela; Pareyson, Davide; Ferrarin, Maurizio

    2015-08-01

    Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuromuscular disorder. CMT1 is primarily demyelinating, CMT2 is primarily axonal, and CMTX1 is characterized by both axonal and demyelinating abnormalities. We investigated the role of somatosensory and muscular deficits on quiet standing and postural stabilization in patients affected by different forms of CMT, comparing their performances with those of healthy subjects. Seventy-six CMT subjects (CMT1A, CMT2 and CMTX1) and 41 healthy controls were evaluated during a sit-to-stand transition and the subsequent quiet upright posture by means of a dynamometric platform. All CMT patients showed altered balance and postural stabilization compared to controls. Multivariate analysis showed that in CMT patients worsening of postural stabilization was related to vibration sense deficit and to dorsi-flexor's weakness, while quiet standing instability was related to the reduction of pinprick sensibility and to plantar-flexor's weakness. Our results show that specific sensory and muscular deficits play different roles in balance impairment of CMT patients, both during postural stabilization and in static posture. An accurate evaluation of residual sensory and muscular functions is therefore necessary to plan for the appropriate balance rehabilitation treatment for each patient, besides the CMT type.

  20. Targeting the colony stimulating factor 1 receptor alleviates two forms of Charcot-Marie-Tooth disease in mice.

    Science.gov (United States)

    Klein, Dennis; Patzkó, Ágnes; Schreiber, David; van Hauwermeiren, Anemoon; Baier, Michaela; Groh, Janos; West, Brian L; Martini, Rudolf

    2015-11-01

    See Scherer (doi:10.1093/awv279) for a scientific commentary on this article.Charcot-Marie-Tooth type 1 neuropathies are inherited disorders of the peripheral nervous system caused by mutations in Schwann cell-related genes. Typically, no causative cure is presently available. Previous preclinical data of our group highlight the low grade, secondary inflammation common to distinct Charcot-Marie-Tooth type 1 neuropathies as a disease amplifier. In the current study, we have tested one of several available clinical agents targeting macrophages through its inhibition of the colony stimulating factor 1 receptor (CSF1R). We here show that in two distinct mouse models of Charcot-Marie-Tooth type 1 neuropathies, the systemic short- and long-term inhibition of CSF1R by oral administration leads to a robust decline in nerve macrophage numbers by ∼70% and substantial reduction of the typical histopathological and functional alterations. Interestingly, in a model for the dominant X-linked form of Charcot-Marie-Tooth type 1 neuropathy, the second most common form of the inherited neuropathies, macrophage ablation favours maintenance of axonal integrity and axonal resprouting, leading to preserved muscle innervation, increased muscle action potential amplitudes and muscle strengths in the range of wild-type mice. In another model mimicking a mild, demyelination-related Charcot-Marie-Tooth type 1 neuropathy caused by reduced P0 (MPZ) gene dosage, macrophage blockade causes an improved preservation of myelin, increased muscle action potential amplitudes, improved nerve conduction velocities and ameliorated muscle strength. These observations suggest that disease-amplifying macrophages can produce multiple adverse effects in the affected nerves which likely funnel down to common clinical features. Surprisingly, treatment of mouse models mimicking Charcot-Marie-Tooth type 1A neuropathy also caused macrophage blockade, but did not result in neuropathic or clinical improvements

  1. Malignant melanoma and Charcot-Marie-Tooth disease: A further case

    Energy Technology Data Exchange (ETDEWEB)

    Manoukian, S.; Briscioli, V.; Lalatta, F. [Instituti Clinici di Perfezionamento, Milan (Italy)

    1997-01-20

    In a previous issue of this journal, Greene et al. described 2 patients with Charcot-Marie-Tooth (CMT) disease who later developed cutaneous malignant melanoma. Although the development of the two diseases in the same patient may have occurred by chance, the authors raised the possibility of a shared neural crest defect or a genetic linkage. Among the patients reported by Greene et al., one had a dominant form of CMT. The patient`s mother and brother were similarly affected. A paternal aunt died of melanoma. The second patient had a neuronal type of CMT. His brother showed the same disease, but the parents were not examined. 7 refs.

  2. The shifting paradigm of Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Echaniz-Laguna, A

    2015-01-01

    Molecular studies have created a paradigm shift in our perception of Charcot-Marie-Tooth disease (CMT). Indeed, CMT has evolved from the concept of a rather homogeneous hereditary disease exclusively involving peripheral nerves to the concept of a highly heterogeneous clinical and genetic syndrome mainly - but sometimes not exclusively - involving the peripheral nervous system. The phenotypic spectrum of CMT overlaps with other inherited neuropathies such as distal hereditary motor neuropathy (dHMN), hereditary sensory and autonomic neuropathy (HSAN), spinal muscular atrophy (SMA) subtypes, and the neuropathies of mitochondrial disorders. At a molecular level, mutations in one given gene may alternatively provoke CMT, HSAN, dHMN or SMA variants. Over the last years, there have been dramatic advances in deciphering the molecular basis for many CMT subtypes and more than 900 different mutations in more than 60 causative genes are now described. However, as 75% of CMT causative genes apparently remain unknown and as disease-specific therapies are not available, major advances are yet to come in the field of CMT.

  3. Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity

    Energy Technology Data Exchange (ETDEWEB)

    Othmane, K.B.; Loprest, L.J.; Wilkinson, K.M. (Duke Univ. Medical Center, Durham, NC (United States)); Middleton, L.T. (Cyprus Institute of Neurology and Genetics, Nicosia (Cyprus)) (and others)

    1993-08-01

    Charcot-Marie-Tooth (CMT) disease type 2 (CMT2) is an inherited peripheral neuropathy characterized by variable age of onset and normal or slightly diminished nerve conduction velocity. CMT2 is pathologically and genetically distinct from CMT type 1 (CMT1). While CMT1 has been shown to be genetically heterogeneous, no chromosomal localization has been established for CMT2. The authors have performed pedigree linkage analysis in six large autosomal dominant CMT2 families and have demonstrated linkage and heterogeneity to a series of microsatellites (D1S160, D1S170, D1S244, D1S228 and D1S199) in the distal region of the short arm of chromosome 1. Significant evidence for heterogeneity was found using admixture analyses and the two-point lod scores. Admixture analyses using the multipoint results for the markers D1S244, D1S228, and D1S199 supported the two-point findings. Three families, DUK662, DUK1241, and 1523 gave posterior probabilities of 1.0, 0.98, and 0.88 of being of the linked type. Multipoint analysis examining the [open quotes]linked[close quotes] families showed that the most favored location for the CMT2A gene is within the interval flanked by D1S244 and D1S228 (odds approximately 70:1 of lying within versus outside that interval). These findings suggest that the CMT2 phenotype is secondary to at least two different genes and demonstrate further heterogeneity in the CMT phenotype.

  4. Analysis of mutations in 17p 11.2 region in patients with Charcot-Marie-Tooth type 1 disease and patients with tomaculose neuropathy

    Directory of Open Access Journals (Sweden)

    Zamurović Nataša

    2002-01-01

    Full Text Available Charcot-Marie-Tooth typedisease (CMT1A and hereditary neuropathy with liability to pressure palsies (HNPP are common inherited disorders of the peripheral nervous system associated with duplication and deletion respectively, of the 17p11.2 segment including the gene of peripheral myelin protein 22. We studied 48 subjects belonging to 29 families with clinical and electrophysiological signs of definite CMT1, 20 patients with suspected CMT phenotype, and 17 patients and healthy members of their families with HNPP. Blood sampling and DNA isolation, PCR, restriction analysis, southern blotting were performed using standard procedures. Of 48 patients with diagnosis of definite CMT1 in 25 (52% we found a 1.5 Mb tandem duplication in chromosome 17p11.2. These duplications were not found in any of 20 sporadic cases with the clinical phenotype of CMT but without reliable electrophysiological data. Only 13 (44.8%of 29 unrelated CMT1 patients from the first group had 17p11.2 duplications. Three of 4 sporadic cases (75% with definite CMT1 had 17p11.2 duplications. Of 17 patients from 6 families with HNPP deletion of 17p11.2 segment was found in 15 (88.2%, as well as in 5 (83.3% of six unrelated cases. Detection of CMT1A/HNPP recombination hotspot is a simple and reliable DNA diagnostic method, which is useful only for the patients with clinically already verified CMT1, and HNPP for further genetic counseling of patients and members of their families.

  5. Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, J.M.; Elliott, J.L.; Yee, W.C. [Washington Univ. School of Medicine, St. Louis, MO (United States)] [and others

    1995-10-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. The neuronal form of this disorder is referred to as Charcot-Marie-Tooth type II disease (CMT2). CMT2 is usually inherited as an autosomal dominant trait with a variable age at onset of symptoms associated with progressive axonal neuropathy. In some families, the locus that predisposes to CMT2 has been demonstrated to map to the distal portion of the short arm of chromosome 1. Other families with CMT2 do not show linkage with 1p markers, suggesting genetic heterogeneity in CMT2. We investigated linkage in a single large kindred with autosomal dominant CMT2. The gene responsible for CMT2 in this kindred (CMT2B) was mapped to the interval between the microsatellite markers D3S1769 and D3S1744 in the 3q13-22 region. Study of additional CMT2 kindreds should serve to further refine the disease gene region and may ultimately lead to the identification of a gene defect that underlies the CMT2 phenotype. 21 refs., 3 figs., 1 tab.

  6. Cx32 gene mutation associated with X-linked recessive Charcot-Marie-Tooth disease

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    The form of Charcot-Marie-Tooth (CMT) neuropathy that maps to Xq13 is X-linked dominant, or X-linked intermediate. Heterozygous females are more mildly affected than hemizygous males. It has been known that this type of CMT is caused by mutations of connexin32 (Cx32) gene. A typical X-linked recessive Charcot-Marie-Tooth Chinese family was analyzed with single strand conformation polymorphism method. A Cx32 gene point mutation, Arg15Gln, in exon 2 was identified in all affected family members, suggesting that this mutation is responsible for the CMT incidence of this family.

  7. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing.

    LENUS (Irish Health Repository)

    Murphy, Sinead M

    2012-07-01

    Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of diseases with approximately 45 different causative genes described. The aims of this study were to determine the frequency of different genes in a large cohort of patients with CMT and devise guidelines for genetic testing in practice.

  8. Charcot-Marie-Tooth disease: The development of a diagnostic platform using next generation sequencing

    DEFF Research Database (Denmark)

    Christensen, Rikke; Væth, Signe; Thorsen, Kasper;

    Background: Charcot-Marie-Tooth Disease (CMT) is one of the most common inherited neurological diseases. Today, more than 70 CMT related genes are known to cause inherited neuropathy. The diagnostic strategy in most laboratories is based on Sanger-sequencing of few genes. In our patient cohort...

  9. [PREGNANCY AND DELIVERY IN A PATIENT WITH CHARCOT-MARIE-TOOTH DISEASE].

    Science.gov (United States)

    Pehlivanov, B; Matev, M

    2016-01-01

    We report a case of a 34 years old primigravida with Charcot-Marie-Tooth disease (CMTD). The course of pregnancy was uneventful with no deterioration of symptoms due to the disease. Performed amniocentesis showed healthy fetus. Planned cesarean section with spinal anesthesia was performed because of the restricted pelvis. The possible issues of combination pregnancy and CMTD are discussed.

  10. Connexin32 gene mutations in X-linked dominant Charcot-Marie-Tooth disease (CMTX1)

    NARCIS (Netherlands)

    Janssen, EAM; Kemp, S; Hensels, GW; Sie, OG; deDieSmulders, CEM; Hoogendijk, JE; deVisser, M; Bolhuis, PA

    1997-01-01

    Single-strand conformational polymorphisms (SSCP) of the connexin32 gene were analyzed in 121 patients possibly affected by Charcot-Marie-Tooth (CMT) disease. The 121 patients were selected from 443 possible CMT/HNPP (hereditary neuropathy with liability to pressure palsies) patients based on geneti

  11. A Review of X-linked Charcot-Marie-Tooth Disease.

    Science.gov (United States)

    Wang, Ying; Yin, Fei

    2016-05-01

    X-linked Charcot-Marie-Tooth disease (CMTX) is the second common genetic variant of CMT. CMTX type 1 causes 90% of CMTX. The most important clinical features of CMTX are similar with other types of CMT; however, a few patients get the central nervous system involved with or without white matter lesions; males are more severely and earlier affected than females. In this review, the authors focus on the origin and classification of CMTX, the central nervous system manifestations of CMTX1, the possible mechanism by which GJB1 mutations cause CMT1X, and the emerging therapeutic strategies for CMTX. Moreover, several cases are presented to illustrate the central nervous system manifestations.

  12. A novel Lys141Thr mutation in small heat shock protein 22 (HSPB8) gene in Charcot-Marie-Tooth disease type 2L.

    Science.gov (United States)

    Nakhro, Khriezhanuo; Park, Jin-Mo; Kim, Ye Jin; Yoon, Bo Ram; Yoo, Jeong Hyun; Koo, Heasoo; Choi, Byung-Ok; Chung, Ki Wha

    2013-08-01

    Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous peripheral neuropathies. HSPB8 gene encodes heat shock protein 22 (HSP22) which belongs to the superfamily of small stress induced proteins. Mutations in HSPB8 are implicated to CMT2L and distal hereditary motor neuropathy 2A (dHMN2A). All three reported HSPB8 mutations are interestingly located in the Lys141 residue. In the present study, we examined a Korean axonal CMT patient who presented distal limb atrophy, sensory loss, areflexia, and axonal loss of large myelinated fibers. Whole exome sequencing identified a novel missense mutation c.422A>C (p.Lys141Thr) in HSPB8 as the underlying cause of the CMT2 patient. The mutation was regarded as a de novo case because both unaffected parents have no such mutation. The patient with HSPB8 mutation is the first case in Koreans. Clinical heterogeneities have been revealed in patients with Lys141 mutation; the present patient revealed similar phenotype of CMT2L. In addition, the lower limb MRI revealed a similarity between our HSPB8 and HSPB1 patients. It seems that the Lys141 site in the alpha-crystallin domain of HSPB8 is regarded as a mutational hot spot for peripheral neuropathy development, and mutations even in the same codon can exhibit different CMT phenotypes.

  13. Charcot-Marie-Tooth disease masquerading as acute demyelinating encephalomyelitis-like illness.

    Science.gov (United States)

    Kim, Gun-Ha; Kim, Kyoung Min; Suh, Sang-Il; Ki, Chang-Seok; Eun, Baik-Lin

    2014-07-01

    X-linked Charcot-Marie-Tooth disease (CMTX1) is a clinically heterogeneous hereditary motor and sensory neuropathy with X-linked transmission. Common clinical manifestations of CMTX1 disease, as in other forms of Charcot-Marie-Tooth (CMT) disease, are distal muscle wasting and weakness, hyporeflexia, distal sensory disturbance, and foot deformities. Mutations in the connexin-32 gene (gap junction protein β1 [GJB1]) are responsible for CMTX1 disease. In this report, we describe a patient with CMTX1 disease presenting with recurrent attacks of transient and episodic acute demyelinating encephalomyelitis (ADEM)-like symptoms without previous signs of lower extremity weakness or foot deformities; the patient, as well as his asymptomatic mother, exhibited a novel GJB1 mutation (p.Met1Ile). Differential diagnosis of recurrent and transient ADEM-like illness, if unexplained, should include the possibility of CMTX1 disease.

  14. Prevalence and origin of De Novo duplications in Charcot-Marie-Tooth disease type 1A: First report of a De Novo duplication with a maternal origin

    Energy Technology Data Exchange (ETDEWEB)

    Blair, I.P.; Nash, J.; Gordon, M.J.; Nicholson, G.A. [Univ. of Sydney, New South Wales (United Kingdom)

    1996-03-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. Sporadic cases of CMT have been described since the earliest reports of the disease. The most frequent form of the disorder, CMT1A, is associated with a 1.5-Mb DNA duplication on chromosome 17p11.2, which segregates with the disease. In order to investigate the prevalence of de novo CMT1A duplications, this study examined 118 duplication-positive CMT1A families. In 10 of these families it was demonstrated that the disease had arisen as the result of a de novo mutation. By taking into account the ascertainment of families, it can be estimated that {>=}10% of autosomal dominant CMT1 families are due to de novo duplications. The CMT1A duplication is thought to be the product of unequal crossing over between parental chromosome 17 homologues during meiosis. Polymorphic markers from within the duplicated region were used to determine the parental origin of these de novo duplications in eight informative families. Seven were of paternal and one of maternal origin. This study represents the first report of a de novo duplication with a maternal origin and indicates that it is not a phenomenon associated solely with male meioses. Recombination fractions for the region duplicated in CMT1A are larger in females than in males. That suggests that oogenesis may be afforded greater protection from misalignment during synapsis, and/or that there may be lower activity of those factors or mechanisms that lead to unequal crossing over at the CMT1A locus. 41 refs., 2 figs.

  15. Coexistent Charcot-Marie-Tooth type 1A and type 2 diabetes mellitus neuropathies in a Chinese family

    OpenAIRE

    A-ping Sun; Lu Tang; Qin Liao; Hui Zhang; Ying-shuang Zhang; Jun Zhang(UT Austin)

    2015-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of the peripheral myelin protein 22 (PMP22) gene on chromosome 17. It is the most common inherited demyelinating neuropathy. Type 2 diabetes mellitus is a common metabolic disorder that frequently causes predominantly sensory neuropathy. In this study, we report the occurrence of CMT1A in a Chinese family affected by type 2 diabetes mellitus. In this family, seven individuals had duplication of the PMP22 gene, although only ...

  16. Charcot-Marie-Tooth disease and posterior scleritis: a case report Doença de Charcot-Marie-Tooth e esclerite posterior: relato de caso

    Directory of Open Access Journals (Sweden)

    Elisabeth N. Martins

    2000-10-01

    Full Text Available Purpose: To describe the unusual association of Charcot-Marie-Tooth disease (CMTD and posterior scleritis. Methods: Case report of a 16-year-old female with decreased visual acuity and pain in both eyes. Results: Ophthalmologic examination showed a posterior scleritis, confirmed by ultrasound and angiofluoresceinography. Foot deformities and sensory dysfunction were identified in the patient and some of her relatives. The diagnosis of CMTD in this patient was confirmed by eletrophysiologic studies. Conclusions: The association of posterior scleritis in a patient with CMTD has never been reported. This is also the first description of an inflammatory ocular disease in these patients.Objetivo: Descrever a associação entre doença de Charcot-Marie-Tooth (DCMT e esclerite posterior. Metodologia: Relato de caso de uma paciente do sexo feminino, 16 anos de idade, com baixa de acuidade visual e dor em ambos os olhos. Resultados: O exame oftalmológico revelou esclerite posterior, observada também por ultra-som e angiofluoresceinografia. Deformidades de pernas e pés foram identificadas na paciente e em seus familiares. O diagnóstico de DCMT na paciente estudada foi confirmado por estudos eletrofisiológicos. Conclusões: A presença de esclerite posterior em paciente com DCMT não é descrita na literatura, não se encontrando também relatos de outras doenças oculares inflamatórias, nestes pacientes.

  17. Myelin protein zero gene mutated in Charcot-Marie-Tooth type 1B patients

    Energy Technology Data Exchange (ETDEWEB)

    Su, Ying; Li, Lanying; Lepercq, J.; Lebo, R.V. (Univ. of California, San Francisco, CA (United States)); Brooks, D.G.; Ravetch, J.V. (Sloan-Kettering Institute, New York, NY (United States)); Trofatter, J.A. (Massachusetts General Hospital, Boston, MA (United States))

    1993-11-15

    The autosomal dominant of Charcot-Marie-Tooth disease (CMT), whose gene is type 1B (CMT1B), has slow nerve conduction with demyelinated Schwann cells. In this study the abundant peripheral myelin protein zero (MPZ) gene, MPZ, was mapped 130 kb centromeric to the Fc receptor immunoglobulin gene cluster in band 1q22, and a major MPZ point mutation was found to cosegregate with CMT1B in one large CMT1B family. The MPZ point mutation in 18 of 18 related CMT1B pedigree 1 patients converts a positively charged lysine in codon 96 to a negatively charged glutamate. The same MPZ locus cosegregates with the CMT1B disease gene in a second CMT1B family [total multipoint logarithm of odds (lod) = 11.4 at [theta] = 0.00] with a splice junction mutation. Both mutations occur in MPZ protein regions otherwise conserved identically in human, rat, and cow since these species diverged 100 million years ago. MPZ protein, expressed exclusively in myelinated peripheral nerve Schwann cells, constitutes >50% of myelin protein. These mutations are anticipated to disrupt homophilic MPZ binding and result in CMT1B peripheral nerve demyelination.

  18. Exacerbation of Charcot-Marie-Tooth type 2E neuropathy following traumatic nerve injury.

    Science.gov (United States)

    Villalón, Eric; Dale, Jeffrey M; Jones, Maria; Shen, Hailian; Garcia, Michael L

    2015-11-19

    Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gait, sensory defects, and deafness. We generated a novel line of CMT2E mice expressing hNF-L(E397K), which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons, and decreased nerve conduction velocity. In this study, we challenged wild type, hNF-L and hNF-L(E397K) mice with crush injury to the sciatic nerve. We analyzed functional recovery by measuring toe spread and analyzed gait using the Catwalk system. hNF-L(E397K) mice demonstrated reduced recovery from nerve injury consistent with increased susceptibility to neuropathy observed in CMT patients. In addition, hNF-L(E397K) developed a permanent reduction in their ability to weight bear, increased mechanical allodynia, and premature gait shift in the injured limb, which led to increasingly disrupted interlimb coordination in hNF-L(E397K). Exacerbation of neuropathy after injury and identification of gait alterations in combination with previously described pathology suggests that hNF-L(E397K) mice recapitulate many of clinical signs associated with CMT2. Therefore, hNF-L(E397K) mice provide a model for determining the efficacy of novel therapies.

  19. Oral Health, Temporomandibular Disorder, and Masticatory Performance in Patients with Charcot-Marie-Tooth Type 2

    Directory of Open Access Journals (Sweden)

    Rejane L. S. Rezende

    2013-01-01

    Full Text Available Background. The aim of this study was to evaluate the oral health status of temporomandibular disorders (TMD and bruxism, as well as to measure masticatory performance of subjects with Charcot-Marie-Tooth type 2 (CMT2. Methods and Results. The average number of decayed, missing, and filled teeth (DMFT for both groups, control (CG and CMT2, was considered low (CG = 2.46; CMT2 = 1.85, P=0.227. The OHIP-14 score was considered low (CG = 2.86, CMT2 = 5.83, P=0.899. The prevalence of self-reported TMD was 33.3% and 38.9% (P=0.718 in CG and CMT2 respectively and for self-reported bruxism was 4.8% (CG and 22.2% (CMT2, without significant difference between groups (P=0.162. The most common clinical sign of TMD was masseter (CG = 38.1%; CMT2 = 66.7% and temporalis (CG = 19.0%; GCMT2 = 33.3% muscle pain. The geometric mean diameter (GMD was not significantly different between groups (CG = 4369; CMT2 = 4627, P=0.157. Conclusion. We conclude that the CMT2 disease did not negatively have influence either on oral health status in the presence and severity of TMD and bruxism or on masticatory performance.

  20. Mutational studies in X-linked Charcot-Marie-Tooth disease (CMTX)

    Energy Technology Data Exchange (ETDEWEB)

    Cherryson, A.K.; Yeung, L.; Kennerson, M.L.; Nicholson, G.A. [Univ. of Syndey, Concord (Australia)

    1994-09-01

    Charcot-Marie-Tooth disease, also known as hereditary motor and sensory neuropathy (HMSN), is a heterogeneous group of slowly progressive disorders of the peripheral nerve. X-linked CMT (CMTX) is characterized by slow motor nerve conduction velocities in affected males and the presence of mildly affected or normal carrier females with intermediate or normal nerve conduction velocities. CMTX, which has an incidence of 3.1 per 100,000 and accounts for approximately 10% of CMT cases, has been mapped to Xq13. One of the genes lying in this region, connexin 32, has been found to contain alterations in individuals affected with X-linked CMT. We have identified our X-linked families from dominant type 1 CMT families using the clinical criteria given above. These families were screened for point mutations in connexin 32. We have identified three missense mutations, a G{r_arrow}A transition at amino acid 35 (valine to methionine), a C{r_arrow}G transition at amino acid 158 (proline to alanine) and a T{r_arrow}A transition at amino acid 182 (serine to threonine). Another family showed a 18 bp deletion, which removed the amino acid 111 to 116 inclusive (histidine, glycine, aspartic acid, proline, leucine, histidine).

  1. Linkage localization of X-linked Charcot-Marie-Tooth disease

    Energy Technology Data Exchange (ETDEWEB)

    Bergoffen, J. (Children' s Hospital, Philadelphia, PA (United States) Univ. of Pennsylvania, Philadelphia (United States)); Trofatter, J.; Haines, J.L. (Massachusetts General Hospital, Boston (United States)); Pericak-Vance, M.A. (Duke Univ., Durham, NC (United States)); Chance, P.F. (Univ. of Utah, Salt Lake City (United States)); Fischbeck, K.H. (Univ. of Pennsylvania, Philadelphia (United States))

    1993-02-01

    Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived from work with four VSSR markers - AR, PGKP1, DXS453, and DXYS1X - in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 ([theta] = 0). 32 refs., 3 figs., 2 tabs.

  2. The Gdap1 knockout mouse mechanistically links redox control to Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Niemann, Axel; Huber, Nina; Wagner, Konstanze M; Somandin, Christian; Horn, Michael; Lebrun-Julien, Frédéric; Angst, Brigitte; Pereira, Jorge A; Halfter, Hartmut; Welzl, Hans; Feltri, M Laura; Wrabetz, Lawrence; Young, Peter; Wessig, Carsten; Toyka, Klaus V; Suter, Ueli

    2014-03-01

    The ganglioside-induced differentiation-associated protein 1 (GDAP1) is a mitochondrial fission factor and mutations in GDAP1 cause Charcot-Marie-Tooth disease. We found that Gdap1 knockout mice (Gdap1(-/-)), mimicking genetic alterations of patients suffering from severe forms of Charcot-Marie-Tooth disease, develop an age-related, hypomyelinating peripheral neuropathy. Ablation of Gdap1 expression in Schwann cells recapitulates this phenotype. Additionally, intra-axonal mitochondria of peripheral neurons are larger in Gdap1(-/-) mice and mitochondrial transport is impaired in cultured sensory neurons of Gdap1(-/-) mice compared with controls. These changes in mitochondrial morphology and dynamics also influence mitochondrial biogenesis. We demonstrate that mitochondrial DNA biogenesis and content is increased in the peripheral nervous system but not in the central nervous system of Gdap1(-/-) mice compared with control littermates. In search for a molecular mechanism we turned to the paralogue of GDAP1, GDAP1L1, which is mainly expressed in the unaffected central nervous system. GDAP1L1 responds to elevated levels of oxidized glutathione by translocating from the cytosol to mitochondria, where it inserts into the mitochondrial outer membrane. This translocation is necessary to substitute for loss of GDAP1 expression. Accordingly, more GDAP1L1 was associated with mitochondria in the spinal cord of aged Gdap1(-/-) mice compared with controls. Our findings demonstrate that Charcot-Marie-Tooth disease caused by mutations in GDAP1 leads to mild, persistent oxidative stress in the peripheral nervous system, which can be compensated by GDAP1L1 in the unaffected central nervous system. We conclude that members of the GDAP1 family are responsive and protective against stress associated with increased levels of oxidized glutathione.

  3. Atypical presentation of Charcot-Marie-Tooth disease 1A: A case report.

    Science.gov (United States)

    Kulkarni, Shilpa D; Sayed, Rafat; Garg, Meenal; Patil, Varsha A

    2015-11-01

    Charcot-Marie-Tooth (CMT) 1A is the most common form of CMT disease and is characterized by duplication of Peripheral myelin protein 22 (PMP22) gene. We report a boy with genetically confirmed CMT1A disease having clinical involvement of hypoglossal and glossopharyngeal nerves, as well as asymmetrical and primarily upper limb involvement. These atypical features widen the clinical spectrum of CMT1A, leading to interesting observations about PMP22 gene related disorders and varied clinical expression of similar genetic mutations.

  4. Pes Cavus and Charcot Marie Tooth Disease: A Case Report and Brief Review of the Literature

    Directory of Open Access Journals (Sweden)

    Levent Ediz

    2011-09-01

    Full Text Available Charcot-Marie-Tooth (CMT is a disease that is highly heterogeneous, both clinically and genetically. Clinical and electrophysiological data are essential for diagnosis. Children with CMT experience acquired foot weakness, contracture and deformity (pes cavus and hammer toes from an early age. Early intervention targeting the foot and ankle may prevent long-term disability in CMT. Here we present a CMT patient with acquired pes cavus and hammer toes and review the literature briefly for diagnosis, treatment, and rehabilitation of CMT. As a result we conclude that CMT should also come into mind in the differential diagnosis of acquired pes cavus and hammer toes.

  5. Sport activity in Charcot-Marie-Tooth disease: A case study of a Paralympic swimmer.

    Science.gov (United States)

    Vita, Giuseppe; La Foresta, Stefania; Russo, Massimo; Vita, Gian Luca; Messina, Sonia; Lunetta, Christian; Mazzeo, Anna

    2016-09-01

    This study reports the positive physical, emotional and psychosocial changes induced by sport activity in a Paralympic swimmer with Charcot-Marie-Tooth (CMT) type 4A. When we compared evaluations before initiating sport activity with those after five years of competitive activity, we found: i) increased proximal muscles strength of upper limbs; ii) augmented ability to propel wheelchair independently; iii) improved quality of life; iv) reduced trait anxiety and striking improvement of depression; v) enhanced self-esteem. Longitudinal studies in large cohorts to evaluate the positive effects of sport activity are needed to support provision of evidence-based advice to patients and families.

  6. Copy Number Variations in a Population-Based Study of Charcot-Marie-Tooth Disease

    Directory of Open Access Journals (Sweden)

    Helle Høyer

    2015-01-01

    Full Text Available Copy number variations (CNVs are important in relation to diversity and evolution but can sometimes cause disease. The most common genetic cause of the inherited peripheral neuropathy Charcot-Marie-Tooth disease is the PMP22 duplication; otherwise, CNVs have been considered rare. We investigated CNVs in a population-based sample of Charcot-Marie-Tooth (CMT families. The 81 CMT families had previously been screened for the PMP22 duplication and point mutations in 51 peripheral neuropathy genes, and a genetic cause was identified in 37 CMT families (46%. Index patients from the 44 CMT families with an unknown genetic diagnosis were analysed by whole-genome array comparative genomic hybridization to investigate the entire genome for larger CNVs and multiplex ligation-dependent probe amplification to detect smaller intragenomic CNVs in MFN2 and MPZ. One patient had the pathogenic PMP22 duplication not detected by previous methods. Three patients had potentially pathogenic CNVs in the CNTNAP2, LAMA2, or SEMA5A, that is, genes related to neuromuscular or neurodevelopmental disease. Genotype and phenotype correlation indicated likely pathogenicity for the LAMA2 CNV, whereas the CNTNAP2 and SEMA5A CNVs remained potentially pathogenic. Except the PMP22 duplication, disease causing CNVs are rare but may cause CMT in about 1% (95% CI 0–7% of the Norwegian CMT families.

  7. Coexistent Charcot-Marie-Tooth type 1A and type 2 diabetes mellitus neuropathies in a Chinese family

    Directory of Open Access Journals (Sweden)

    A-ping Sun

    2015-01-01

    Full Text Available Charcot-Marie-Tooth disease type 1A (CMT1A is caused by duplication of the peripheral myelin protein 22 (PMP22 gene on chromosome 17. It is the most common inherited demyelinating neuropathy. Type 2 diabetes mellitus is a common metabolic disorder that frequently causes predominantly sensory neuropathy. In this study, we report the occurrence of CMT1A in a Chinese family affected by type 2 diabetes mellitus. In this family, seven individuals had duplication of the PMP22 gene, although only four had clinical features of polyneuropathy. All CMT1A patients with a clinical phenotype also presented with type 2 diabetes mellitus. The other three individuals had no signs of CMT1A or type 2 diabetes mellitus. We believe that there may be a genetic link between these two diseases.

  8. Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease.

    LENUS (Irish Health Repository)

    Murphy, Sinéad M

    2011-09-01

    The Charcot-Marie-Tooth neuropathy score (CMTNS) is a reliable and valid composite score comprising symptoms, signs, and neurophysiological tests, which has been used in natural history studies of CMT1A and CMT1X and as an outcome measure in treatment trials of CMT1A. Following an international workshop on outcome measures in Charcot-Marie-Tooth disease (CMT), the CMTNS was modified to attempt to reduce floor and ceiling effects and to standardize patient assessment, aiming to improve its sensitivity for detecting change over time and the effect of an intervention. After agreeing on the modifications made to the CMTNS (CMTNS2), three examiners evaluated 16 patients to determine inter-rater reliability; one examiner evaluated 18 patients twice within 8 weeks to determine intra-rater reliability. Three examiners evaluated 63 patients using the CMTNS and the CMTNS2 to determine how the modifications altered scoring. For inter- and intra-rater reliability, intra-class correlation coefficients (ICCs) were ≥0.96 for the CMT symptom score and the CMT examination score. There were small but significant differences in some of the individual components of the CMTNS compared with the CMTNS2, mainly in the components that had been modified the most. A longitudinal study is in progress to determine whether the CMTNS2 is more sensitive than the CMTNS for detecting change over time.

  9. Exclusive expression of the Rab11 effector SH3TC2 in Schwann cells links integrin-α6 and myelin maintenance to Charcot-Marie-Tooth disease type 4C.

    Science.gov (United States)

    Vijay, Sauparnika; Chiu, Meagan; Dacks, Joel B; Roberts, Rhys C

    2016-07-01

    Charcot-Marie-Tooth disease type 4C (CMT4C) is one of the commonest autosomal recessive inherited peripheral neuropathies and is associated with mutations in the Rab11 effector, SH3TC2. Disruption of the SH3TC2-Rab11 interaction is the molecular abnormality underlying this disease. However, why SH3TC2 mutations cause an isolated demyelinating neuropathy remains unanswered. Here we show that SH3TC2 is an exclusive Schwann cell protein expressed late in myelination and is downregulated following denervation suggesting a functional role in myelin sheath maintenance. We support our data with an evolutionary cell biological analysis showing that the SH3TC2 gene, and its paralogue SH3TC1, are derived from an ancestral homologue, the duplication of which occurred in the common ancestor of jawed vertebrates, coincident with the appearance of Schwann cells and peripheral axon myelination. Furthermore, we report that SH3TC2 associates with integrin-α6, suggesting that aberrant Rab11-dependent endocytic trafficking of this critical laminin receptor in myelinated Schwann cells is connected to the demyelination seen in affected nerves. Our study therefore highlights the inherent evolutionary link between SH3TC2 and peripheral nerve myelination, pointing also towards a molecular mechanism underlying the specific demyelinating neuropathy that characterizes CMT4C.

  10. Postural instability in Charcot-Marie-Tooth type 1A patients is strongly associated with reduced somatosensation.

    NARCIS (Netherlands)

    Linden, M.H. van der; Linden, S.C. van der; Hendricks, H.T.; Engelen, B.G.M. van; Geurts, A.C.H.

    2010-01-01

    In order to determine the influence of somatosensory impairments, due to the loss of large myelinated fibres, on the postural stability of Charcot-Marie-Tooth 1A (CMT) patients, a cross-sectional balance assessment was done. Nine CMT patients were compared with eight patients with a distal type of S

  11. Junctophilin-1 is a modifier gene of GDAP1-related Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Pla-Martín, David; Calpena, Eduardo; Lupo, Vincenzo; Márquez, Celedonio; Rivas, Eloy; Sivera, Rafael; Sevilla, Teresa; Palau, Francesc; Espinós, Carmen

    2015-01-01

    Mutations in the GDAP1 gene cause different forms of Charcot-Marie-Tooth (CMT) disease, and the primary clinical expression of this disease is markedly variable in the dominant inheritance form (CMT type 2K; CMT2K), in which carriers of the GDAP1 p.R120W mutation can display a wide range of clinical severity. We investigated the JPH1 gene as a genetic modifier of clinical expression variability because junctophilin-1 (JPH1) is a good positional and functional candidate. We demonstrated that the JPH1-GDAP1 cluster forms a paralogon and is conserved in vertebrates. Moreover, both proteins play a role in Ca(2+) homeostasis, and we demonstrated that JPH1 is able to restore the store-operated Ca(2+) entry (SOCE) activity in GDAP1-silenced cells. After the mutational screening of JPH1 in a series of 24 CMT2K subjects who harbour the GDAP1 p.R120W mutation, we characterized the JPH1 p.R213P mutation in one patient with a more severe clinical picture. JPH1(p.R213P) cannot rescue the SOCE response in GDAP1-silenced cells. We observed that JPH1 colocalizes with STIM1, which is the activator of SOCE, in endoplasmic reticulum-plasma membrane puncta structures during Ca(2+) release in a GDAP1-dependent manner. However, when GDAP1(p.R120W) is expressed, JPH1 seems to be retained in mitochondria. We also established that the combination of GDAP1(p.R120W) and JPH1(p.R213P) dramatically reduces SOCE activity, mimicking the effect observed in GDAP1 knock-down cells. In summary, we conclude that JPH1 and GDAP1 share a common pathway and depend on each other; therefore, JPH1 can contribute to the phenotypical consequences of GDAP1 mutations.

  12. The central nervous system phenotype of X-linked Charcot-Marie-Tooth disease: a transient disorder of children and young adults.

    Science.gov (United States)

    Al-Mateen, Majeed; Craig, Alexa Kanwit; Chance, Phillip F

    2014-03-01

    We describe 2 patients with X-linked Charcot-Marie-Tooth disease, type 1 (CMTX1) disease and central nervous system manifestations and review 19 cases from the literature. Our first case had not been previously diagnosed with Charcot-Marie-Tooth disease, and the second case, although known to have Charcot-Marie-Tooth disease, was suspected of having CMTX1 after presentation with central nervous system manifestations. The most common central nervous system manifestations were transient and included dysarthria, ataxia, hemiparesis, and tetraparesis resembling periodic paralysis. Of the 21 patients, 19 presented at 21 years of age or younger, implicating CMTX1 with transient central nervous system manifestations as a disorder that predominantly affects children and adolescents. CMTX1 should be included in the differential diagnosis of patients who present with transient central nervous system phenomena, including stroke-like episodes, tetraparesis suggestive of periodic paralysis, dysarthria, ataxia, or combinations of these deficits. Reversible, bilateral, nonenhancing white matter lesions and restricted diffusion on magnetic resonance imaging are characteristic features of the central nervous system phenotype of CMTX1.

  13. Anesthetic Management of a Patient With Charcot-Marie-Tooth Disease.

    Science.gov (United States)

    Ohshita, Naohiro; Oka, Saeko; Tsuji, Kaname; Yoshida, Hiroaki; Morita, Shosuke; Momota, Yoshihiro; Tsutsumi, Yasuo M

    2016-01-01

    Charcot-Marie-Tooth disease (CMTD) is a hereditary peripheral neuropathy and is characterized by progressive muscle atrophy and motor-sensory disorders in all 4 limbs. Most reports have indicated that major challenges with general anesthetic administration in CMTD patients are the appropriate use of nondepolarizing muscle relaxants and preparation for malignant hyperthermia in neuromuscular disease. Moderate sedation may be associated with the same complications as those of general anesthesia, as well as dysfunction of the autonomic nervous system, reduced perioperative respiratory function, difficulty in positioning, and sensitivity to intravenous anesthetic agents. We decided to use intravenous sedation in a CMTD patient and administered midazolam initially and propofol continuously, with total doses of 1.5 mg and 300 mg, respectively. Anesthesia was completed in 3 hours and 30 minutes without adverse events. We suggest that dental anesthetic treatment with propofol and midazolam may be effective for patients with CMTD.

  14. 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).

  15. Next-generation sequencing and genetic diagnosis of Charcot-Marie-Tooth disease

    Directory of Open Access Journals (Sweden)

    Ashok Verma

    2014-01-01

    Full Text Available Over 70 different Charcot-Marie-Tooth disease (CMT–associated genes have now been discovered and their number is growing. Conventional genetic testing for all CMT genes is cumbersome, expensive, and impractical in an individual patient. Next-generation sequencing (NGS technology allows cost-effective sequencing of large scale DNA, even entire exome (coding sequences or whole genome and thus, NGS platform can be employed to effectively target a large number or all CMT-related genes for accurate diagnosis. This overview discusses how NGS can be strategically used for genetic diagnosis in patients with CMT or unexplained neuropathy. A comment is made to combine simple clinical and electrophysiological algorithm to assign patients to major CMT subtypes and then employ NGS to screen for all known mutations in the subtype-specific CMT gene panel.

  16. Charcot-Marie-Tooth disease and pathways to molecular based therapies.

    Science.gov (United States)

    Harel, T; Lupski, J R

    2014-11-01

    The discovery in 1991 that chromosome 17p12 duplication is associated with Charcot-Marie-Tooth (CMT) disease marked the beginning of an era of molecular insight into this disorder, which encompasses the peripheral motor and sensory neuropathies. A mere two decades later, over 40 subtypes of CMT have been molecularly defined and many have been extensively studied in vitro and in animal models, providing the framework for a more comprehensive understanding of the biological pathways dictating myelination, axonal dynamics, and axon-glia interactions. The advent of next-generation sequencing technologies offers opportunities in both research and clinical settings for gene discovery, further molecular understanding and diagnosis, and calls for modifications of the existing algorithms guiding genetic testing. Although treatment is mainly supportive at this time, advances in this field are anticipated as the molecular basis of CMT is unraveled.

  17. Connexin mutations in X-linked Charcot-Marie-Tooth disease

    Energy Technology Data Exchange (ETDEWEB)

    Bergoffen, J. (Univ. of Pennsylvania Medical School, Philadelphia, PA (United States)); Scherer, S.S.; Wang, S.; Scott, M.; Bone, L.J.; Chen, K.; Lensch, M.W.; Fischbeck, K.H. (Univ. of Pennsylvania Medical School, PA (United States)); Paul, D.L. (Harvard Medical School, Boston, MA (United States)); Change, P.F. (Univ. of Pennsylvania Medical School and Neurology Division, Philadelphia, PA (United States))

    1993-12-24

    X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry techniques, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a gap junction protein, suggest that connexin32 plays an important role in peripheral nerve.

  18. [Therapy for Charcot-Marie-Tooth Disease: From the Standpoint of Neurologists].

    Science.gov (United States)

    Nakagawa, Masanori

    2016-01-01

    To date, there is no approved pharmacologic treatment for any form of Charcot-Marie-Tooth disease (CMT). However, some clinical or preclinical trials for CMT1A have been undertaken, for example Neurotrophin-3, PXT3003, and neuregulin-1. Gene therapy for CMT1X, CMT2F and Giant axonal neuropathy using animal model or culture cells have been reported with some interesting results. Stem cell research for example iPS cells derived from patients with CMT2A or CMT2E, is being conducted to clarify the mechanism of CMT and find therapeutic clues. The development of new surrogate markers for clinical trials is also needed. Additionally, steps should be taken to improve the quality of life of patients with CMT, including pain control and life style enhancement.

  19. Unusual manifestations of Charcot-Marie-Tooth disease: A clinical observation

    Directory of Open Access Journals (Sweden)

    Akhila Kumar Panda

    2014-01-01

    Full Text Available Charcot-Marie-Tooth disease (CMT is the most common hereditary neuromuscular disorder. Careful assessment of clinical presentations, mode of inheritance, electrophysiological studies, and genetic analysis form the basis for the diagnosis of CMT. CMT4 is a group of progressive motor and sensory axonal demyelinating neuropathies. It is distinguished from other forms of CMT by autosomal recessive pattern of inheritance, variable clinical manifestations, electrophysiological study, nerve biopsy, and specific genetic studies. Here, we report an interesting case of hereditary neuropathy with recessive inheritance pattern who presented with combined clinical phenotypes of 4B1, 4C, and 4D subtypes. The histopathological study revealed onion bulb appearance suggestive of demyelination and remyelination phenomenon. The overlapping clinical manifestation may create a diagnostic challenge which would be confirmed by specific molecular analysis.

  20. Pé cavo adquirido na doença de Charcot-Marie-Tooth Acquired pes cavus in Charcot-Marie-Tooth disease

    Directory of Open Access Journals (Sweden)

    Daniel Augusto Carvalho Maranho

    2009-01-01

    Full Text Available As neuropatias sensitivomotoras hereditárias, principalmente a doença de Charcot-Marie-Tooth, manifestam-se frequentemente com o aparecimento de pé cavovaro, deformidade caracterizada pela acentuação fixa do arco plantar e inversão do retropé. O diagnóstico da doença de base e a cuidadosa avaliação do paciente fornecem os elementos-chave para decisão do tratamento. O cavo pode situar-se no antepé, retropé ou ser o resultado da associação das duas localizações. Deformidades combinadas, principalmente varismo e garras dos artelhos, devem ser bem avaliadas; as características clínicas como grau das alterações, acometimento da força muscular, flexibilidade e idade são fatores importantes para a decisão da conduta. O tratamento conservador do pé cavovaro por meio de fisioterapia, palmilhas e adaptação nos calçados é reservado ao paciente mais jovem ou casos levemente acometidos. Entretanto, há tendência de agravamento das deformidades devido à característica progressiva da doença neurológica de base. Assim, o tratamento cirúrgico pelas técnicas clássicas é indicado precocemente, sendo importante identificar as alterações primárias, diferenciá-las das secundárias e corrigi-las, se possível. As transferências musculares são usadas no sentido de minimizar o desequilíbrio, estruturas retraídas são seccionadas ou alongadas e osteotomias localizadas devem ser preferíveis às artrodeses, que são reservadas para pés rígidos e muito deformados de pacientes adultos.Hereditary motor and sensory neuropathies, especially Charcot-Marie-Tooth disease, are frequently expressed with an acquired cavusvarus foot which is characterized by a fixed increase of the plantar arch and hindfoot inversion. Diagnosis of the underlying condition achieved through careful patient assessment and local evaluations is the keystone for decision-making about the adequate treatment. The cavus may present as an isolated deformity of

  1. Clinical and genetic spectra in a series of Chinese patients with Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Wang, Rui; He, Jin; Li, Jin-Jing; Ni, Wang; Wu, Zhi-Ying; Chen, Wan-Jin; Wang, Yi

    2015-12-01

    The aim of this study was to determine the clinical features and frequencies of genetic subtypes in a series of patients with Charcot-Marie-Tooth (CMT) disease from Eastern China. Patients were divided into three subtypes, CMT1, CMT2 and hereditary neuropathy with liability to pressure palsy (HNPP), according to their electrophysiological manifestations. Multiplex ligation-dependent probe analysis (MLPA) was performed to detect duplications/deletions in the PMP22 gene. The coding regions and splice sites of the GJB1, MPZ, MFN2 and GDAP-1 genes were determined by direct sequencing. Among the 148 patients in the study, 37.2% of the cases had mutations in genes assessed. The mutation detection rate was higher in patients with family histories than in spontaneous cases. PMP22 duplication (13.5%) was predominant in this group of patients, followed by PMP22 deletion (11.5%), and point mutations in GJB1 (8.8%), MPZ (2.0%) and MFN2 (0.7%). Three novel mutations (c.151T>C and c.310 A>G in GJB1 and c.1516 C>G in MFN2) were detected. A small deletion in PMP22 exon 4 was detected in a patient with severe CMT1. Genetic tests have great value in CMT patients with family histories. The frequency of PMP22 duplications was lower in Asian patients than in others. We suggest that genetic testing strategies in CMT patients should be primarily based on electromyography data.

  2. X inactivation in females with X-linked Charcot-Marie-Tooth disease.

    LENUS (Irish Health Repository)

    Murphy, Sinéad M

    2012-07-01

    X-linked Charcot-Marie-Tooth disease (CMT1X) is the second most common inherited neuropathy, caused by mutations in gap junction beta-1 (GJB1). Males have a uniformly moderately severe phenotype while females have a variable phenotype, suggested to be due to X inactivation. We aimed to assess X inactivation pattern in females with CMT1X and correlate this with phenotype using the CMT examination score to determine whether the X inactivation pattern accounted for the variable phenotype in females with CMT1X. We determined X inactivation pattern in 67 females with CMT1X and 24 controls using the androgen receptor assay. We were able to determine which X chromosome carried the GJB1 mutation in 30 females. There was no difference in X inactivation pattern between patients and controls. In addition, there was no correlation between X inactivation pattern in blood and phenotype. A possible explanation for these findings is that the X inactivation pattern in Schwann cells rather than in blood may explain the variable phenotype in females with CMT1X.

  3. Characterization of gait parameters in patients with Charcot-Marie-Tooth disease.

    Directory of Open Access Journals (Sweden)

    Kuruvilla A

    2000-01-01

    Full Text Available The gait of five patients with Charcot-Marie-Tooth(CMT disease was analyzed using light-emitting diodes and a force plate. The flexion-extension motions of the hips, knees, and ankles, as well as their moments (vector sums of forces acting at the joints in the flexion-extension and abduction-adduction planes, were quantified. The gait of the CMT patients showed abnormalities consistent with both distal weakness (ankle dorsi- and plantar-flexors and weakness of the hip abductor muscles. The latter weakness appeared to produce asymmetric hip moments and truncal instability in the mediolateral plane during ambulation. However, the extent to which the gait was abnormal appeared not to be exclusively related to the severity of the sensorimotor conduction deficits in the peripheral nerves. In the four patients for whom nerve conduction velocity studies were available, decrease in the lower-extremity distal conduction velocities and evoked motor amplitude potentials did not correlate with the severity and extent of the gait abnormalities.

  4. Charcot-Marie-Tooth Disease and Related Hereditary Neuropathies: From Gene Function to Associated Phenotypes.

    Science.gov (United States)

    Pareyson, D; Saveri, P; Piscosquito, G

    2014-10-10

    Charcot-Marie-Tooth disease (CMT) and related neuropathies are a genetically highly heterogeneous group of neurodegenerative disorders. CMT affects both the sensory and motor nerves, distal Hereditary Motor Neuropathies (dHMN) are phenotypically similar disorders involving only motor nerves, while Hereditary Sensory and Autonomic Neuropathies (HSAN) are rare distinct disorders affecting sensory and sometimes autonomic nerves. Almost 70 genes have been identified as responsible for these disorders. It is astonishing to learn how diverse are the cellular sublocalisation and the functional roles of the encoded proteins of CMT-associated genes which all lead to similar disorders of the peripheral nervous system. Myelin formation and maintenance, mitochondrial dynamics, cytoskeleton organization, axonal transport, and vesicular trafficking are the most frequently involved pathways. However, dysfunction of several activities from the nucleus to the neuromuscular junction forms the basis for these hereditary neuropathies, making it challenging predicting the functions of newly identified mutated genes. In this review we will discuss the function and related phenotypes of all the genes thus far associated with CMT, dHMN, and HSAN.

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

    Science.gov (United States)

    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.

  6. Charcot-Marie-Tooth-linked mutant GARS is toxic to peripheral neurons independent of wild-type GARS levels.

    Directory of Open Access Journals (Sweden)

    William W Motley

    2011-12-01

    Full Text Available Charcot-Marie-Tooth disease type 2D (CMT2D is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS. In addition to GARS, mutations in three other tRNA synthetase genes cause similar neuropathies, although the underlying mechanisms are not fully understood. To address this, we generated transgenic mice that ubiquitously over-express wild-type GARS and crossed them to two dominant mouse models of CMT2D to distinguish loss-of-function and gain-of-function mechanisms. Over-expression of wild-type GARS does not improve the neuropathy phenotype in heterozygous Gars mutant mice, as determined by histological, functional, and behavioral tests. Transgenic GARS is able to rescue a pathological point mutation as a homozygote or in complementation tests with a Gars null allele, demonstrating the functionality of the transgene and revealing a recessive loss-of-function component of the point mutation. Missense mutations as transgene-rescued homozygotes or compound heterozygotes have a more severe neuropathy than heterozygotes, indicating that increased dosage of the disease-causing alleles results in a more severe neurological phenotype, even in the presence of a wild-type transgene. We conclude that, although missense mutations of Gars may cause some loss of function, the dominant neuropathy phenotype observed in mice is caused by a dose-dependent gain of function that is not mitigated by over-expression of functional wild-type protein.

  7. Multicolor in situ hybridization and linkage analysis order Charcot-Marie-Tooth type I (CMTIA) gene-region markers

    Energy Technology Data Exchange (ETDEWEB)

    Lebo, R.V.; Lynch, E.D.; Golbus, M.S. (Univ. of California, San Francisco (United States)); Bird, T.D. (Univ. of Washington, Seattle (United States)); Barker, D.F.; O' Connell, P.; Chance, P.F. (Univ. of Utah, Salt Lake City (United States))

    1992-01-01

    This study demonstrates a clear and current role for multicolor in situ hybridization in expediting positional cloning studies of unknown disease genes. Nine polymorphic DNA cosmids have been mapped to eight ordered locations spanning the Charcot-Marie-Tooth type 1 (CMT1A) disease gene region in distal band 17p11.2, by multicolor in situ hybridization. When used with linkage analysis, these methods have generated a fine physical map and have firmly assigned the CMT1A gene to distal band 17p11.2. Linkage analysis with four CMT1A pedigrees mapped the CMT1A gene with respect to two flanking markers. Additional loci were physically mapped and ordered by in situ hybridization and analysis of phase-known recombinants in CMT1A pedigrees. These data demonstrate the ability of in situ hybridization to resolve loci within 0.5 Mb on early-metaphase chromosomes. Multicolor in situ hybridization also excluded the possibility of pericentric inversions in two unrelated patients with CMT1 and neurofibromatosis type 1. When used with pulsed-field gel electrophoresis, multicolor in situ hybridization can establish physical location, order, and distance in closely spaced chromosome loci.

  8. Identification of A Novel SBF2 Frameshift Mutation in Charcot-Marie-Tooth Disease Type 4B2 Using Whole-exome Sequencing

    Institute of Scientific and Technical Information of China (English)

    Meiyan Chen; Xin Yi; Ming Qi; Jing Wu; Ning Liang; Lihui Tang; Yanhua Chen; Huishuang Chen; Wei Wei; Tianying Wei; Hui Huang

    2014-01-01

    Charcot–Marie–Tooth disease type 4B2 with early-onset glaucoma (CMT4B2, OMIM 604563) is a genetically-heterogeneous childhood-onset neuromuscular disorder. Here, we report the case of a 15-year-old male adolescent with lower extremity weakness, gait abnormalities, foot deformities and early-onset glaucoma. Since clinical diagnosis alone was insufficient for providing pathogenetic evidence to indicate that the condition belonged to a consanguineous family, we applied whole-exome sequencing to samples from the patient, his parents and his younger brother, assuming that the patient’s condition is transmitted in an autosomal recessive pattern. A frame-shift mutation, c.4571delG (P.Gly1524Glufs*42), was revealed in the CMT4B2-related gene SBF2 (also known as MTMR13, MIM 607697), and this mutation was found to be homozygous in the proband and heterozygous in his parents and younger brother. Together with the results of clinical diagnosis, this case was diagnosed as CMT4B2. Our finding further demonstrates the use of whole-exome sequencing in the diagnosis and treatment of rare diseases.

  9. [Molecular diagnosis of axonal forms of Charcot-Marie-Tooth disease].

    Science.gov (United States)

    Latour, P; Vial, C

    2009-12-01

    Charcot-Marie-Tooth (CMT) disease is the most common cause of inherited peripheral neuropathies with a frequency estimated at 1/2500. Electroneuromyographic examination distinguishes a myelinic form (CMT1) and an axonal form of the disease (CMT2). Significant genetic heterogeneity is found in CMT, with 15 genes or loci for CMT2. To date, a molecular diagnosis has not been established for most CMT2 patients and the distribution of identified mutations is wide spreading over nearly all genes. Simple guidelines for daily practice are difficult to establish from compilation of mutation reports or consultation of databases; little simplification can be expected from future findings. We present our results of molecular diagnosis for 251 CMT2 index cases characterized by their mode of inheritance (217 dominant and 34 recessive cases), and a motor conduction velocity in median nerve equal to or above to 38m/s. For each case, at least one of the genes known to date for CMT2 (MFN2, RAB7, GARS, NF-L, HSPB1, GDAP1, MPZ, HSPB8, GJB1, DNM2, YARS, LMNA, and MED25) was studied. Around 22% of diagnoses were established and efficiency was comparable for dominant or recessive cases. For dominant cases, the first objective was to search for mutations of proteins connexin32, mitofusin2 and P0. For recessive cases, GDAP1 provided the key to molecular diagnosis; lamin A/C mutations were only found for patients with an ethnic background from North Africa. Heat shock proteins HSPB1 and HSPB8 were implicated in a significant proportion of "spinal" (or pure motor) CMT2. NF-L or RAB7 mutations were rare. We did not identify any deleterious mutations in GARS, DNM2, YARS orMED2. We propose a simple decision tree for molecular diagnosis of CMT2.

  10. A locus-specific database for mutations in GDAP1 allows analysis of genotype-phenotype correlations in Charcot-Marie-Tooth diseases type 4A and 2K

    Directory of Open Access Journals (Sweden)

    Cassereau Julien

    2011-12-01

    Full Text Available Abstract Background The ganglioside-induced differentiation-associated protein 1 gene (GDAP1, which is involved in the Charcot-Marie-Tooth disease (CMT, the most commonly inherited peripheral neuropathy, encodes a protein anchored to the mitochondrial outer membrane. The phenotypic presentations of patients carrying GDAP1 mutations are heterogeneous, making it difficult to determine genotype-phenotype correlations, since the majority of the mutations have been found in only a few unrelated patients. Locus-specific databases (LSDB established in the framework of the Human Variome Project provide powerful tools for the investigation of such rare diseases. Methods and Results We report the development of a publicly accessible LSDB for the GDAP1 gene. The GDAP1 LSDB has adopted the Leiden Open-source Variation Database (LOVD software platform. This database, which now contains 57 unique variants reported in 179 cases of CMT, offers a detailed description of the molecular, clinical and electrophysiological data of the patients. The usefulness of the GDAP1 database is illustrated by the finding that GDAP1 mutations lead to primary axonal damage in CMT, with secondary demyelination in the more severe cases of the disease. Conclusion Findings of this nature should lead to a better understanding of the pathophysiology of CMT. Finally, the GDAP1 LSDB, which is part of the mitodyn.org portal of databases of genes incriminated in disorders involving mitochondrial dynamics and bioenergetics, should yield new insights into mitochondrial diseases.

  11. Genetics of Charcot-Marie-Tooth (CMT Disease within the Frame of the Human Genome Project Success

    Directory of Open Access Journals (Sweden)

    Vincent Timmerman

    2014-01-01

    Full Text Available Charcot-Marie-Tooth (CMT neuropathies comprise a group of monogenic disorders affecting the peripheral nervous system. CMT is characterized by a clinically and genetically heterogeneous group of neuropathies, involving all types of Mendelian inheritance patterns. Over 1,000 different mutations have been discovered in 80 disease-associated genes. Genetic research of CMT has pioneered the discovery of genomic disorders and aided in understanding the effects of copy number variation and the mechanisms of genomic rearrangements. CMT genetic study also unraveled common pathomechanisms for peripheral nerve degeneration, elucidated gene networks, and initiated the development of therapeutic approaches. The reference genome, which became available thanks to the Human Genome Project, and the development of next generation sequencing tools, considerably accelerated gene and mutation discoveries. In fact, the first clinical whole genome sequence was reported in a patient with CMT. Here we review the history of CMT gene discoveries, starting with technologies from the early days in human genetics through the high-throughput application of modern DNA analyses. We highlight the most relevant examples of CMT genes and mutation mechanisms, some of which provide promising treatment strategies. Finally, we propose future initiatives to accelerate diagnosis of CMT patients through new ways of sharing large datasets and genetic variants, and at ever diminishing costs.

  12. Central Nervous System Demyelination in a Charcot-Marie-Tooth Type 1A Patient

    OpenAIRE

    Christos Koros; Maria-Eleftheria Evangelopoulos; Costas Kilidireas; Elisabeth Andreadou

    2013-01-01

    Introduction. Central nervous system involvement, either clinical or subclinical, has been reported mainly in X-linked Charcot-Marie-Tooth (CMT-X) patients. Case Presentation. We present the case of a 31-year-old man with a genetically confirmed history of CMT1A who developed CNS involvement mimicking multiple sclerosis (MS). Clinical, imaging, and laboratory findings suggested an autoimmune CNS demyelination. Discussion. Although the simultaneous existence of CMT1A and MS could be coincident...

  13. Misunderstanding of foot drop in a patient with charcot-marie-tooth disease and lumbar disk herniation.

    Science.gov (United States)

    Han, Youngmin; Kim, Kyoung-Tae; Cho, Dae-Chul; Sung, Joo-Kyung

    2015-04-01

    We report the case of 57-year-old woman diagnosed with Charcot-Marie-Tooth (CMT) disease and lumbar disk herniation (LDH). She had left leg weakness and foot numbness, foot deformity (muscle atrophy, high arch, and clawed toes). The lumbar spine MRI showed LDH at L4-5. Additionally, electrophysiology results were consistent with chronic peripheral motor-sensory polyneuropathy (axonopathy). In genetic testing, 17p11.2-p12 duplication/deletions characteristic of CMT disease were observed. We confirmed the patient's diagnosis as CMT disease and used conservative treatment.

  14. Minimally Invasive Early Operative Treatment of Progressive Foot and Ankle Deformity Associated With Charcot-Marie-Tooth Disease.

    Science.gov (United States)

    Boffeli, Troy J; Tabatt, Jessica A

    2015-01-01

    Charcot-Marie-Tooth disease is a neuromuscular disorder that commonly results in a predictable pattern of progressive bilateral lower extremity weakness, numbness, contracture, and deformity, including drop foot, loss of ankle eversion strength, dislocated hammertoes, and severe cavus foot deformity. Late stage reconstructive surgery will be often necessary if the deformity becomes unbraceable or when neuropathic ulcers have developed. Reconstructive surgery for Charcot-Marie-Tooth deformity is generally extensive and sometimes staged. Traditional reconstructive surgery involves a combination of procedures, including tendon lengthening or transfer, osteotomy, and arthrodesis. The described technique highlights our early surgical approach, which involves limited intervention before the deformity becomes rigid, severe, or disabling. We present 2 cases to contrast our early minimally invasive technique with traditional late stage reconstruction. Charcot-Marie-Tooth disease affects different muscles at various stages of disease progression. As 1 muscle becomes weak, the antagonist will overpower it and cause progressive deformity. The focus of the early minimally invasive approach is to decrease the forces that cause progressive deformity yet maintain function, where possible. Our goal has been to maintain a functional and braceable foot and ankle, with the hope of avoiding or limiting the extent of future major reconstructive surgery. The presented cases highlight the patient selection criteria, the ideal timing of early surgical intervention, the procedure selection criteria, and operative pearls. The early minimally invasive approach includes plantar fasciotomy, Achilles tendon lengthening, transfer of the peroneus longus to the fifth metatarsal, Hibbs and Jones tendon transfer, and hammertoe repair of digits 1 to 5.

  15. 腓骨肌萎缩症2型(CMT2)小鼠模型的研究进展%Research progress in the mouse models of Charcot-Marie-Tooth disease type 2 (CMT2)

    Institute of Scientific and Technical Information of China (English)

    于珍; 栾春杰; 顾鸣敏

    2014-01-01

    腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)是人类最常见的遗传性运动和感觉神经疾病之一,全球群体发病率约为1/2500.CMT主要分为脱髓鞘型(包括CMT1,CMT3,CMT4和CMTX1)和轴索型(CMT2).迄今为止,先后已有17个CMT2的致病基因被定位和克隆,然而对这些基因的致病机制所知甚少.建立CMT2小鼠模型是从动物水平研究突变基因致病机制的有效手段.目前已成功构建了近10种CMT2的转基因小鼠、基因敲除小鼠或基因敲入小鼠模型,其中尤以带有人源致病基因的转基因小鼠模型为多.文章简要介绍了CMT2小鼠模型构建策略,着重阐述了CMT2小鼠模型的研究进展,并对个别小鼠模型进行了剖析.

  16. Charcot-Marie-Tooth disease and dilated cardiomyopathy. A rare combination. Enfermedad de Charcot-Marie-Tooth y miocardiopatía dilatada. Una rara asociación.

    Directory of Open Access Journals (Sweden)

    Rafael Pila Pérez

    2011-07-01

    Full Text Available

    Se presenta el caso de un paciente de 50 años de edad, con 14 años de evolución de manifestaciones clínicas, destacándose las alteraciones musculoesqueléticas de los cuatro miembros con atrofia de las prominencias tenar e hipotenar y de la musculatura de ambas piernas. Se destacó la presencia de alteraciones sensitivas en miembros inferiores con distribución en calcetín, atrofia, atonía, arreflexia y marcha equina. Desde el punto de vista cardiaco, el paciente presentaba un fibriloaleteo. La radiografía de tórax mostró un aumento marcado del área cardiaca y la ecocardiografía puso de manifiesto una miocardiopatía dilatada. El estudio histopatológico confirmó la presencia de la enfermedad de Charcot-Marie-Tooth asociada a miocardiopatía dilatada. El diagnóstico se basó en las características clínicas, la velocidad de conducción motora, y el estudio histopatológico, que demostró desmielinización con lesiones en “cebolla”, si bien faltaron los estudios genéticos. La enfermedad de Charcot-Marie-Tooth es una enfermedad rara; aproximadamente un 60 % de los pacientes que la padecen, son portadores de una duplicación del cromosoma 17. Por ello, se consideró oportuno transmitir la experiencia de este caso.

    The case of a 50 years old male patient is presented. Along 14 years of clinical evolution, four limbs musculoskeletal disorders with atrophy of the thenar and hypothenar prominences and muscles of both legs had been emphasized. The presence of sensory impairment in lower limbs with stocking distribution, atrophy, weakness, areflexia and equine gait were very peculiar in this case. From the cardiac point of view, the patient presented a fibrillation/flutter. Chest radiography showed a marked increase in the cardiac area and echocardiography revealed dilated cardiomyopathy. Histopathological examination confirmed the presence of Charcot-Marie-Tooth disease associated with dilated cardiomyopathy. While genetic

  17. A novel mutation in GJB1 (c.212T>G) in a Chinese family with X-linked Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Xiao, Fei; Tan, Jia-ze; Zhang, Xu; Wang, Xue-Feng

    2015-03-01

    Gap junction protein beta 1 (GJB1) gene mutations lead to X-linked Charcot-Marie-Tooth (CMTX) disease. We investigated a Chinese family with CMTX and identified a novel GJB1 point mutation. Clinical and electrophysiological features of the pedigree were examined, and sequence alterations of the coding region of GJB1 that encode connexin32 were determined by direct sequencing. Sequence alignment of the mutation site was performed using Clustal W. Mutation effects were analysed using PolyPhen-2, SIFT and Mutation Taster software. The three-dimensional structures of the mutant and wild-type proteins were predicted by modeling with SWISS MODEL online software. The affected family members displayed typical Charcot-Marie-Tooth phenotypes, but phenotypic heterogeneity was observed. Nerve conduction velocities of all affected patients were slow. Sequencing of GJB1 revealed a heterozygous T>G missense mutation at nucleotide 212 in the proband, the proband's mother and the proband's daughter. The affected male sibling of the proband displayed a hemizygous missense mutation with T>G transition at the identical position on the GJB1 gene. This mutation resulted in an amino acid change from isoleucine to serine that was predicted to lead to tertiary structural alterations that would disrupt the function of the GJB1 protein. A novel point mutation in GJB1 was detected, expanding the spectrum of GJB1 mutations known to be associated with CMTX.

  18. Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes.

    Science.gov (United States)

    Nouioua, Sonia; Hamadouche, Tarik; Funalot, Benoit; Bernard, Rafaëlle; Bellatache, Nora; Bouderba, Radia; Grid, Djamel; Assami, Salima; Benhassine, Traki; Levy, Nicolas; Vallat, Jean-Michel; Tazir, Meriem

    2011-08-01

    Autosomal recessive Charcot-Marie-Tooth diseases, relatively common in Algeria due to high prevalence of consanguineous marriages, are clinically and genetically heterogeneous. We report on two consanguineous families with demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMT4) associated with novel homozygous mutations in the MTMR2 gene, c.331dupA (p.Arg111LysfsX24) and PRX gene, c.1090C>T (p.Arg364X) respectively, and peculiar clinical phenotypes. The three patients with MTMR2 mutations (CMT4B1 family) had a typical phenotype of severe early onset motor and sensory neuropathy with typical focally folded myelin on nerve biopsy. Associated clinical features included vocal cord paresis, prominent chest deformities and claw hands. Contrasting with the classical presentation of CMT4F (early-onset Dejerine-Sottas phenotype), the four patients with PRX mutations (CMT4F family) had essentially a late age of onset and a protracted and relatively benign evolution, although they presented marked spine deformities. These observations broaden the spectrum of clinical phenotypes associated with these two CMT4 forms.

  19. Mouse model for Charcot Marie-Tooth as a tool to better understand the disease

    OpenAIRE

    Barneo Muñoz, Manuela

    2016-01-01

    Introducción La enfermedad de Charcot-Marie-Tooth (CMT) es uno de los trastornos neurológicos hereditarios más comunes que afecta a 17-40 de cada 100.000 personas según poblaciones; concretamente esta cifra se sitúa en 28 personas de cada 100.000 en España. La enfermedad recibe el nombre de los tres médicos que la identificaron por primera vez en 1886; Jean-Marie Charcot y Pierre Marie en París, Francia y Howard Henry Tooth en Cambridge, Inglaterra. La enfermedad de CMT, también conocida c...

  20. 腓骨肌萎缩症1型临床与电生理分析%Clinical and Electrophysiological Analysis of Charcot-Marie-Tooth Disease Type 1

    Institute of Scientific and Technical Information of China (English)

    张家良; 常建军

    2005-01-01

    目的:分析腓骨肌萎缩症1型(charcot-marie-tooth disease,CMT1)患者的临床与电生理特点. 方法:对1家系24人(已故2例)中7例(已故1例)CMT1患者临床特点进行总结,分析其中6例的电生理特征,包括肌电图(EMG)、运动神经传导速度(MCV)和感觉神经传导速度(SCV). 结果:4例于青少年期发病,有肢体远端肌无力和萎缩、腱反射减弱或消失、足畸形等典型的临床症状;3例EMG出现纤颤、正相电位,6例有运动电位时限延长;3例下肢SCV引不出,1例MCV引不出.结论:同一家系的CMT1型患者,临床表现亦差异较大;电生理特点为下肢神经病变重于上肢,感觉神经病变重于运动神经,且受累的严重程度不一致.

  1. 腓骨肌萎缩症4型遗传学研究进展%Advances in genetic studies of Charcot-Marie-Tooth disease type 4 (CMT4)

    Institute of Scientific and Technical Information of China (English)

    许烨; 张嘉莹; 杨博宇; 何志宏; 张慕晨; 于珍; 顾鸣敏

    2015-01-01

    腓骨肌萎缩症也称夏科-马利-杜斯氏病(Charcot-Marie-Tooth disease,CMT),是人类最常见的遗传性周围神经病之一,其遗传方式以常染色体显性遗传为主,也有部分呈常染色体隐性遗传或X连锁显性或隐性遗传.根据临床表型将CMT分为脱髓鞘型(CMT1)、轴突型(CMT2)和中间型(DI-CMT).常染色体隐性遗传的CMT1(AR-CMT1,也称CMT4型)临床表现除了CMT常见的四肢远端进行性肌无力和萎缩,以及高足弓和爪形手外,常起病早,进展迅速,并有不同程度的感觉障碍和脊柱畸形(以脊柱侧凸为主).近年来的研究显示,CMT4有11种亚型,其中有些亚型的致病机制较明确,有些亚型存在建立者突变,有些亚型还局限在临床描述和突变检出上.文章综述了CMT4的最新研究进展,包括各亚型的临床表现、致病机制和小鼠模型等.

  2. Mutational analysis of the myelin protein zero (MPZ) gene associated with Charcot-Marie-Tooth neuropathy type 1B

    Energy Technology Data Exchange (ETDEWEB)

    Roa, B.B.; Warner, L.E.; Lupski, J.R. [Baylor College of Medicine, Houston, TX (United States)] [and others

    1994-09-01

    The MPZ gene that maps to chromosome 1q22q23 encodes myelin protein zero, which is the most abundant peripheral nerve myelin protein that functions as a homophilic adhesion molecule in myelin compaction. Association of the MPZ gene with the dysmyelinating peripheral neuropathies Charcot-Marie-Tooth disease type 1B (CMT1B) and the more severe Dejerine-Sottas syndrome (DSS) was previously demonstrated by MPZ mutations identified in CMT1B and in rare DSS patients. In this study, the coding region of the MPZ gene was screened for mutations in a cohort of 74 unrelated patients with either CMT type 1 or DSS who do not carry the most common CMT1-associated molecular lesion of a 1.5 Mb DNA duplication on 17p11.2-p12. Heteroduplex analysis detected base mismatches in ten patients that were distributed over three exons of MPZ. Direct sequencing of PCR-amplified genomic DNA identified a de novo MPZ mutation associated with CMT1B that predicts an Ile(135)Thr substitution. This finding further confirms the role of MPZ in the CMT1B disease process. In addition, two polymorphisms were identified within the Gly(200) and Ser(228) codons that do not alter the respective amino acid residues. A fourth base mismatch in MPZ exon 3 detected by heteroduplex analysis is currently being characterized by direct sequence determination. Previously, four unrelated patients in this same cohort were found to have unique point mutations in the coding region of the PMP22 gene. The collective findings on CMT1 point mutations could suggest that regulatory region mutations, and possibly mutations in CMT gene(s) apart from the MPZ, PMP22 and Cx32 genes identified thus far, may prove to be significant for a number of CMT1 cases that do not involve DNA duplication.

  3. Novel mutations in the connexin 32 gene associated with X-linked Charcot-Marie-Tooth disease

    Energy Technology Data Exchange (ETDEWEB)

    Tan, C.; Ainsworth, P. [Victoria Hospital, Ontario (Canada)]|[Childrens Hospital of Western Ontario (Canada)

    1994-09-01

    Charcot-Marie-Tooth disease is a pathologically and genetically hetergenous group of disorders that cause a progressive neuropathy, defined pathologically by degeneration of the myelin (CMT 1) of the axon (CMT 2) of the peripheral nerves. An X-linked type of the demyelinating form of this disorder (CMT X) has recently been linked to mutations in the connexin 32 (Cx32) gene, which codes for a 284 amino acid gap junction protein found in myelinated peripheral nerve. To date some 7 different mutations in this gene have been identified as being responsible for CMT X. The majority of these predict nonconservative amino acid substitutions, while one is a frameshift mutation which predicts a premature stop at codon 21. We report the results of molecular studies on three further local CMT X kindreds. The Cx32 gene was amplified by PCR in three overlapping fragments 300-450 bp in length using leukocyte-derived DNA as template. These were either sequenced directly using a deaza dGTP sequencing protocol, or were cloned and sequenced using a TA vector. In two of the kindreds the affected members carried a point mutation which was predicted to effect a non-conservative amino acid change within the first transmembrane domain. Both of these mutations caused a restriction site alteration (the loss of an Nla III and the creation of a Pvu II, respectively), and the former mutation was observed to segregate with the clinicial phenotype in affected family members. Affected members of the third kindred, which was a very large multigenerational family that had been extensively studied previously, were shown to carry a point mutation predicted to cause a premature truncation of the Cx32 gene product in the intracellular carboxy terminus. This mutation obliterated an Rsa I site which allowed a rapid screen of several other family members.

  4. [Current Status of Genetic Diagnosis of Charcot-Marie-Tooth Disease: Variety of the Disease-causing Genes].

    Science.gov (United States)

    Hashiguchi, Akihiro; Higuchi, Yujiro; Takashima, Hiroshi

    2016-01-01

    At least 40 genes have been associated with Charcot-Marie-Tooth disease (CMT) and the related inherited neuropathies. Genetic studies have revealed the following factors as causes of inherited neuropathies: myelin components, transcription factors for myelination, myelin maintenance systems, differentiation factors of the peripheral nerve, neurofilaments, protein transfer systems, mitochondrial proteins, DNA repair, RNA/protein synthesis, ion channels, and aminoacyl-tRNA synthetases. Since 2007, we have tried to screen for mutations in CMT patients using microarrays or next generation sequencers. As a result, the detection rate of gene mutations has improved to about 25%. In this study, we applied target resequencing to 72 genes. From the negative examples, we identified the cases based on clinical course, family history, and electrophysiological findings, and then performed exome analysis. We then tried to identify novel causative genes by analyzing the enormous data obtained from our exome analysis.

  5. Charcot-Marie-Tooth syndrome and neurofibromatosis type 1 with multiple neurofibromas of the entire spinal nerve roots.

    Science.gov (United States)

    Onu, David O; Hunn, Andrew W; Peters-Willke, Jens

    2013-07-13

    The coexistence of polyneuropathy which has the definite clinical and electromyographical findings consistent with Charcot-Marie-Tooth (CMT) syndrome and neurofibromatosis type 1 (NF1) has infrequently been reported. We describe a patient with both CMT and NF1, who had multiple neurofibromas involving the entire spinal neural axis. In addition, he had multiple neurofibromas distributed within the ileopsoas and gluteus muscles and subcutaneous tissues. These lesions were detected readily by MRI and the patient underwent successful surgical resection of the largest tumours compressing bilateral C2 nerve roots. To our knowledge, this is the first reported case of CMT syndrome coexisting with NF1 in which multiple neurofibromas involved the entire spinal nerve roots. We discuss the diagnostic and therapeutic challenges, emphasising the role of MRI and electrophysiology in such cases and provide a literature review.

  6. Charcot-Marie-Tooth disease and dilated cardiomyopathy. A rare combination.

    Directory of Open Access Journals (Sweden)

    Rafael Pila Pérez

    2011-07-01

    Full Text Available Se presenta el caso de un paciente de 50 años de edad, con 14 años de evolución de manifestaciones clínicas, destacándose las alteraciones musculoesqueléticas de los cuatro miembros con atrofia de las prominencias tenar e hipotenar y de la musculatura de ambas piernas. Se destacó la presencia de alteraciones sensitivas en miembros inferiores con distribución en calcetín, atrofia, atonía, arreflexia y marcha equina. Desde el punto de vista cardiaco, el paciente presentaba un fibriloaleteo. La radiografía de tórax mostró un aumento marcado del área cardiaca y la ecocardiografía puso de manifiesto una miocardiopatía dilatada. El estudio histopatológico confirmó la presencia de la enfermedad de Charcot-Marie-Tooth asociada a miocardiopatía dilatada. El diagnóstico se basó en las características clínicas, la velocidad de conducción motora, y el estudio histopatológico, que demostró desmielinización con lesiones en “cebolla”, si bien faltaron los estudios genéticos. La enfermedad de Charcot-Marie-Tooth es una enfermedad rara; aproximadamente un 60 % de los pacientes que la padecen, son portadores de una duplicación del cromosoma 17. Por ello, se consideró oportuno transmitir la experiencia de este caso.

  7. Dynamic pedobarography and radiographic evaluation of surgically treated cavovarus foot deformity in children with Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Erickson, Steven; Hosseinzadeh, Pooya; Iwinski, Henry J; Muchow, Ryan C; Talwalkar, Vishwas R; Walker, Janet L; Milbrandt, Todd A

    2015-07-01

    Pedobarography is a common tool for the evaluation of foot deformity. We describe our radiographic and pedobarographic outcomes of surgical treatment of cavovarus foot deformity in children with Charcot-Marie-Tooth disease. Nineteen patients for a total of 30 feet were included. Preoperative and postoperative dynamic pedobarographic measurements were made and analyzed using the five-mask technique. Pedobarographic measures showed statistical significance for increased contact area and decreased peak forces in most mask areas after surgical treatment. Peak pressure and redistribution of varus pressure patterns trended toward improvement. We found pedobarographic studies helpful; however, pedobarographic data are somewhat difficult to interpret and should be used in addition to clinical and radiographic examination.

  8. Research progress in molecular genetics of Charcot-Marie-Tooth disease type 2%腓骨肌萎缩症2型分子遗传学研究进展

    Institute of Scientific and Technical Information of China (English)

    肖智权; 张付峰; 唐北沙

    2007-01-01

    腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)是一类最常见的遗传性周围神经病之一,发病率为1/2500。主要呈常染色体显性(autosomal dominant,AD)遗传,也可呈常染色体隐性遗传(autosomal recessive,AR)及连锁显性(x-linked dominant,XD)或隐性遗传(X-linked recessive,XR)。随着分子遗传学研究的进展,近几年对CMT2型的研究已经取得很大的进展,相继克隆了多个基因并不断发现新的致病基因(表1)。

  9. Clinical, neurophysiological and morphological study of dominant intermediate Charcot-Marie-Tooth type C neuropathy.

    Science.gov (United States)

    Thomas, Florian P; Guergueltcheva, Velina; Gondim, Francisco A A; Tournev, Ivailo; Rao, Chitharanjan V; Ishpekova, Boryana; Kinsella, Laurence J; Pan, Yi; Geller, Thomas J; Litvinenko, Ivan; De Jonghe, Peter; Scherer, Steven S; Jordanova, Albena

    2016-03-01

    Dominant intermediate Charcot-Marie-Tooth neuropathy subtype C (DI-CMTC) was associated with mutations in the YARS gene, encoding tyrosyl-tRNA synthetase, in two large unrelated Bulgarian and US pedigrees and one sporadic case. Here for the first time we describe the clinical, neurophysiological and histopathological features, and phenotypic differences between these two DI-CMTC families. Twenty-one affected individuals from the US family and 27 from the Bulgarian family were evaluated. The mean age of onset in US subjects was 10.7 years in men and 7.3 years in women, while in the Bulgarian participants it was 18.2 years in men and 33.7 years in women. The course was slowly progressive. Extensor digitorum brevis atrophy was uniform. Atrophy and/or weakness of upper and lower limb muscles were found in over 50 % of the subjects. Nerve conduction studies (NCS) were abnormal in all US adults and five of six children and all Bulgarian patients except one asymptomatic 25-year-old man. Median motor NCS were in the range of 29.5-45.6 m/s in the US family and 24.7-57.8 m/s in the Bulgarian family. Sural sensory nerve action potentials were absent in 14/21 and 4/12 NCS from adult US and Bulgarian participants, respectively. Analysis of sural nerve biopsies from US patients revealed age-dependent morphological changes of axonal degeneration, absence of onion bulbs, and <10 % fibers with segmental remyelination. Our findings provide further insights into the diagnosis and pathology of intermediate CMT. They also extend the phenotypic spectrum of peripheral neuropathies associated with aminoacyl-tRNA synthetase mutations.

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

    Science.gov (United States)

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

    2016-03-01

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

  11. Recurrent Episodes of Stroke-Like Symptoms in a Patient with Charcot-Marie-Tooth Neuropathy X Type 1

    Directory of Open Access Journals (Sweden)

    Ning Wu

    2015-12-01

    Full Text Available Charcot-Marie-Tooth disease (CMT, also known as hereditary motor sensory neuropathy, is a heterogeneous group of disorders best known for causing inherited forms of peripheral neuropathy. The X-linked form, CMTX1, is caused by mutations in the gap junction protein beta 1 (GJB1 gene, expressed both by peripheral Schwann cells and central oligodendrocytes. Central manifestations are known but are rare, and there are few case reports of leukoencephalopathy with transient or persistent neurological deficits in patients with this CMT subtype. Here, we report the case of a man with multiple male and female family members affected by neuropathy who carries a pathologic mutation in GJB1. He has experienced three transient episodes with variable neurological deficits over the course of 7 years with corresponding changes on magnetic resonance imaging (MRI. This case illustrates CMT1X as a rare cause of transient neurological deficit and demonstrates the evolution of associated reversible abnormalities on MRI over time. To the best of our knowledge, this report provides the longest period of serial imaging in a single patient with this condition in the English language literature.

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

    Science.gov (United States)

    2015-04-28

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

  13. DGAT2 Mutation in a Family with Autosomal-Dominant Early-Onset Axonal Charcot-Marie-Tooth Disease.

    Science.gov (United States)

    Hong, Young Bin; Kang, Junghee; Kim, Ji Hyun; Lee, Jinho; Kwak, Geon; Hyun, Young Se; Nam, Soo Hyun; Hong, Hyun Dae; Choi, Yu-Ri; Jung, Sung-Chul; Koo, Heasoo; Lee, Ji Eun; Choi, Byung-Ok; Chung, Ki Wha

    2016-05-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and is a genetically and clinically heterogeneous disorder. We examined a Korean family in which two individuals had an autosomal-dominant axonal CMT with early-onset, sensory ataxia, tremor, and slow disease progression. Pedigree analysis and exome sequencing identified a de novo missense mutation (p.Y223H) in the diacylglycerol O-acyltransferase 2 (DGAT2) gene. DGAT2 encodes an endoplasmic reticulum-mitochondrial-associated membrane protein, acyl-CoA:diacylglycerol acyltransferase, which catalyzes the final step of the triglyceride (TG) biosynthesis pathway. The patient showed consistently decreased serum TG levels, and overexpression of the mutant DGAT2 significantly inhibited the proliferation of mouse motor neuron cells. Moreover, the variant form of human DGAT2 inhibited the axonal branching in the peripheral nervous system of zebrafish. We suggest that mutation of DGAT2 is the novel underlying cause of an autosomal-dominant axonal CMT2 neuropathy. This study will help provide a better understanding of the pathophysiology of axonal CMT and contribute to the molecular diagnostics of peripheral neuropathies.

  14. Absence of Dystrophin Related Protein-2 disrupts Cajal bands in a patient with Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Brennan, Kathryn M; Bai, Yunhong; Pisciotta, Chiara; Wang, Suola; Feely, Shawna M E; Hoegger, Mark; Gutmann, Laurie; Moore, Steven A; Gonzalez, Michael; Sherman, Diane L; Brophy, Peter J; Züchner, Stephan; Shy, Michael E

    2015-10-01

    Using exome sequencing in an individual with Charcot-Marie-Tooth disease (CMT) we have identified a mutation in the X-linked dystrophin-related protein 2 (DRP2) gene. A 60-year-old gentleman presented to our clinic and underwent clinical, electrophysiological and skin biopsy studies. The patient had clinical features of a length dependent sensorimotor neuropathy with an age of onset of 50 years. Neurophysiology revealed prolonged latencies with intermediate conduction velocities but no conduction block or temporal dispersion. A panel of 23 disease causing genes was sequenced and ultimately was uninformative. Whole exome sequencing revealed a stop mutation in DRP2, c.805C>T (Q269*). DRP2 interacts with periaxin and dystroglycan to form the periaxin-DRP2-dystroglycan complex which plays a role in the maintenance of the well-characterized Cajal bands of myelinating Schwann cells. Skin biopsies from our patient revealed a lack of DRP2 in myelinated dermal nerves by immunofluorescence. Furthermore electron microscopy failed to identify Cajal bands in the patient's dermal myelinated axons in keeping with ultrastructural pathology seen in the Drp2 knockout mouse. Both the electrophysiologic and dermal nerve twig pathology support the interpretation that this patient's DRP2 mutation causes characteristic morphological abnormalities recapitulating the Drp2 knockout model and potentially represents a novel genetic cause of CMT.

  15. Bicyclic-Capped Histone Deacetylase 6 Inhibitors with Improved Activity in a Model of Axonal Charcot-Marie-Tooth Disease.

    Science.gov (United States)

    Shen, Sida; Benoy, Veronick; Bergman, Joel A; Kalin, Jay H; Frojuello, Mariana; Vistoli, Giulio; Haeck, Wanda; Van Den Bosch, Ludo; Kozikowski, Alan P

    2016-02-17

    Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitro model for CMT2, these inhibitors were able to restore the mitochondrial axonal transport deficits. Combining structure-based development of HDAC6 inhibitors, screening in N2a cells and in a neuronal model for CMT2F, and preliminary ADMET and pharmacokinetic profiles, resulted in the selection of compound 23d that possesses improved biochemical, functional, and druglike properties compared to tubastatin A.

  16. A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients.

    Science.gov (United States)

    Choi, B-O; Nakhro, K; Park, H J; Hyun, Y S; Lee, J H; Kanwal, S; Jung, S-C; Chung, K W

    2015-06-01

    Charcot-Marie-Tooth disease 2A (CMT2A) is the most common axonal form of peripheral neuropathy caused by a defect in the mitofusin 2 (MFN2) gene, which encodes an outer mitochondrial membrane GTPase. MFN2 mutations result in a large range of phenotypes. This study analyzed the prevalence of MFN2 mutation in Korean families with their assorted phenotypes (607 CMT families and 160 CMT2 families). Direct sequencing of the MFN2 coding exons or whole-exome sequencing has been applied to identify causative mutations. A total of 21 mutations were found in 36 CMT2 families. Comparative genotype-phenotype correlations impacting severity, onset age, and specific symptoms were assessed. Most mutations were seen in the GTPase domain (∼86%). A deletion mutation found in the transmembrane helices is reported for the first time, as well as five novel mutations at other domains. MFN2 mutations made up 5.9% of total CMT families, whereas 22.9% in CMT2 families, of which 27.8% occurred de novo. Interestingly, patient phenotypes ranged from mild to severe even for the same mutation, suggesting other factors influenced phenotype and penetrance. This CMT2A cohort study will be useful for molecular diagnosis and treatment of axonal neuropathy.

  17. Autosomal recessive MFN2-related Charcot-Marie-Tooth disease with diaphragmatic weakness: Case report and literature review.

    Science.gov (United States)

    Tan, Christopher A; Rabideau, Marina; Blevins, Amy; Westbrook, Marjorie Jody; Ekstein, Tali; Nykamp, Keith; Deucher, Anne; Harper, Amy; Demmer, Laurie

    2016-06-01

    Pathogenic variants in the mitofusin 2 gene (MFN2) are the most common cause of autosomal dominant Charcot-Marie-Tooth (CMT2) disease, which is typically characterized by axonal sensorimotor neuropathy. We report on a 7-month-old white female with hypotonia, motor delay, distal weakness, and motor/sensory axonal neuropathy in which next-generation sequencing analysis identified compound heterozygous pathogenic variants (c.2054_2069_1170del and c.392A>G) in MFN2. A review of the literature reveals that sporadic and familial cases of compound heterozygous or homozygous pathogenic MFN2 variants have been infrequently described, which indicates that MFN2 can also be inherited in a recessive manner. This case highlights several clinical findings not typically associated with MFN2 pathogenic variants, including young age of onset and rapidly progressing diaphragmatic paresis that necessitated tracheostomy and mechanical ventilation, and adds to the growing list of features identified in autosomal recessive MFN2-related CMT2. Our patient with MFN2-related CMT2 expands the clinical and mutational spectrum of individuals with autosomal recessive CMT2 and identifies a new clinical feature that warrants further observation. © 2016 Wiley Periodicals, Inc.

  18. A Novel Mutation of GDAP1 Associated with Charcot-Marie-Tooth Disease in An Iranian Family

    Directory of Open Access Journals (Sweden)

    Esmaeel MOHAMMADI PARGOO

    2012-06-01

    Full Text Available As a result of higher distributed consanguinity in the Mediterranean region and the Middle East, autosomal-recessive forms of Charcot-Marie-Tooth (ARCMT are more common in these areas. CMT disease caused by mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1 gene is a severe autosomal recessive neuropathy resulting in either demyelinating CMT4A neuropathy or axonal neuropathy with vocal cord paresis. The patient was an 8-year-old boy with AR inheritance that showed some delayed achievement of motor milestones, including walking, also bilateral foot drop, wasting of distal muscles in the legs, pes cavus and marked weakness of the foot dorsiflexors. He had no hoarseness or vocal cord paralysis. Total genomic DNA was extracted from whole peripheral blood of the patient and his family by using standard procedures. PCR- sequencing method were used to analysis the whole coding regions of the GDAP1 gene. A novel homozygote insertion of T nucleotide in codon 34 was detected (c.100_101insT that probably led to an early stop codon. This mutation may be associated with a common haplotype, suggesting a common ancestor that needs further investigation in the Iranian population.

  19. Long-Range Structural Effects of a Charcot-Marie-Tooth Disease-Causing Mutation in Human Glycyl-TRNA Synthetase

    Energy Technology Data Exchange (ETDEWEB)

    Xie, W.; Nangle, L.A.; Zhang, W.; Schimmel, P.; Yang, X.-L.

    2009-06-04

    Functional expansion of specific tRNA synthetases in higher organisms is well documented. These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease, the most common heritable disease of the peripheral nervous system. At least 10 disease-causing mutant alleles of GlyRS have been annotated. These mutations scatter broadly across the primary sequence and have no apparent unifying connection. Here we report the structure of wild type and a CMT-causing mutant (G526R) of homodimeric human GlyRS. The mutation is at the site for synthesis of glycyl-adenylate, but the rest of the two structures are closely similar. Significantly, the mutant form diffracts to a higher resolution and has a greater dimer interface. The extra dimer interactions are located {approx}30 {angstrom} away from the G526R mutation. Direct experiments confirm the tighter dimer interaction of the G526R protein. The results suggest the possible importance of subtle, long-range structural effects of CMT-causing mutations at the dimer interface. From analysis of a third crystal, an appended motif, found in higher eukaryote GlyRSs, seems not to have a role in these long-range effects.

  20. Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-Tooth disease (CMT4).

    Science.gov (United States)

    Piscosquito, Giuseppe; Saveri, Paola; Magri, Stefania; Ciano, Claudia; Gandioli, Claudia; Morbin, Michela; Bella, Daniela D; Moroni, Isabella; Taroni, Franco; Pareyson, Davide

    2016-09-01

    Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive (AR) demyelinating neuropathy associated to SH3TC2 mutations, characterized by early onset, spine deformities, and cranial nerve involvement. We screened 43 CMT4 patients (36 index cases) with AR inheritance, demyelinating nerve conductions, and negative testing for PMP22 duplication, GJB1 and MPZ mutations, for SH3TC2 mutations. Twelve patients (11 index cases) had CMT4C as they carried homozygous or compound heterozygous mutations in SH3TC2. We found six mutations: three nonsense (p.R1109*, p.R954*, p.Q892*), one splice site (c.805+2T>C), one synonymous variant (p.K93K) predicting altered splicing, and one frameshift (p.F491Lfs*32) mutation. The splice site and the frameshift mutations are novel. Mean onset age was 7 years (range: 1-14). Neuropathy was moderate-to-severe. Scoliosis was present in 11 patients (severe in 4), and cranial nerve deficits in 9 (hearing loss in 7). Scoliosis and cranial nerve involvement are frequent features of this CMT4 subtype, and their presence should prompt the clinician to look for SH3TC2 gene mutations. In our series of undiagnosed CMT4 patients, SH3TC2 mutation frequency is 30%, confirming that CMT4C may be the most common AR-CMT type.

  1. [A case of Charcot-Marie-Tooth disease 1 B with Val 146Phe mutation of myelin protein zero showing a severe clinical phenotype].

    Science.gov (United States)

    Ohnishi, A; Aoki, A; Yamamoto, T; Tsuji, S

    2000-03-01

    A 15-year-old boy had complaints of progressive gait disturbance and foot deformity. He started to walk at the age of 18 months. Since two years of age, he had noticed unstable gait. He showed evident scoliosis and enlarged great auricular nerves. Moderate to slight degrees of muscular atrophy and weakness of distal upper, and proximal and distal lower limbs were observed. Pes equinovarus deformity of both feet was obvious. Muscle stretch reflexes were absent in both limbs except decreased triceps brachii reflex. Vibratory sensation was decreased severely in the toes and mildly in the fingers. In cerebrospinal fluid, protein was mildly elevated. Median nerve motor conduction velocity was 5.0 m/sec. On sural nerve biopsy, both demyelinated and remyelinated axons and onion-bulbs without hypomyelination were observed. Therefore, the diagnosis of Charcot-Marie-Tooth disease 1 was made. The direct sequencing of the genomic DNA encoding the Po gene revealed a mutant allele, a guanine to thymine substitution of nucleotide position 436, which caused a substitution of phenylalanine for valine at amino acid position 146. This type of Po mutation is different from any type of Po mutation reported in the literature.

  2. Efficacy of focal mechanic vibration treatment on balance in Charcot-Marie-Tooth 1A disease: a pilot study.

    Science.gov (United States)

    Pazzaglia, Costanza; Camerota, F; Germanotta, M; Di Sipio, E; Celletti, C; Padua, L

    2016-07-01

    Patients affected by Charcot-Marie-Tooth (CMT) disease experience an impaired balance. Although the causes of the postural instability are not fully understood, somatosensory system seems to play a key role. Mechanical vibration seems to act on the somatosensory system and to improve its function. The aim of our study was to evaluate the effects of focal mechanical vibration (fMV) on the balance of CMT 1A patients. We enrolled 14 genetically confirmed CMT 1A patients (8 female and 6 male, mean age 492 years, range 32-74, mean duration of disease: 13 years, range 1-30). Patients underwent a 3-day fMV treatment on quadriceps and triceps surae and were evaluated before the treatment as well as 1 week and 1 month after the end of the treatment. The primary outcome measure was the Berg Balance Scale (BBS) and the secondary were the Dynamic Gait Index (DGI), the 6 Min Walking Test (6MWT), the muscular strength of lower limbs, the Quality of Life (QoL) questionnaire and the stabilometric variables. The statistical analysis showed a significant modification of the BBS due to the effect of treatment (p treatment applied on lower limbs of CMT 1A patients determined an improvement of balance as detected by the BBS. The concurrent improvement of stabilometric variables in the eyes closed condition only suggests that fMV acts mostly on somatosensory afferences. Further studies are needed to confirm these data on a larger sample of CMT patients.

  3. Efeitos do uso de órteses na Doença de Charcot-Marie-Tooth: atualização da literatura Orthoses effects in Charcot-Marie-Tooth Disease: update

    Directory of Open Access Journals (Sweden)

    Rouse Barbosa Pereira

    2012-12-01

    Full Text Available A Doença de Charcot-Marie-Tooth (DCMT é a neuropatia periférica hereditária mais comum em seres humanos, apresentando incidência de 1:2.500 pessoas. A fraqueza distal crural na DCMT provoca inúmeras alterações na marcha, como, por exemplo, na velocidade, no comprimento, na largura e cadência dos passos. Vários recursos em reabilitação têm sido propostos para gerenciar os problemas de deambulação, dentre eles, destaca-se a utilização de órteses. O objetivo deste estudo é apresentar e discutir os resultados de estudos sobre os efeitos da utilização de órteses nos padrões de marcha na DCMT. Neste estudo foi utilizada atualização da literatura através das principais bases de dados nacionais/internacionais (SciELO, LILACS e MEDLINE, publicados entre os anos de 2006-2012. O tratamento da DCMT consiste em fisioterapia e utilização de equipamentos de assistência, visto que ainda não há fármacos ou terapia gênica capaz de atenuar os danos clínicos e funcionais. Tal associação busca maximizar a função e melhorar a qualidade de vida desses pacientes, na tentativa de evitar agravos adicionais relativos à incapacidade física. A partir de atualização de literatura é possível concluir que existe consenso sobre a utilização de órteses nos membros inferiores para promover a estabilização das articulações do tornozelo e um padrão de deambulação mais funcional, evitando sinergias inadequadas de movimento e atenuando o risco de quedas.Charcot-Marie-Tooth (CMT disease is the most common hereditary peripheral neuropathy in humans, presenting incidence of 1:2.500 people. The distal crural weakness of the CMT causes numerous gait impairment changes, for example, velocity, length, width and cadence of the steps. Several rehabilitation resources have been proposed to manage the walking problems, among them, the use of orthoses is highlighted. The objective of this study was to present and discuss the results of

  4. Surgical treatment of cavus foot in Charcot-Marie-tooth disease: a review of twenty-four cases: AAOS exhibit selection.

    Science.gov (United States)

    Faldini, Cesare; Traina, Francesco; Nanni, Matteo; Mazzotti, Antonio; Calamelli, Carlotta; Fabbri, Daniele; Pungetti, Camilla; Giannini, Sandro

    2015-03-18

    Charcot-Marie-Tooth disease is the single most common diagnosis associated with cavus foot. The imbalance involving intrinsic and extrinsic muscles has been suggested as the main pathogenetic cause of cavus foot in this disease. The goal of surgical treatment is to correct the deformity to obtain a plantigrade foot. In the presence of a flexible deformity and the absence of degenerative arthritis, preserving as much as possible of the overall range of motion of the foot and ankle is advisable. Twenty-four cavus feet in twelve patients with Charcot-Marie-Tooth disease were included in the study. Clinical evaluation was summarized with the Maryland Foot Score. Radiographic evaluation assessed calcaneal pitch, Meary angle, Hibb angle, and absence of degenerative joint changes. Only patients who had a flexible deformity, with varus of the heel reducible in the Coleman-Andreasi test, and did not have degenerative joint arthritis were included in this study. Surgical treatment consisted in plantar fasciotomy, midtarsal osteotomy, extensor hallucis longus tendon transfer to the first metatarsal (Jones procedure), and dorsiflexion osteotomy of the first metatarsal. Mean follow-up was six years (range, two to thirteen years). The mean Maryland Foot Score was 72 preoperatively and 86 postoperatively. The postoperative result was rated as excellent in twelve feet (50%), good in ten (42%), and fair in two (8%). Mean calcaneal pitch was 34° preoperatively and 24° at the time of the latest follow-up, the mean Hibb angle was 121° preoperatively and 136° postoperatively, and the mean Meary angle was 25° preoperatively and 2° postoperatively. Plantar fasciotomy, midtarsal osteotomy, the Jones procedure, and dorsiflexion osteotomy of the first metatarsal yielded adequate correction of flexible cavus feet in patients with Charcot-Marie-Tooth disease in the absence of fixed hindfoot deformity. The fact that the improvement in the outcome score was only modest may be attributable

  5. Conduction block and tonic pupils in Charcot-Marie-Tooth disease caused by a myelin protein zero p.Ile112Thr mutation.

    LENUS (Irish Health Repository)

    Murphy, Sinéad M

    2011-03-01

    We report a patient with Charcot-Marie-Tooth disease (CMT) due to the p.Ile112Thr mutation in myelin protein zero (MPZ) who presented with a patchy neuropathy with conduction block and tonic pupils. Conduction block is unusual in inherited neuropathies, while pupil abnormalities are recognised to occur in CMT especially due to MPZ mutations. This case highlights that patchy demyelinating neuropathy with conduction block may occur in p.Ile112Thr MPZ mutations. Involvement of the pupils, as in this case, may be a pointer towards a genetic rather than inflammatory cause of neuropathy.

  6. Comparison of clinical manifestations and electrophysiological features in patients with chronic inflamma-tory demyelinating polyneuropathy and Type-I Charcot Marie Tooth Disease%慢性炎性脱髓鞘性多发性神经病与腓骨肌萎缩症-I型的临床及神经电生理比较

    Institute of Scientific and Technical Information of China (English)

    刘璟洁; 韩萍; 高震; 巩付华; 马晓灵; 向莉

    2016-01-01

    Objectives To compare clinical manifestations and electrophysiological features in patients with chron⁃ic inflammatory demyelinating polyneuropathy (CIDP) and Type-I Charcot Marie Tooth Disease (CMT-I) for guiding dif⁃ferential diagnosis. Methods Data including clinical manifestations and electrophysiological indexes was collected from thirty-one CIDP cases and 28 CMT-I cases. Correlation analysis was used to assess the association of the severity of electrophysiology with the severity of clinical symptoms. Results There were statistically significant differences in onset site, sensory dysfunction, foot deformity and cerebrospinal fluid protein between these two groups (P0.05). Conclusions Differential diagnoses of CIDP and CMT-I can be made based on clinical manifestations and electro⁃physiological features.%目的:比较慢性炎性脱髓鞘性多发性神经病(chronic inflammatory demyelinating polyneuropathy, CI⁃DP)与腓骨肌萎缩症-I型(type-I Charcot Marie Tooth disease,CMT-I)的临床及神经电生理特点,以指导两者的鉴别诊断。方法纳入CIDP患者31例、CMT-I患者28例,收集其一般临床资料并对两组患者进行神经电生理检测,比较两组患者的临床特点及电生理指标,并对电生理严重程度与临床症状严重程度进行相关性分析。结果CIDP与CMT-I两组患者起病部位、主观感觉障碍、足部畸形、脑脊液蛋白比较有统计学差异(P<0.05)。运动末梢潜伏期(distal motor latency, DML)、运动传导速度(motor conduction velocity, MCV)、感觉传导速度(sensory conduction velocity, SCV)、传导阻滞/波形离散、下肢神经继发性轴索变性具有统计学差异(P<0.05)。失神经电位、MUAP形态异常、募集减少具有统计学差异(P<0.05)。CIDP临床症状严重程度与电生理严重程度有相关性(r=0.84, P<0.05);而CMT-I临床症状严重程度与电生理严重程度分离,不具有相关性(r=0.27, P

  7. The effect of HSPB8 gene mutation on cell viability in Charcot-Marie-Tooth disease type 2L%腓骨肌萎缩症2L热休克蛋白B8过表达对细胞相对活力的影响

    Institute of Scientific and Technical Information of China (English)

    李书剑; 唐北沙; 赵国华; 张如旭; 夏昆; 潘乾

    2011-01-01

    Objective To study the effect of Charcot-Marie-Tooth 2L disease causing gene K141N mutation in heat shock protein B8 gene (HSPB8)on cell viability.Methods By using liposome transfection technique,wt HSPB8,K141N HSPB8 eukaryotic expression vector and green fluorescent protein (GFP) vector were transfected into SHSY-5Y cell,respectively.Twenty-four hours later,the cells were treated with 44℃ lethal heat shock for 40 minutes.The relative viability of SHSY-5Y cells in each group was tested by using tetrazole blue colorimetric method (methyl thiazolyl tetrazolium,MTT).Results There were significant differences among the light absorption value of GFP,pEGFP-wt HSPB8 and pEGFP-K141N HSPB8 transfected groups after heat shock (P < 0.05 ),indicating that the relative viability of cells overexpressed with wt HSPB8 and K141N HSPB8 was different from that of control cells.The viability of cells overexpressing wt HSPB8 was highest,followed by cells overexpressed with K141N HSPB8.The viability of cells tranfected with GFP only was the lowest.Conclusion HSPB8 may play an important role in the protection of cells under lethal heat shock treatment,and the K141N mutation can impair the protective effect.%目的 探讨轴索型腓骨肌萎缩症2L(axonal Charcot-Marie-Tooth disease type 2L,CMT2L)K141N突变的热休克蛋白B8(heat shock protein B8,HSPB8)对细胞相对活力的影响.方法 应用脂质体转染技术,将野生型HSPB8(wt HSPB8)和K141N突变型HSPB8( K141N HSPB8)分别转染SHSY-5Y细胞,使其过量表达上述蛋白,以表达绿色荧光蛋白(green fluorescent protein,GFP)为阴性对照,转染24 h后用44℃致死性热休克处理40 min,用四甲基偶氮唑蓝(methyl thiazolyl tetrazolium,MTT)比色法检测SHSY-5Y细胞的相对活力.结果 未处理组pEGFP-wt HSPB8与pEGFP-K141N HSPB8组间吸光度值比较P>0.05,而热休克处理组pEGFP-wt HSPB8与pEGFP-K141N HSPB8组间吸光度值比较P<0.05,表明热休克处理后各组细胞相对活力

  8. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy

    NARCIS (Netherlands)

    K.G. Claeys; S. Züchner; M. Kennerson; J. Berciano; A. Garcia; K. Verhoeven; E. Storey; J.R. Merory; H.M.E. Bienfait; M. Lammens; E. Nelis; J. Baets; E. de Vriendt; Z.N. Berneman; I. de Veuster; J.M. Vance; G. Nicholson; V. Timmerman; P. de Jonghe

    2009-01-01

    Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B familie

  9. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy.

    NARCIS (Netherlands)

    Claeys, K.G.; Zuchner, S.; Kennerson, M.; Berciano, J.; Garcia, A.; Verhoeven, K.; Storey, E.; Merory, J.R.; Bienfait, H.M.; Lammens, M.M.Y.; Nelis, E.; Baets, J.; Vriendt, E. De; Berneman, Z.N.; Veuster, I. De; Vance, J.M.; Nicholson, G.; Timmerman, V.; Jonghe, P. de

    2009-01-01

    Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B familie

  10. LITAF mutations associated with Charcot-Marie-Tooth disease 1C show mislocalization from the late endosome/lysosome to the mitochondria.

    Directory of Open Access Journals (Sweden)

    Andressa Ferreira Lacerda

    Full Text Available Charcot-Marie-Tooth (CMT disease is one of the most common heritable neuromuscular disorders, affecting 1 in every 2500 people. Mutations in LITAF have been shown to be causative for CMT type 1C disease. In this paper we explore the subcellular localization of wild type LITAF and mutant forms of LITAF known to cause CMT1C (T49M, A111G, G112S, T115N, W116G, L122V and P135T. The results show that LITAF mutants A111G, G112S, W116G, and T115N mislocalize from the late endosome/lysosome to the mitochondria while the mutants T49M, L122V, and P135T show partial mislocalization with a portion of the total protein present in the late endosome/lysosome and the remainder of the protein localized to the mitochondria. This suggests that different mutants of LITAF will produce differing severity of disease. We also explored the effect of the presence of mutant LITAF on wild-type LITAF localization. We showed that in cells heterozygous for LITAF, CMT1C mutants T49M and G112S are dominant since wild-type LITAF localized to the mitochondria when co-transfected with a LITAF mutant. Finally, we demonstrated how LITAF transits to the endosome and mitochondria compartments of the cell. Using Brefeldin A to block ER to Golgi transport we demonstrated that wild type LITAF traffics through the secretory pathway to the late endosome/lysosome while the LITAF mutants transit to the mitochondria independent of the secretory pathway. In addition, we demonstrated that the C-terminus of LITAF is necessary and sufficient for targeting of wild-type LITAF to the late endosome/lysosome and the mutants to the mitochondria. Together these data provide insight into how mutations in LITAF cause CMT1C disease.

  11. Molecular analyses of unrelated Charcot-Marie-Tooth (CMT) disease patients suggest a high frequency of the CMT1A duplication

    Energy Technology Data Exchange (ETDEWEB)

    Wise, C.A.; Davis, S.N.; Heju, Z.; Pentao, L.; Patel, P.I.; Lupski, J.R. (Baylor College of Medicine, Houston, TX (United States)); Garcia, C.A. (Louisiana State Univ. School of Medicine, New Orleans, LA (United States))

    1993-10-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. One form of CMT, CMT type 1A, is characterized by uniformly decreased nerve conduction velocities, usually shows autosomal dominant inheritance, and is associated with a large submicroscopic duplication of the p11.2-p12 region of chromosome 17. A cohort of 75 unrelated patients diagnosed clinically with CMT and evaluated by electrophysiological methods were analyzed molecularly for the presence of the CMT1A DNA duplication. Three methodologies were used to assess the duplication: Measurement of dosage differences between RFLP alleles, analysis of polymorphic (GT)[sub n] repeats, and detection of a junction fragment by pulsed-field gel electrophoresis. The CMT1A duplication was found in 68% of the 63 unrelated CMT patients with electrophysiological studies consistent with CMT type 1 (CMT1). The CMT1A duplication was detected as a de novo event in two CMT1 families. Twelve CMT patients who did not have decreased nerve conduction velocities consistent with a diagnosis of CMT type 2 (CMT2) were found not to have the CMT1A duplication. The most informative molecular method was the detection of the CMT1A duplication-specific junction fragment. Given the high frequency of the CMT1A duplication in CMT patients and the high frequency of new mutations, the authors conclude that a molecular test for the CMT1A DNA duplication is very useful in the differential diagnosis of patients with peripheral neuropathies. 61 refs., 4 figs.

  12. Mutation Analysis of Gap Junction Protein Beta 1 and Genotype-Phenotype Correlation in X-linked Charcot-Marie-Tooth Disease in Chinese Patients

    Institute of Scientific and Technical Information of China (English)

    Bo Sun; Zhao-Hui Chen; Li Ling; Yi-Fan Li; Li-Zhi Liu; Fei Yang; Xu-Sheng Huang

    2016-01-01

    Background:Among patients with Charcot-Marie-Tooth disease (CMT),the X-linked variant (CMTX) caused by gap junction protein beta 1 (GJB1) gene mutation is the second most frequent type,accounting for approximately 90% of all CMTX.More than 400 mutations have been identified in the GJB1 gene that encodes connexin 32 (CX32).CX32 is thought to form gap junctions that promote the diffusion pathway between cells.GJB1 mutations interfere with the formation of the functional channel and impair the maintenance of peripheral myelin,and novel mutations are continually discovered.Methods:We included 79 unrelated patients clinically diagnosed with CMT at the Department of Neurology of the Chinese People's Liberation Army General Hospital from December 20,2012,to December 31,2015.Clinical examination,nerve conduction studies,and molecular and bioinformatics analyses were performed to identify patients with CMTX 1.Results:Nine GJB1 mutations (c.283G>A,c.77C>T,c.643C>T,c.515C>T,c.191G>A,c.610C>T,c.490C>T,c.491G>A,and c.44G>A) were discovered in nine patients.Median motor nerve conduction velocities of all nine patients were < 38 m/s,resembling CMT Type 1.Three novel mutations,c.643C>T,c.191G>A,and c.610C>T,were revealed and bioinformatics analyses indicated high pathogenicity.Conclusions:The three novel missense mutations within the GJB1 gene broaden the mutational diversity of CMT 1 X.Molecular analysis of family members and bioinformatics analyses of the afflicted patients confirmed the pathogenicity of these mutations.

  13. Clinical features and gene mutations of patients with Charcot-Marie-Tooth disease type 1 and type 2%腓骨肌萎缩症1型和2型的临床与基因突变特点

    Institute of Scientific and Technical Information of China (English)

    郭鹏; 张保刚; 王相斌; 宋福聪; 冯文霞; 唐北沙; 夏昆

    2011-01-01

    Objective To investigate the clinical and genetic mutation characteristics of patients with Charcot-Marie-Tooth disease type 1 and type 2. Methods The clinical manifestations, electrophysiological and pathological characteristics were retrospectively analyzed in patients with Charcot-Marie-Tooth ( CMT) disease type 1 and type 2 and 91 CMT pedigrees,and the PMP22 large fragment duplication mutation and the gene mutation of PMP22,MPZ.SIMPLE,EGR2, RAB7, NEFL, MFN2, Hsp27, Hsp22 were analyzed. Results The age of onset in patients with CMT 1 was earlier, and most frequently first symptoms were weakness and atrophy in distal end of lower limbs with hypesthesia, and neurogenic examination showed obvious atrophy in leg muscle with weakness or vanishing of reflection of knee and ankle,and there was talipes cavus in all the patients. Neuro-electrophysiological examination showed that nerve conduction velocity was decreased. Pathological examination showed the pathological changes of demyelination, and gene mutation analysis showed large fragment duplication mutation and the MPZ gene mutation,in contrast to that,the incidence of CMT1 was lower,the age of onset was later,and the pathological changes of locomotor system were more obvious than those in sensing system, nerve conductive velocity was within normal range, pathological changes presented axonal degeneration, and gene mutation analysis showed gene mutation in MFN2, Hsp27and Hsp22. Conclusion The clinical manifestations of CMTlare different from those of CMT2,and the analysis results for gene mutation are coincident with clinical characteristics,with high accuracy, little injury,earlier diagmosis, which is worth being applied generally in clinic, especially for the patients with family history or their relatives with high risk factors.%目的 探讨腓骨肌萎缩症(CMT)1型和2型患者的临床与基因突变的特点.方法 对临床诊断为CMT1型和CMT2型91个家系先证者的临床表现、电生理和病理

  14. Doença de Charcot-Marie-Tooth: estudo da biópsia do nervo sural em 41 pacientes Charcot-Marie-Tooth disease: sural nerve biopsy findings in 41 patients

    OpenAIRE

    Freitas,Marcos R. G.; Osvaldo J. M. Nascimento; Leila Chimelli; Freitas,Gabriel R. de

    1995-01-01

    São apresentados os resultados da biópsia do nervo sural à microscopia óptica e eletrônica (ME) em 41 pacientes com doença de Charcot-Marie-Tooth (CMT) Por estudos de neurocondução prévios nove eram do tipo I e 32 do tipo II. No tipo I, todos tinham grande diminuição do número de fibras, sendo os histogramas do tipo unimodal. Encontramos imagens de desmielinização, remielinização, formação de bulbos de cebola e de regeneração. Um paciente apresentava espessamento da bainha de mielina (atrofia...

  15. Crystallization and preliminary X-ray analysis of a native human tRNA synthetase whose allelic variants are associated with Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Xie, Wei; Schimmel, Paul; Yang, Xiang-Lei

    2006-12-01

    Glycyl-tRNA synthetase (GlyRS) is one of a group of enzymes that catalyze the synthesis of aminoacyl-tRNAs for translation. Mutations of human and mouse GlyRSs are causally associated with Charcot-Marie-Tooth disease, the most common genetic disorder of the peripheral nervous system. As the first step towards a structure-function analysis of this disease, native human GlyRS was expressed, purified and crystallized. The crystal belonged to space group P4(3)2(1)2 or its enantiomorphic space group P4(1)2(1)2, with unit-cell parameters a = b = 91.74, c = 247.18 A, and diffracted X-rays to 3.0 A resolution. The asymmetric unit contained one GlyRS molecule and had a solvent content of 69%.

  16. Multiplex Detection and Genotyping of Point Mutations Involved in Charcot-Marie-Tooth Disease Using a Hairpin Microarray-Based Assay

    Directory of Open Access Journals (Sweden)

    Yasser Baaj

    2009-01-01

    Full Text Available We previously developed a highly specific method for detecting SNPs with a microarray-based system using stem-loop probes. In this paper we demonstrate that coupling a multiplexing procedure with our microarray method is possible for the simultaneous detection and genotyping of four point mutations, in three different genes, involved in Charcot-Marie-Tooth disease. DNA from healthy individuals and patients was amplified, labeled with Cy3 by multiplex PCR; and hybridized to microarrays. Spot signal intensities were 18 to 74 times greater for perfect matches than for mismatched target sequences differing by a single nucleotide (discrimination ratio for “homozygous” DNA from healthy individuals. “Heterozygous” mutant DNA samples gave signal intensity ratios close to 1 at the positions of the mutations as expected. Genotyping by this method was therefore reliable. This system now combines the principle of highly specific genotyping based on stem-loop structure probes with the advantages of multiplex analysis.

  17. 进行性腓肌萎缩症的神经电生理学研究%Study of electroneurophysiology on Charcot-Marie-Tooth disease

    Institute of Scientific and Technical Information of China (English)

    陈菁华; 林丽丽; 魏丽玲

    2007-01-01

    Objective To explore the diagnostic value of electroneurophisology in patients with charcot-Ma-rie-Tooth disease(CMT).Methods Electromyogram(EMG),Motor nerve conduction velocity(MCV),Sensory nenre conduction velocity(SCV) and F wave were measured in 31 cases with Charcot-Marie-Tooth disease(CMT).Resuits The abnormality rate of EMG was 90%,MCV was 100%,SCV was 90%,and F wave was 34%.Conclu-sion The electroneurophysiology is very practical and valuable in diagnosing Charcot-Marie-Tooth disease.%目的 研究进行性腓肌萎缩症患者的肌电图、周围神经传导速度及F反应特点,探讨神经电生理检查对诊断该病的价值.方法 对31例进行性腓肌萎缩症患者的肌电图(EMG)、运动神经传导速度(MCV)、感觉神经传导速度(SCV)及F波进行检测.结果 肌电图异常率90%,运动神经传导速度异常率100%,感觉神经传导速度异常率90%,F波检测异常率34%.结论 神经电生理检查是诊断进行性腓肌萎缩症的可靠方法.

  18. Selected items from the Charcot-Marie-Tooth (CMT) Neuropathy Score and secondary clinical outcome measures serve as sensitive clinical markers of disease severity in CMT1A patients.

    Science.gov (United States)

    Mannil, Manoj; Solari, Alessandra; Leha, Andreas; Pelayo-Negro, Ana L; Berciano, José; Schlotter-Weigel, Beate; Walter, Maggie C; Rautenstrauss, Bernd; Schnizer, Tuuli J; Schenone, Angelo; Seeman, Pavel; Kadian, Chandini; Schreiber, Olivia; Angarita, Natalia G; Fabrizi, Gian Maria; Gemignani, Franco; Padua, Luca; Santoro, Lucio; Quattrone, Aldo; Vita, Giuseppe; Calabrese, Daniela; Young, Peter; Laurà, Matilde; Haberlová, Jana; Mazanec, Radim; Paulus, Walter; Beissbarth, Tim; Shy, Michael E; Reilly, Mary M; Pareyson, Davide; Sereda, Michael W

    2014-11-01

    This study evaluates primary and secondary clinical outcome measures in Charcot-Marie-Tooth disease type 1A (CMT1A) with regard to their contribution towards discrimination of disease severity. The nine components of the composite Charcot-Marie-Tooth disease Neuropathy Score and six additional secondary clinical outcome measures were assessed in 479 adult patients with genetically proven CMT1A and 126 healthy controls. Using hierarchical clustering, we identified four significant clusters of patients according to clinical severity. We then tested the impact of each of the CMTNS components and of the secondary clinical parameters with regard to their power to differentiate these four clusters. The CMTNS components ulnar sensory nerve action potential (SNAP), pin sensibility, vibration and strength of arms did not increase the discriminant value of the remaining five CMTNS components (Ulnar compound motor action potential [CMAP], leg motor symptoms, arm motor symptoms, leg strength and sensory symptoms). However, three of the six additional clinical outcome measures - the 10m-timed walking test (T10MW), 9 hole-peg test (9HPT), and foot dorsal flexion dynamometry - further improved discrimination between severely and mildly affected patients. From these findings, we identified three different composite measures as score hypotheses and compared their discriminant power with that of the CMTNS. A composite of eight components CMAP, Motor symptoms legs, Motor symptoms arms, Strength of Legs, Sensory symptoms), displayed the strongest power to discriminate between the clusters. As a conclusion, five items from the CMTNS and three secondary clinical outcome measures improve the clinical assessment of patients with CMT1A significantly and are beneficial for upcoming clinical and therapeutic trials.

  19. Progress in molecular diagnosis of Charcot-Marie-Tooth-disease type 1 (CMT 1, HMSN I) and hereditary neuropathy with liability to pressure palsies (HNPP) by fluorescence in situ hybridization (FISH)-detection of a potential genetic mosaicism

    Energy Technology Data Exchange (ETDEWEB)

    Bathke, K.; Liehr. T.; Ekici, A. [Institute for Human Genetics, Erlange (Germany)] [and others

    1994-09-01

    We tested 20 CMT 1 patients characterized according to the criteria of the European CMT consortium by Southern hybridization of MspI restricted genomic DNA with probes pVAW409R1, pVAW412Hec and pEW401HE. In 11 of the 20 CMT 1 cases (55%), we observed a duplication in 17q11.2; one patient had a dinucleotide insertion in exon 6 of the PO-gene (5%). One HNPP case had a typical 17p11.2 deletion. Analysis of CA-repeats was performed with primers RM11GT and Mfd41; SSCP-analysis of the PO, PMP22 and Cx32-genes is in progress. FISH was carried out with probe pVAW409R1. 125 interphase nuclei were analyzed for each proband by counting the signals per nucleus. Normal cells show a characteristic distribution of signals: 1 signal in 5.9% of nuclei, 2 in 86.3% and 3 in 7.8%. A duplication is indicated by a shift to 3 signals in more than approximately 60% and 2 in less than 25% of the nuclei. In contrast, the 17p11.2 deletion of the HNPP patient shifts to 82.4% of nuclei with a single hybridization signal versus 14.4% with 2 signals. We detected one case with significantly abnormal distribution of interphase nuclei hybridization signals compared to cultures of normal cells and to those with 17p11.2 duplication or deletion: 3.2% nuclei revealed 1 signal, 48.0% two signals and 48.8% 3 signals, indicating a pathogenic but moderate dosis increase compared to the throughout duplicated cases. FISH with probe pVAW409R1 is a versatile tool to detect the HNPP deletion both in interphase nuclei and in metaphase chromosomes. In CMT 1 disease interphase nuclei are required for FISH analysis due to the small duplication of 1.5 Mbp. In contrast to Southern techniques, FISH is able to detect genetic mosaicism.

  20. Recombination hot spot in 3.2-kb region of the Charcot-Marie Tooth type 1A repeat sequences: New tools for molecular diagnosis of hereditary neuropathy with liability to pressure palsies and of Charcot-Marie-Tooth type 1A

    Energy Technology Data Exchange (ETDEWEB)

    Lopes, J.; LeGuern, E.; Gouider, R.; Tardieu, S.; Abbas, N. [Hopital de la Salpetriere, Paris (France)] [and others

    1996-06-01

    Charcot-Marie-Tooth type 1A (CMT1A) disease and hereditary neuropathy with liability to pressure palsies (HNPP) are autosomal dominant neuropathies, associated, respectively, with duplications and deletions of the same 1.5-Mb region on 17p11.2-p12. These two rearrangements are the reciprocal products of an unequal meiotic crossover between the two chromosome 17 homologues, caused by the misalignment of the CMT1A repeat sequences (CMT1A-REPs), the homologous sequences flanking the 1.5-Mb CMT1A/HNPP monomer unit. In order to map recombination breakpoints within the CMT1A-REPs, a 12.9-kb restriction map was constructed from cloned EcoRI fragments of the proximal and distal CMT1A-REPs. Only 3 of the 17 tested restriction sites were present in the proximal CMT1A-REP but absent in the distal CMT1A-REP, indicating a high degree of homology between these sequences. The rearrangements were mapped in four regions of the CMT1A-REPs by analysis of 76 CMT1A index cases and 38 HNPP patients, who were unrelated. A hot spot of crossover breakpoints located in a 3.2-kb region accounted for three-quarters of the rearrangements, detected after EcoRI/SacI digestion, by the presence of 3.2-kb and 7.8-kb junction fragments in CMT1A and HNPP patients, respectively. These junction fragments, which can be detected on classical Southern blots, permit molecular diagnosis. Other rearrangements can also be detected by gene dosage on the same Southern blots. 25 refs., 4 figs., 2 tabs.

  1. 周围髓鞘蛋白22基因重复突变致夏科-马里-图斯病1A亚型的临床变异性%Clinical variability of Charcot-Marie-Tooth disease type 1A patients with PMP22 duplication mutation

    Institute of Scientific and Technical Information of China (English)

    段晓慧; 顾卫红; 王国相; 郝莹; 王康; 汪仁斌; 孙少杰; 杨斯柳

    2010-01-01

    目的 探讨夏科-马里-图斯病(CMT)患者周围髓鞘蛋白22(PMP22)基因重复突变特征及临床变异性.方法 联合应用改良的等位基因特异性PCR-双酶切和基于荧光标记毛细管电泳短串联重复序列(STR)分析对45例临床拟诊CMT患者进行PMP22基因重复突变的检测,详细分析其中阳性病例的临床特征.结果 在45例拟诊CMT患者中共检测出PMP22基因重复病例21例,包括10例临床特征符合四肢远端萎缩无力的典型CMT1型患者和11例不典型的CMT患者,后者具有特殊表型:1例仅以轻度头晕就诊;1例合并听力障碍;2例以反复发作性肢体无力起病;2例伴有上肢姿势性震颤;4例伴有小脑性共济失调;1例伴有癫(癎)发作.结论 PMP22基因重复突变为CMT病最常见的病因,改良的等位基因特异性PCR-双酶切提供了一种准确、可靠并易于操作的检测方法,有助于该病的诊断和鉴别.同时,通过综合分析PMP22重复突变阳性的CMT1A患者临床表现、电生理及病理特征,提示该组疾病具有高度的临床变异性.%Objective To investigate the characteristics of PMP22 duplication mutation and the clinical variability of Charcot-Marie-Tooth disease type 1A (CMT1A) patients. Methods PMP22 duplication mutation analysis were performed in 45 cases diagnosed probably CMT by combination of improved allele-specific PCR-restriction enzyme digestion and short tandem repeat (STR) analysis based on laser-induced fluorescence detection in capillary electrophoresis. The clinical features of the positive cases were precisely analyzed. Results With the combined use of two methods, PMP22 duplication was detected in 21 cases, i.e. 10 CMT1 cases with typical presentations including weakness and atrophy in the distal limbs, and 11 atypical cases with special phenotypes including 1 case with mild dizziness, 1 case with hearing loss, 2 cases with recurrent limbs weakness, 2 cases with postural tremor in the upper limbs, 4

  2. The comparative study on electrophysiological changes in patients with hereditary neuropathy with liability to pressure palsy and patients with Charcot-Marie-Tooth 1 A type disease%CMT1A型与遗传性压迫易感性周围神经病的神经电生理对比研究

    Institute of Scientific and Technical Information of China (English)

    宋春莉; 王哲; 刘丽波; 周丽娜; 唐攀; 梁战华; 韩杰; 孙大勇

    2013-01-01

    目的 探讨腓骨肌萎缩症1A型(CMT1A)与遗传性压力易感性神经病(HNPP)在神经电生理检测的不同特点.方法 记录9例CMT1A型和12例HNPP患者的临床特点,对两组患者进行了正中神经、尺神经、胫神经、腓总神经运动神经传导速度检测和正中神经、尺神经、胫神经、腓浅神经、腓肠神经感觉神经传导速度检测.结果 CMT1A型患者存在广泛的电生理异常,四肢周围神经NCV都明显减慢或消失,而且感觉和运动减慢程度一致,并且对任何节段周围神经的影响程度相同;HNPP患者的电生理特点是广泛的SCV不同程度减慢,而MCV减慢相对较轻且不同节段程度不同,主要是末端潜伏期值延长,以及明显的运动神经易卡压部位传导阻滞.结论 神经电生理检测是该两种疾病诊断及鉴别诊断的重要手段,短节段电位检测可证实HNPP的嵌压部位.%Objective To investigate different feature of electrophysiology in patients with hereditary neuropathy with liability to pressure palsy ( HNPP) and patients with Charcot-Marie-Tooth disease. Methods Record clinical features from 9 patients of CMT1A and 12 patients of HNPP,compare two groups of patients with motor nerve conduction velocity testing in median nerve,ulnar nerve,tibial nerve,peroneal nerve,as well as the sensory nerve conduction velocity in median nerve,ulnar nerve,tibial nerve,superficial peroneal nerve and sural nerve. Result Limb peripheral nerve NCV of CMT1A type patients are slowed down or disappeared, degree in SCV and MCV also decreased, suggest a wide range of electrophysiological abnormalities impacting on every segment. HNPP patients display extensive SCV decreases with different degree. At the same time MCV slow down relatively mild and vary different degrees in different segments, distal latency values display prolonged as well as motor nerve conduction block in easily entrapment site. Conclusion Nerve electrophysiological testing is

  3. 腓骨肌萎缩症(CMT)1型的临床、神经电生理及CMT1A型基因诊断方法的研究%Study on the clinic, neuro-electrophysiology of Charcot-Marie-Tooth disease type 1 and the gene diagnosis methods of CMT1 A

    Institute of Scientific and Technical Information of China (English)

    史磊; 曹秉振

    2013-01-01

    目的 观察腓骨肌萎缩症(CMT)1型患者的临床表现及神经电生理特点,同时利用两种不同方法检测CMT1A型相关基因是否存在突变,并分析两种方法的临床应用价值以进一步确定CMT1A型的诊断.方法 对临床确诊为CMT1型的5例患者进行详细的临床及神经电生理检查,同时对所有患者利用等位基因特异性PCR及MLPA两种方法进行PMP22基因重复突变检测.结果 4例患者20岁前发病,其中2例有家族史,1例患者30岁左右发病.临床特点为进行性四肢远端无力伴肌萎缩,四肢远端感觉减退,腱反射均减弱或消失,2例患者出现弓型足.神经电生理检查示神经传导速度减慢,波幅轻度降低.两种基因检测均发现1例患者存在PMP22基因重复突变.结论 CMT1型发病年龄较早,主要表现为进行性四肢无力伴肌萎缩,神经电生理可见神经传导速度明显降低,波幅略有降低.等位基因特异性PCR和MLPA两种方法检测基因突变结果一致.%Objective To study the clinical and neuro-electrophysiological features of Charcot-Marie-Tooth type 1. Two methods were combined to detect mutations in CMT 1A - related genes and comparison of the two methods was performed to determine the clinical value for further diagnosis of CMT1 A. Methods 5 cases of patients with CMT1 underwent detailed clinical and neuro-electrophysiology examinations. Allele-specific PCR and multiplex ligation-dependent probe amplification type CMT1 ( MLPA-CMT1) were respectively used to detect PMP22 gene duplication mutation in 5 cases. Results Two cases has a family history. age at onset was in the first or second decade except one patient. The clinical features were slowly progressive distalmuscle weakness , atrophy and end - brush form sensory decrement, diminshed or absent tendon reflexes. There are foot deformity in 2 patients. EMG showed conduction velocities highly decreased and volatility decreased slightly. One patient was detected

  4. Clinical and electrophysiological characteristics of Charcot-Marie-Tooth disease type 1A patients with PMP22 duplication mutation%周围髓鞘蛋白22基因重复突变致夏科-马里-图斯病1A亚型的临床和神经电生理特征

    Institute of Scientific and Technical Information of China (English)

    汪仁斌; 严莉; 段晓慧; 毛坤; 孙少杰; 董明睿; 焦劲松; 王国相

    2012-01-01

    目的 探讨周围髓鞘蛋白22(PMP22)基因重复突变阳性的夏科-马里-图斯病(CMT) 1A亚型患者临床和神经电生理改变特点.方法 总结21例PMP22基因重复突变阳性的CMT1A患者的临床特点,并分析其神经电生理特征.结果 21例患者中,10例临床特征符合四肢远端萎缩无力的典型CMT1型表现,另外11例呈不典型性,如仅有头晕、合并听力障碍、上肢姿势性震颤、反复发作性肢体无力、伴有小脑性共济失调及癫(痢)等.10例患者肌电图出现纤颤电位和(或)正锐波,15例患者运动单位电位时限延长.神经传导存在广泛异常,所有患者被检的运动或感觉神经传导速度存在不同程度的减慢或消失.结论 PMP22重复突变阳性的CMT1A患者具有较高的临床异质性,其电生理特点为肌电图呈神经源性损害,感觉神经病变重于运动神经,下肢受累程度重于上肢,神经电生理检查对CMT1A的诊断很重要.%Objective To investigate the clinical and electrophysiological characteristics in Charcot-Marie-Tooth disease(CMT ) type 1A patients with (peripheral myetin protein22,PMP22) duplication mutation. Methods Twenty one patients with CMT 1A were retrospectively studied. Routine electromyography ( EMG) and nerve conduction had been performed in all patients. Hie clinical and electrophysiological features were analyzed. Results 10 of 21 patients showed typical presentations including weakness and atrophy in the distal parts of limbs, and 11 atypical cases with special phenotypes including mild dizziness, hearing loss, postural tremor in the upper limbs, recurrent limbs weakness , cerebellar ataxia and epilepsy. EMG detected fibrillation potentials and positive sharp waves in 10 patients and prolonged duration of motor unit potentials in 15 patients respectively. Nerve conduction studies revealed decreased nerve conductive velocity or unelicited potentials in all detected nerves in the patients. Conclusion The CMT 1

  5. Mutation analysis for a family affected with Charcot-Marie-Tooth disease type 4C%一个腓骨肌萎缩症4C型家系的SH3TC2基因突变分析

    Institute of Scientific and Technical Information of China (English)

    于珍; 张嘉莹; 许烨; 杨博宇; 何志宏; 张慕晨; 沈薇; 顾鸣敏

    2016-01-01

    目的 明确1个腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)家系的分子遗传发病机制.方法 抽提家系成员外周血基因组DNA;应用目标外显子捕获及二代测序技术对先证者的72个候选基因进行基因突变筛查,并对可疑基因进行Sanger测序验证;用PyMOL-1软件对突变基因的蛋白质结构进行分子模拟.结果 先证者SH3TC2基因第11外显子中检出c.1894G>A纯合错义突变(p.E632K);先证者父母及女儿均为c.1894G>A杂合突变携带者,其他家系成员及300名正常对照者中均未检测到该突变.经检索NCBI、HGMD、1000 genome等数据库,c.1894G>A突变为未报道过的新突变.分子模拟显示该基因突变改变了SH3TC2蛋白的三维构象.结论 SH3TC2基因突变可能与该CMT4C型家系先证者的发病有关.新发现的c.1894G>A突变(p.E632K)扩展了SH3TC2基因的突变谱.%Objective To identify potential mutation in a Chinese family affected with Charcot-Marie-Tooth disease(CMT).Methods Clinical data of the family was collected,and genomic DNA was extracted from peripheral blood samples of the family members.Seventy-two candidate genes of the proband were captured and sequenced by targeted next-generation sequencing,and the results were confirmed by Sanger sequencing.The protein structure was predicted with PyMOL-1 software.Results A homozygous missense mutation c.1894G>A(p.E632K) was identified in the exon 11 of the SH3TC2 gene in the proband.Heterozygous c.1894G>A mutation was also detected in the proband's father,mother and daughter,but not in the healthy family members and 300 normal controls.Retrieval of the NCBI,HGMD and 1000 genome databases has verified the c.1894G> A to be as a novel mutation.Computer simulation has suggested that the mutation has altered the 3D structure of the SH3TC2 protein.Conclusion The proband was diagnosed as CMT4C,for which the underlying gene was SH3TC2.This finding has expanded the spectrum of SH3TC2 mutation

  6. Charcot-Marie-Tooth病的研究与诊断进展%Progress of Research and Diagnosis of Charcot-Marie-Tooth Disease

    Institute of Scientific and Technical Information of China (English)

    朱琳; 胡静

    2011-01-01

    Charcot-Marie-Tooth disease(CMT) is % group of the most common familial peripheral neuropathies with highly genetic and clinical heterogeneity. CMT accounts for aboul 90% of hereditary neuropathies. CMT has similar clinical manifestations. Now there are at least .15 subtypes, which makes great difficulties in diagnosiing the disease. Therefore, this arliclc review;, the effective diagnostic methods of detailing the phenotypes and screening disease-related geres bused on the analysis of the clinical presentations, electrophysiology. Peripheral nerve pathology and causative genes of the subtypes of CMT.%Charcot-Marie-Tooth病,是一组最常见的在遗传和临床上都具有高度异质性的家族性周围神经病,约占全部遗传性神经病的90%.其基本临床表现相似,目前已知的亚型多达35种,为该病的确诊带来极大困难.因此,本文综述该病各亚型的临床、电生理、周围神经病理、致病基因及有效诊断方法.

  7. A novel mutation in the nerve-specific 5'UTR of the GJB1 gene causes X-linked Charcot-Marie-Tooth disease.

    LENUS (Irish Health Repository)

    Murphy, Sinéad M

    2011-03-01

    X-linked Charcot-Marie-Tooth disease (CMT1X) is the second most common cause of CMT, and is usually caused by mutations in the gap junction protein beta 1 (GJB1) gene which codes for connexin 32 (CX32). CX32 has three tissue-specific promoters, P1 which is specific for liver and pancreas, P1a specific for liver, oocytes and embryonic stem cells, and P2 which is nerve-specific. Over 300 mutations have been described in GJB1, spread throughout the coding region. We describe two families with X-linked inheritance and a phenotype consistent with CMT1X who did not have mutations in the GJB1 coding region. The non-coding region of GJB1 was sequenced and an upstream exon-splicing variant found at approximately - 373G>A which segregated with the disease in both families and was not present in controls. This substitution is located at the last base of the nerve-specific 5\\'UTR and thus may disrupt splicing of the nerve-specific transcript. Online consensus splice-site programs predict a reduced score for the mutant sequence vs. the normal sequence. It is likely that other mutations within the GJB1 non-coding regions account for the CMT1X families who do not have coding region mutations.

  8. 腓骨肌萎缩症分子突变研究现状%An overview of molecular mutations of charcot marie tooth disease

    Institute of Scientific and Technical Information of China (English)

    范晓博

    2010-01-01

    腓骨肌萎缩症(charcot marie tooth disease,CMT)是一组高发病率的周围神经系统的单基因遗传病,具有临床和遗传异质性.可分为CMT1型,CMT2型,CMTX型和CMT4型.近些年随着分子遗传学和分子生物学的快速发展,已经发现了很多CMT的相关致病基因.主要包括外周髓鞘蛋白22基因、髓鞘蛋白零蛋白基因、间隙连接蛋白-32基因、驱动蛋白1B基因、Ras相关蛋白7基因、小分子热休克蛋白27基因等.本文就CMT相关致病基因研究现状作一综述.

  9. Expression of a dynamin 2 mutant associated with Charcot-Marie-Tooth disease leads to aberrant actin dynamics and lamellipodia formation.

    Science.gov (United States)

    Yamada, Hiroshi; Kobayashi, Kinue; Zhang, Yubai; Takeda, Tetsuya; Takei, Kohji

    2016-08-15

    Specific mutations in dynamin 2 are linked to Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy. However, the effects of these mutations on dynamin function, particularly in relation to the regulation of the actin cytoskeleton remain unclear. Here, selected CMT-associated dynamin mutants were expressed to examine their role in the pathogenesis of CMT in U2OS cells. Ectopic expression of the dynamin CMT mutants 555Δ3 and K562E caused an approximately 50% decrease in serum stimulation-dependent lamellipodia formation; however, only K562E caused aberrations in the actin cytoskeleton. Immunofluorescence analysis showed that the K562E mutation resulted in the disappearance of radially aligned actin bundles and the simultaneous appearance of F-actin clusters. Live-cell imaging analyses showed F-actin polymers of decreased length assembled into immobile clusters in K562E-expressing cells. The K562E dynamin mutant colocalized with the F-actin clusters, whereas its colocalization with clathrin-coated pit marker proteins was decreased. Essentially the same results were obtained using another cell line, HeLa and NG108-15 cells. The present study is the first to show the association of dynamin CMT mutations with aberrant actin dynamics and lamellipodia, which may contribute to defective endocytosis and myelination in Schwann cells in CMT.

  10. Pathologic and genetic features in 6 Chinese X-linked Charcot-Marie-Tooth disease type 1 families%X连锁Charcot-Marie-Tooth病1型六个家系的病理和基因突变特点

    Institute of Scientific and Technical Information of China (English)

    栾兴华; 乔晓会; 吕鹤; 王朝霞; 李越星; 袁云

    2012-01-01

    Objectives To report pathological and genetic features of 6 Chinese families with Xlinked Charcot-Marie-Tooth disease type 1 ( CMTX1 ).Methods The index cases from 6 families with CMTX1 are males with onset of disease between 11 and 24 years old.All of them had distal leg muscle weakness,accompanied with areflexia and sensory loss in the feet.Additionally,the index 1 presented with recurrent encephalopathy and the index case 5 with cerebellar ataxia.Peripheral neuropathy was found in 12 family members,while other 7 members showed talipescavus and hyporeflexia.Sural nerve biopsies were performed in all index cases.Connexin 32(Cx32) gene was analyzed in the index cases,8 affected and 10unaffected family members as well as 50 healthy women control subjects.Results Mild to moderate loss of myelinated fiber with axonal degeneration and regeneration clusters were found in all index cases. Thin myelin fibers were found in 5,small onion bulbs in 3 and inflammatory infiltrates in 2.Five novel mutations (I20T,I127F,D178G,A197V,403_404insT) and one L10L synonymous mutation were detected in the 6index cases and their affected family members.The same mutations,in heterozygous state,were detected in 4 female family members without clinical symptoms,but not found in 6 male unaffected family members.The same mutations were not found in healthy control subjects.Conclusions The CMTX1 patients in our study present predominantly axonal lesions.Frequent novel Cx32 gene mutations indicated that private mutations may be common in Chinese CMTX1 patients.%目的 报道6个X连锁Charcot-Marie-Tooth病1型(CMTX1)家系的神经病理和基因型改变特点.方法 6个CMTX1家系的先证者均为男性,发病年龄11 ~24岁,出现下肢远端为主的肌无力、腱反射减低和轻度感觉减退.先证者1伴随发作性白质脑病,先证者5伴随小脑性共济失调.12名家系成员也出现周围神经损害症状,另7名存在高弓足或腱反射减低.对6例先证者行腓

  11. 突变缝隙连接蛋白32在X连锁Charcot-Marie-Tooth病1型患者的外周血管内皮细胞异常表达%Mutant connexin 32 abnormally distributed in the vascular endothelial cells of X-linked Charcot-Marie-Tooth disease type 1 patients

    Institute of Scientific and Technical Information of China (English)

    栾兴华; 洪道俊; 乔晓会; 吕鹤; 王朝霞; 袁云

    2011-01-01

    Objective To investigate expression distribution of mutant connexin 32 (Cx32) protein in human endothelial cells in patients with X-linked Charcot-Marie-Tooth disease type 1 ( CMTX1 ) .Methods Nerve biopsies were performed in 3 patients with CMTX1 and in 3 non-CMTX1 controls. Cx32 mutations of c. 379A > T( I127F), c. 533A > G(D178G) and c. 590C > T(A197V) were identified in these 3 patients respectively. Immunofluorescent (IMF) staining of nerve blood vessel was processed with antibodies against Cx32, Yon Willebrand factor and Cx40. The mutant Cx32 was constructed in pEGFP-N plasmid (pEGFP-N1-Cx32) and was transfected in HeLa cells. Cx32 and GRP78, a marker of endoplasmic reticulum ( ER), were stained by IMF in HeLa cells to investigate expression of mutant Cx32. Results In 3 control cases, Cx32 was visualized by IMF staining as dots along gap junction of vascular endothelial cells,and it was coexisted with Cx40. However, immunoreactivity of Cx32 in 3 patients was predominantly decreased and was not located in endothelial gap junction. The transfection of 3 Cx32 mutants into HeLa cells demonstrated the pathogenic changes. The cells with the mutation c. 379A >T found Cx32 accumulations in the cytoplasm; the cells with mutation c. 533A >G showed few staining positive dots surrounding the nuclear and the cells with c. 590C > T showed dot-like expression of Cx32 both in the cytoplasmicand cell membrane. The mutant Cx32 was not overlapped with expression of the marker of ER.ConclusionsMutant Cx32 might cause dysfunction of endothelial gap-junctions due to the abnormal expression of Cx32 in level and location in the vascular endothelial cells of CMTX1 patients.%目的 观察突变缝隙连接蛋白32( Cx32)在X连锁的Charcot-Marie-Tooth病1型(CMTX1)患者血管内皮细胞的表达规律。方法 对3例经Cx32基因检查证实的CMTX1患者(突变位点分别为c.379A>T、c.533A>G和c.590C>T点突变)进行腓肠神经活体组织检查,同

  12. 基因重复的进行性腓骨肌萎缩症1A型临床与电生理研究%Clinical and electrophysiological study on charcot-Marie-Tooth disease type 1A with gene duplication.

    Institute of Scientific and Technical Information of China (English)

    笪宇威; 沈定国; 苏凤霞; 刘淑贤

    2001-01-01

    Objective  To study the clinical and electrophysiological features in Charcot-Marie-Tooth disease type 1A with gene duplication.Methods Clinical symptoms and signs were summarized in 22 patients from 21 unrelated families. Electromyography (EMG) as well as motor conduction velocities (MCV) and sensory conduction velocities (SCV) examinations were performed in all patients. Results Evidence of CMT was initially detected within the second decade in 18 patients. Nearly half of patients were sporadic cases. The typical clinical manifestations of CMT1A were weakness and atrophy in the distal limbs, weakness or absence of the tendon reflexes, talipes equinovarus and postural tremor the upper limb. Additionally, some special symptoms and signs were also observed occasionally, including brisk tendon reflexes, extensor plantar responses, scoliosis, foot ulcers and nystagmus. EMG revealed that 77.3% of the patients had fibrillation and positive sharp potentials. 81.8% of them had prolonged motor unit potential limit. Median MCV showed there was no significant difference between CMT1A patients and CMT1 patients without duplication (t=1.63, P>0.05). Values of SCV and MCV for the lower limbs were not obtained in 20 patients and more than 2/3 of the patients respectively. Conclusions The clinical features of CMT1A included high frequent of sporadic cases, early onset in the second decade and various manifestations. The electrophysiological features were that the damages of nerves for the lower limbs were more severer than those in the upper limbs and the damages of the sensory nerves were more severer than those of the motor nerves. The phenotype was variable although the genotype was the same in CMT1A patients with PMP22 duplication.%目的研究有基因重复的进行性腓骨肌萎缩症1A型(Charcot-Marie-Tooth病1A,CMT1A)临床与电生理特点。方法对来自21个家系的22名CMT1A病人临床特点进行总结,同时分析其电

  13. NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype.

    Science.gov (United States)

    Berciano, José; Peeters, Kristien; García, Antonio; López-Alburquerque, Tomás; Gallardo, Elena; Hernández-Fabián, Arantxa; Pelayo-Negro, Ana L; De Vriendt, Els; Infante, Jon; Jordanova, Albena

    2016-02-01

    The purpose of this study was to describe a pedigree with NEFL N98S mutation associated with a dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) and heterogeneous early-onset phenotype. The pedigree comprised two patients, the proband and her son, aged 38 and 5 years. The proband, evaluated at age 31, showed delayed motor milestones that, as of the second decade, evolved into severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound. By then, a working diagnosis of sporadic early onset cerebellar ataxia with peripheral neuropathy was established. Screening of mutations associated with SCA and autosomal recessive cerebellar ataxias was negative. Her son showed a mild phenotype characterized by delayed motor milestones, and lower-limb hypotonia and areflexia. Electrophysiology in both patients showed nerve conduction slowing in the intermediate range, both in proximal and distal nerve segments, but where compound muscle action potentials exhibited severe attenuation there was conduction slowing down to the demyelinating range. In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy; furthermore, on water sensitive MRI sequences there was edema of calf muscles. We conclude that the NEFL N98S mutation is associated with a DI-CMT phenotype characterized by early-onset sensorimotor neuropathy delaying motor milestones, which may evolve into a severe and complex clinical picture including cerebellar ataxia.

  14. Clinical classification and gene mutation of Chinese probands with Charcot-Marie-Tooth disease Analysis of 57 cases

    Institute of Scientific and Technical Information of China (English)

    Ruxu Zhang; Xiaobo Li; Xiaohong Zi; Shunxiang Huang; Fufeng Zhang; Kun Xia; Qian Pan; Beisha Tang

    2011-01-01

    Charcot-Mafie-Tooth (CMT) disease is the most common inherited peripheral neuropathic disorder.CMT is clinically and genetically heterogeneous. To date, 27 genes associated with the disease have been cloned. The present study carried out clinical classification according to clinical,electrophysiological and pathological features, conducted inheritance classification according to inheritance patterns, and performed mutation analysis of 13 CMT disease genes (PMP22, CX32,HSPB1, MNF2, MPZ, HSPB8, GDAP1, NFL, EGR2, SIMPLE, RAB7, LMNA, MTMR2) in 57 Chinese probands with CMT. Five cases of AD-CMT1 and 13 cases of sporadic CMT1 were diagnosed as CMT1A; five cases of X-CMT1, one case of X-CMT2 and one case of sporadic CMT1 were diagnosed as CMTX1; four cases of AD-CMT2 were diagnosed as CMT2F; one case of AD-CMT2 and one case of sporadic CMT2 were diagnosed as CMT2A2; one case of AD-CMT2 was diagnosed as CMT2L; one case of AD-CMT2 was diagnosed as CMT2J; one case of AR-CMT1 was diagnosed as CMT4A. Among the 57 CMT probands, seven genotypes were determined among 34 patients, with a detection rate of 59.6%. The results indicated that the clinical classification and inheritance classification are indispensable for selecting potential disease genes for mutation detection, and for efficient molecular diagnosis.

  15. Charcot-Marie-Tooth Disease

    Science.gov (United States)

    ... of symptoms is very gradual. The degeneration of motor nerves results in muscle weakness and atrophy in the ... of symptoms is very gradual. The degeneration of motor nerves results in muscle weakness and atrophy in the ...

  16. Irradiação contralateral de força para a ativação do músculo tibial anterior em portadores da doença de Charcot-Marie-Tooth: efeitos de um programa de intervenção por FNP Contralateral force irradiation for the activation of tibialis anterior muscle in carriers of Charcot-Marie-Tooth disease: effect of PNF intervention program

    Directory of Open Access Journals (Sweden)

    Paula C. Meningroni

    2009-10-01

    Full Text Available OBJETIVO: Avaliar a resposta do músculo tibial anterior (TA após um protocolo de cinco semanas com irradiação contralateral de força através de diagonais de facilitação neuromuscular proprioceptiva (FNP em pacientes com polineuropatia desmielinizante associada à doença de Charcot-Marie-Tooth do tipo 1A (CMT-1A. MÉTODOS: Participaram deste estudo 12 pacientes, de ambos os sexos. Eles foram tratados em uma frequência de duas vezes por semana, durante cinco semanas. Em cada sessão, foram utilizadas as diagonais de Chopping, extensão-adução com rotação interna (EARI e flexão-abdução com rotação interna (FARI. As diagonais foram repetidas quatro vezes, em ambos os membros superiores e inferiores; cada diagonal tinha duração média de 6 segundos. Durante as execuções, a resposta muscular do TA foi registrada por um eletromiógrafo de superfície, desprezando-se os 2 segundos iniciais e finais de cada diagonal. A média dos valores de Root Mean Square (RMS das quatro repetições foi normalizada em porcentagem. Os dados iniciais e finais foram submetidos ao teste em t para amostras pareadas com valores de p significativos OBJECTIVE: To evaluate the response of the tibialis anterior (TA muscle following a five-week protocol with contralateral irradiation force through Proprioceptive Neuromuscular Facilitation (PNF diagonals in patients with demyelinating polyneuropathy associated with Charcot-Marie-Tooth disease type 1A (CMT-1A. METHODS: The study included 12 patients of both sexes. They were treated twice-weekly for 5 weeks. At each session, they performed the following diagonal patterns: chopping, extension-adduction with internal rotation (EAIR and flexion-abduction with internal rotation (FAIR. The diagonals were repeated four times, in both upper and lower limbs, with each repetition lasting six seconds on average. During execution, the response of the TA muscle was recorded by a surface electromyograph disregarding the

  17. Dysfunction in the hip joints in children with Charcot-Marie-Tooth syndrome (literature review

    Directory of Open Access Journals (Sweden)

    Иван Юрьевич Поздникин

    2015-09-01

    Full Text Available A review of the literature on the treatment of children with dysfunction in the hip joints in motor-sensory neuropathy Charcot-Marie-Tooth is presented. Peculiarities of disease diagnosis and the approach used in the treatment of patients are described. The Charcot-Marie-Tooth syndrome is a hereditary neuromuscular disease characterized by progressive atrophy of the distal muscle group of the lower limbs. According to international authors, the incidence of hip joint dysfunction in this condition is at least 10%, ranking second only to foot deformities. In the Russian literature, the problem has not been adequately interpreted. Early diagnosis of dysfunction in the hip joints during Charcot-Marie-Tooth syndrome is complicated by the child's age and is characterized by progression. Conflicting clinical signs and trivial symptoms of the disease also confuse diagnosis, until it becomes clearer in adolescence or the second or third decade of life. Surgical reconstructive operations on the hip joint often occur too late, and they are accompanied by a greater frequency of neurological complications. Practitioner awareness coupled with an early diagnosis of hip subluxation and decentration and complex orthopedic and neurological examinations of children with the disease of Charcot-Marie-Tooth should result in more favorable outcomes.

  18. Neuroelectrophysiological and pathological features of Charcot-Marie-Tooth disease ( report of 2 cases)%腓骨肌萎缩症的神经电生理及病理学特点(附2例报告)

    Institute of Scientific and Technical Information of China (English)

    刘艳; 黄辉; 王超; 赵玉红

    2012-01-01

    目的 探讨腓骨肌萎缩症(CMT)的神经电生理及病理学特点.方法 回顾性分析2例腓骨肌萎缩症患者的神经电生理及病理学资料.结果 本组患者主要表现为慢性进行性双下肢远端肌无力和肌萎缩,弓形足,伴有双上肢受累,腱反射消失,四肢感觉障碍.神经电生理检查显示神经传导速度减慢,神经源性损害;神经活检显示节段性脱髓鞘,部分区域“洋葱球样”改变;电镜显示有髓神经密度中度减少,髓鞘破坏;肌活检显示肌纤维萎缩呈角形.结论 CMT的神经电生理特点为神经源性损害;病理学特点为周围神经节段性脱髓鞘和神经源性肌萎缩.%Objective To explore the features of neuroelectrophysiological and pathological of Charcot-Marie-Tooth disease (CMT). Methods The neuroelectrophysiological and pathological datas of 2 CMT patients were analyzed retrospectively. Results The clinical manifestations of the 2 cases were chronic progressive of lower limbs distal muscle weakness and muscle atrophy, bow foot, and with double upper limbs involved, the tendon reflexes were disappeared and sensory disturbance in limbs. Electrophysiological examination showed nerve conduction velocity decreased and neurogenic damages. Nerve biopsy showed that there were segmental demyelination and "onion ball" structure in some lesion. Electron microscope showed that the density of myelinated nerve fibers was moderate reduced and myelin damage. Muscle biopsy showed the muscle fibers atrophy with angle type. Conclusions The neuroelectrophysiology feature of CMT is neurogenic damages. The pathological features are segmental demyelination of peripheral nerve and neural atrophy.

  19. Peria xin and Charcot-Marie-Tooth DiseaseS ubtype 4F%Periaxin与腓骨肌萎缩症4 F亚型

    Institute of Scientific and Technical Information of China (English)

    任页玫(综述); 石亚伟(审校)

    2015-01-01

    Periaxin是施万细胞特异表达的一种蛋白,在维持髓鞘稳定性方面起重要作用,该基因突变将导致脱髓鞘型常染色体隐性遗传的腓骨肌萎缩症4F 亚型发生。从分子遗传学角度探讨腓骨肌萎缩症4F亚型发病的机制已成为目前研究的热点。从 periaxin的分布、结构与功能开展研究,寻找与其相互作用的蛋白质并揭示其互作的生物学意义,从蛋白质水平上研究腓骨肌萎缩症的发病机制具有重要意义。%Periaxin is expressed by myelinating Schwann cells ,which plays an essential role in stabiliza-tion of the myeline sheath.Periaxin mutations cause autosomal recessive,demyelination neuropathy,Charcot-Marie-Tooth 4F(CMT4F) subtype.Molecular genetics mechanism of CMT4F subtype has been one of the hot spots in the research field.The study of periaxin distribution,structures and functions,finding the interacting proteins with periaxin will reveal its biological function ,and lay the foundation for the research of CMT patho-genesis on the protein level.

  20. Refined genetic mapping of X-linked Charcot-Marie-Tooth neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Fain, P.R.; Barker, D.F.; Chance, P.F. (Univ. of Utah, School of Medicine, Salt Lake City, UT (United States))

    1994-02-01

    Genetic linkage studies were conducted in four multigenerational families with X-linked Charcot-Marie-Tooth disease (CMTX), using 12 highly polymorphic short-tandem-repeat markers for the pericentromeric region of the X Chromosome. Pairwise linkage analysis with individual markers confirmed tight linkage of CMTX to the pericentromeric region in each family. Multipoint analyses strongly support the order DXS337-CMTX-DXS441-(DXS56, PGK1). 38 refs., 2 figs., 1 tab.

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

    Science.gov (United States)

    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.

  2. Ultrasonographic nerve enlargement of the median and ulnar nerves and the cervical nerve roots in patients with demyelinating Charcot-Marie-Tooth disease: distinction from patients with chronic inflammatory demyelinating polyneuropathy.

    Science.gov (United States)

    Sugimoto, Takamichi; Ochi, Kazuhide; Hosomi, Naohisa; Takahashi, Tetsuya; Ueno, Hiroki; Nakamura, Takeshi; Nagano, Yoshito; Maruyama, Hirofumi; Kohriyama, Tatsuo; Matsumoto, Masayasu

    2013-10-01

    Demyelinating Charcot-Marie-Tooth disease (CMT) and chronic inflammatory demyelinating polyneuropathy (CIDP) are both demyelinating polyneuropathies. The differences in nerve enlargement degree and pattern at multiple evaluation sites/levels are not well known. We investigated the differences in nerve enlargement degree and the distribution pattern of nerve enlargement in patients with demyelinating CMT and CIDP, and verified the appropriate combination of sites/levels to differentiate between these diseases. Ten patients (aged 23-84 years, three females) with demyelinating CMT and 16 patients (aged 30-85 years, five females) with CIDP were evaluated in this study. The nerve sizes were measured at 24 predetermined sites/levels from the median and ulnar nerves and the cervical nerve roots (CNR) using ultrasonography. The evaluation sites/levels were classified into three regions: distal, intermediate and cervical. The number of sites/levels that exhibited nerve enlargement (enlargement site number, ESN) in each region was determined from the 24 sites/levels and from the selected eight screening sites/levels, respectively. The cross-sectional areas of the peripheral nerves were markedly larger at all evaluation sites in patients with demyelinating CMT than in patients with CIDP (p demyelinating CMT and CIDP were 0.90 and 0.94, respectively, with the cut-off value set at four. Nerve ultrasonography is useful to detect nerve enlargement and can clarify morphological differences in nerves between patients with demyelinating CMT and CIDP.

  3. ELECTRONEUROPHYSIOLOGICAL CHARACTERISTIC ANALYSIS WITH CHARCOT-MARIE-TOOTH DISEASE%腓骨肌萎缩症患者神经电生理检测特征性分析

    Institute of Scientific and Technical Information of China (English)

    张鸿雁

    2014-01-01

    目的:探讨腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)患者的神经电生理改变特点;方法:应用肌电诱发电位仪对6例腓骨肌萎缩症患者进行电生理检测,对检查结果进行回顾性总结和分析.结果:6例患者运动或感觉神经传导速度均存在不同程度的减慢、消失或波幅降低,且下肢重于上肢;6例患者被检肌肉均呈现不同程度神经源性损害.结论:CMT的神经电生理特点是神经源性损害,神经电生理检查是发现和诊断CMT的可靠方法.

  4. Genetic heterogeneity and clinical variability of charcot-Marie-Tooth disease%腓骨肌萎缩症的遗传异质性和临床变异性

    Institute of Scientific and Technical Information of China (English)

    王国相; 段晓慧; 顾卫红

    2010-01-01

    @@ 一、前言 夏科-马里-图斯病(Charcot-Marie-Tooth disease,CMT),又名腓骨肌萎缩症,是一组最常见的周围神经单基因遗传病,患病率约为1/2500,遗传方式有常染色体显性遗传、常染色体隐性遗传和X连锁遗传.其典型临床表现为青年期起病,缓慢进展的远端肌力减退及肌肉萎缩,弓形足,锤状趾,腱反射消失,四肢远端深感觉障碍.临床上依据电生理和病理的改变主要分为脱髓鞘型(CMT1/HMSN1)和轴索型(CMT2/HMSN2),此外还存在一些特殊类型,如CMT3、CMT4、CMTX和显性遗传中间型CMT(CMTDI,表1).

  5. Mutation analysis of neurofilament-light gene in Chinese Charcot-Marie-Tooth disease%神经丝轻链基因在腓骨肌萎缩症中的突变分析

    Institute of Scientific and Technical Information of China (English)

    罗巍; 唐北沙; 赵国华; 李崎; 萧剑锋; 杨期东; 夏家辉

    2003-01-01

    目的探讨神经丝轻链基因(neurofilament-light gene, NF-L)在中国人腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)中的突变特点. 方法应用聚合酶链反应-单链构象多态性技术结合DNA序列分析方法,对32个来自全国5省汉族的CMT家系先证者进行了NF-L基因的突变分析. 结果32例先证者中只有1例患者出现异常条带,经DNA测序证实该患者在NF-L基因的外显子3发生了1329C→T碱基改变,由于编码的氨基酸未改变,均为酪氨酸(Tyr),为一种同义突变. 结论 NF-L基因突变可能在中国人的腓骨肌萎缩症患者中少见.

  6. Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations.

    NARCIS (Netherlands)

    Azzedine, H.; Ravise, N.; Verny, C.; Gabreëls-Festen, A.A.W.M.; Lammens, M.M.Y.; Grid, D.; Vallat, J.M.; Durosier, G.; Senderek, J.; Nouioua, S.; Hamadouche, T.; Bouhouche, A.; Guilbot, A.; Stendel, C.; Ruberg, M.; Brice, A.; Birouk, N.; Dubourg, O.; Tazir, M.; LeGuern, E.

    2006-01-01

    BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked, and autosomal recessive (AR) CMT. A locus responsible for the demyelinating form of ARCMT was assigned to the

  7. Clinical and pathological differences in common subtypes of Charcot-Marie-Tooth disease%常见腓骨肌萎缩症亚型的临床和神经病理改变差异分析

    Institute of Scientific and Technical Information of China (English)

    刘菁菁; 吕鹤; 王朝霞; 刘靖; 左越焕; 贺茂林; 袁云

    2016-01-01

    目的 探讨腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)常见亚型的临床表现和周围神经病理改变.方法 收集2005-2015年就诊于我院神经内科门诊并经基因检查证实的81例CMT患者,其中CMT1A型31例(38.3%),CMTX1型19例(23.5%),CMT2A2型16例(19.8%),其他9种少见CMT亚型患者合计15例(1.2%~4.9%).比较其中48例3种常见类型患者在平均发病年龄、病程、下肢远端肌力、高弓足出现率之间的差异,同时比较其腓肠神经病理改变的差异.结果 CMT1A型患者的发病年龄为(12.00 ±6.77)岁,CMTX1型(11.81±4.65)岁,CMT2A2型(5.00±2.68)岁(Brown-Forsythe检验,P=0.001).CMT1A型病程为(12.00±6.75)年,CMTX1型为(8.50±4.75)年,CMT2A2型为(5.00±2.73)年(Brown-Forsythe检验,P=0.001).下肢足背伸肌力在CMT1A为Ⅳ(0,Ⅴ)级,CMTX1为Ⅲ+(0,Ⅳ)级,CMT2A2为0(0,Ⅳ)级(H=11.359,P=0.020).高弓足出现在15/23的CMT1A型、10/16的CMTX1型和1/9的CMT2A2型患者(Fisher检验,P=0.017).3例出现脑部症状患者均为CMTX1型.3例伴随有视力下降的患者均为CMT2A2型.腓肠神经有髓神经纤维的洋葱球样结构出现在23/23的CMT1A、5/16的CMTX1和2/9的CMT2A2患者(Fisher检验,P=0.000);再生簇出现在16/23的CMT1A、16/16的CMTX1和9/9的CMT2A2患者(x2=7.666,P=0.016).上述指标在3组间差异均具有统计学意义.结论 CMT1A型、CMTX1型和CMT2A2型是本组患者最常见的CMT亚型,关注发病年龄、病程、肌力下降程度、高弓足出现率、脑部以及视神经损害的出现有助于三者的临床区分,注意有髓神经纤维洋葱球样结构和再生簇出现程度也有助于其病理分型.%Objective To analyze the differences of the clinical and neuropathological features among the common Charcot-Marie-Tooth disease (CMT) subtypes.Methods There were 81 CMT patients confirmed by genetic testing from 2005 to 2015 in Department of Neurology,Peking University First Hospital,including 31 cases of CMT1A (38.3%),19

  8. 中国汉族人群腓骨肌萎缩症Cx32基因突变分析%Mutation screening of Cx32 in Han Chinese patients with Charcot-Marie-Tooth disease

    Institute of Scientific and Technical Information of China (English)

    张如旭; 罗巍; 资晓宏; 夏昆; 蔡芳; 萧剑峰; 赵国华; 张付峰; 沈潞; 江泓; 唐北沙

    2005-01-01

    Objective: To investigate the Cx32 mutation features and the clinical manifestations of Chinese patients with Charcot-Marie-Tooth disease(CMT). Methods: Twenty-four of 65 unrelated CMT patients were selected for Cx32 mutation screening after the exclusion of the CMT1A 1.5 Mb duplication and male-to-male transmission. The motor and sensory nerve conduction studies were performed in all probands and most of their affected family members to establish the clinical CMT1 ,CMT2 or CMT intermediate diagnosis. The presence of mutations in the coding region of Cx32 was detected by single-strand conformation polymorphism analysis combined with direct sequencing. Results: We found 7 different point mutations in the coding region of Cx32 in a total of 7 families. All the patients were mildly to moderately affected with a clinical CMT1 or CMT intermediate diagnosis. The mutation Arg15Gln was inherited with X-linked recessive trait in family 1 involved in our study. The Arg75Trp mutation was detected in a family with X-linked dominant CMT and autosomal recessive nonsydromic hearing loss. The clinical phenotype of the Thr188Ala mutation was firstly reported. Conclusion: Seven different Cx32 point mutations were detected and the percentage of Chinese CMT families with Cx32 mutation is about 10% in our study. The inheritance model of CMT secondary to Cx32 mutation could be X-linked dominant, X-linked recessive or sporadic. Male patients are usually more severely affected than females with slower nerve conduction velocities. Cx32 mutation screening should be firstly performed in those CMT families without male-to-male transmission and CMT1A duplication.

  9. 腓骨肌萎缩症患者的临床与神经电生理特征分析%THE CLINICAL ANALYISI AND NEUROELECTROPHYSIOLOGICAL CHARACTERISTICS IN PATIENTS WITH CHARCOT-MARIE-TOOTH DISEASE(CMT)

    Institute of Scientific and Technical Information of China (English)

    黄献; 宋治; 郑文; 黄顺祥

    2010-01-01

    目的:探讨腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)的临床与神经电生理特征;方法:应用肌电图仪检测和分析21例腓骨肌萎缩症患者的电生理特征,包括肌电图和运动、感觉神经传导速度;分析电生理特征与临床之间的关系;结果:16例患者肌电图出现纤颤电位和(或)正锐波,17例患者运动单位(MUP)时限延长.11例腓总神经、13例胫神经运动传导速度(MCV)未引出,1例正中神经、2例尺神经MCV未引出,3例正中神经、2例尺神经MCV正常,其余均有不同程度减慢;15例腓肠神经感觉神经传导速度(SCV)未引出,3例正中神经、6例尺神经SCV未引出,7例正中神经、5例尺神经SCV正常,其余均有不同程度减慢.结论:CMT患者的神经电生理特征大多数呈神经原性损害,运动和感觉神经传导速度有不同程度的受累,下肢的神经病变重于上肢,临床表现结合神经肌电图检查有助于CMT的确诊.

  10. An analysis of electroneurophysiological and clinical characteristics in patients with charcot- Marie-Tooth disease%腓骨肌萎缩症的临床及神经电生理特点分析

    Institute of Scientific and Technical Information of China (English)

    邹艺; 刘英; 李素荣; 胥勋成; 高国勋

    2008-01-01

    目的:探讨腓骨肌萎缩症即夏科-马里-图思病(Charcot-Marie-Tooth disease, CMT)的临床及神经电生理特点.方法:应用肌电图仪检测和分析28例CMT患者的电生理特征,包括肌电图(EMG)、运动神经传导速度(MCV)、感觉神经传导速度(SCV).结果:主要症状有弓形足、垂足、鹤腿和腱反射消失;21例患者EMG出现纤颤电位、正锐波,25例患者运动单位电位(MUP)时限延长.14例患者下肢SCV未引出,12例患者下肢MCV未引出,正中神经SCV有6例未引出,而对应的MCV只有2例未引出.结论:该组CMT患者电生理特点为EMG呈神经原性损害.下肢神经病变重于上肢.感觉、运动神经均受累,感觉神经病变重于运动神经.神经电生理检查是诊断腓骨肌萎缩症的可靠方法.

  11. 腓骨肌萎缩症患者致病基因突变特点的研究%The characteristics of gene mutations in Chinese patients with Charcot-Marie-Tooth disease

    Institute of Scientific and Technical Information of China (English)

    张付峰; 张成; 潘乾; 蔡芳; 郭鹏; 唐北沙; 赵国华; 罗巍; 夏昆; 刘小民; 肖剑锋; 张如旭; 陈彪

    2005-01-01

    目的探讨腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)致病基因的突变特点.方法应用实时荧光定量PCR方法、聚合酶链反应-单链构象多态性分析(PCR-SSCP)或PCR直接测序等方法对113个确诊的CMT家系进行了PMP22、MPZ、CX32、EGR2、GDAP1、NEFL、HSP22、HSP27等致病基因进行突变检测.结果发现有36个家系为PMP22重复突变所致,7个家系为CX32基因突变所致,1个家系为MPZ基因突变所致,1个家系为GDAP1基因突变所致,1个家系为HSP22基因突变所致,1个家系为HSP27基因突变所致,未发现PMP22、EGR2和NEFL基因点突变.结论 CMT的PMP22基因重复突变所占比例为31.9%, CX32基因突变所占比例为6.2%, HSP22、HSP27、MPZ和GDAP1基因点突变所占比例均为0.9%,PMP22、EGR2和NEFL基因点突变少见.

  12. 腓骨肌萎缩症1型患者肌电图及PMP22基因特点分析%Electromyography and PMP22 gene analysis in patients with type 1 Charcot-Marie-Tooth disease

    Institute of Scientific and Technical Information of China (English)

    潘晓丽; 潘志宏; 张楠楠; 高红

    2015-01-01

    目的:探讨和研究腓骨肌萎缩症1型(Charcot‐Marie‐Tooth disease 1,CMT1)患者肌电图和 PMP22基因改变特点。方法对43例CM T1患者进行常规神经传导速度和肌电图检查,应用PCR双酶切方法对其中33例CM T1患者及15名健康志愿者(对照组)检测17p11.2‐12 PM P22基因重复序列(即1760 bp片段)。33例CM T1患者依有无17p11.2‐12 PM P22基因特异性片段分为 PM P22基因特异性片段阳性组与阴性组,比较两组患者神经传导改变有无差异。结果43例患者均行肌电图检测,均表现为运动或感觉神经传导速度存在明显减慢(100%),感觉神经病变重于运动神经,下肢受累程度重于上肢;所检129块肌肉中,88块(68.2%)呈神经源性损害。经 PM P22基因学检测的33例中20例(60.6%)检测出1760 bp片断,对照组均未检测到此片段。PM P22基因特异性片段阳性组感觉神经传导速度、运动神经传导速度及远端潜伏期与阴性组比较差异均无统计学意义(P>0.05)。结论 CMT1患者肌电图改变具有其特异性,结合PCR‐双酶切法检测 PMP22特异性基因重复序列可提高诊断CM T1的准确性及敏感性。%Objective To study the electromyography and PM P22 gene features in patients with type 1 Charcot‐Marie‐Tooth (CMT ) disease . Methods Routine electromyography and nerve conduction were performed in 43 patients with CMT 1 .Polymerase chain reaction (PCR) combined with restriction enzyme digestion was used to detect PMP22 gene duplication on chromosome 17p11.2‐12 (1760 bp) in 33 CMT 1 patients and 15 healthy volunteers (the control group) .According to the presence or absence of 17 p11.2‐12 PMP22 gene segments ,33 CMT 1 patients were divided into the positive group and the negative group . Parameters of nerve conduction were compared between two groups .Results All of the patients had the nerve conduction velocities slower or disappeared

  13. Perk Ablation Ameliorates Myelination in S63del-Charcot-Marie-Tooth 1B Neuropathy.

    Science.gov (United States)

    Musner, Nicolò; Sidoli, Mariapaola; Zambroni, Desireè; Del Carro, Ubaldo; Ungaro, Daniela; D'Antonio, Maurizio; Feltri, Maria L; Wrabetz, Lawrence

    2016-01-01

    In peripheral nerves, P0 glycoprotein accounts for more than 20% of myelin protein content. P0 is synthesized by Schwann cells, processed in the endoplasmic reticulum (ER) and enters the secretory pathway. However, the mutant P0 with S63 deleted (P0S63del) accumulates in the ER lumen and induces a demyelinating neuropathy in Charcot-Marie-Tooth disease type 1B (CMT1B)-S63del mice. Accumulation of P0S63del in the ER triggers a persistent unfolded protein response. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an ER stress sensor that phosphorylates eukaryotic initiation factor 2 alpha (eIF2alpha) in order to attenuate protein synthesis. We have shown that increasing phosphophorylated-eIF2alpha (P-eIF2alpha) is a potent therapeutic strategy, improving myelination and motor function in S63del mice. Here, we explore the converse experiment:Perkhaploinsufficiency reduces P-eIF2alpha in S63del nerves as expected, but surprisingly, ameliorates, rather than worsens S63del neuropathy. Motor performance and myelin abnormalities improved in S63del//Perk+/- compared with S63del mice. These data suggest that mechanisms other than protein translation might be involved in CMT1B/S63del neuropathy. In addition,Perkdeficiency in other cells may contribute to demyelination in a non-Schwann-cell autonomous manner.

  14. Postural stabilization and balance assessment in Charcot-Marie-Tooth 1A subjects.

    Science.gov (United States)

    Lencioni, T; Rabuffetti, M; Piscosquito, G; Pareyson, D; Aiello, A; Di Sipio, E; Padua, L; Stra, F; Ferrarin, M

    2014-09-01

    The aim of the present study was to assess postural stabilization skill in adult subjects affected by Charcot-Marie-Tooth disease (CMT) type 1A. For this purpose ground reaction force (GRF) was measured by means of a piezoelectric force platform during the sit-to-stand (STS) movement, until a steady state erect posture was achieved. Specific indexes to quantify Centre of Mass acceleration, both during postural stabilization and during quiet standing, were computed using a mathematical model. Forty-seven CMT1A subjects were recruited for the study, and the control group was formed by forty-one age- and sex-matched healthy subjects. The results show that CMT1A subjects are less stable than controls during the quiet stance. Greater difficulty (high values of Yinf, the final instability rate) to maintain erect posture appears to be mainly associated with plantar-flexor muscle weakness, rather than to damage of the proprioceptive system. The worst performances shown by CMT1A subjects in the stabilization phase (high values of I, the global index of postural stabilization performance) seem to be associated with reduced muscle strength and the loss of large sensory nerve fibres. Distal muscle weakness appears to affect both postural stabilization and quiet erect posture. The presented protocol and the analysis of postural stabilization parameters provide useful information on CMT1A balance disorders.

  15. Advances in the study of genetic characteristics and molecular mechanisms in Charcot-Marie-Tooth disease%腓骨肌萎缩症的遗传特征及致病机制的研究进展

    Institute of Scientific and Technical Information of China (English)

    徐汪洋; 孙莲花; 顾鸣敏

    2010-01-01

    腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)是一类常见的遗传性周围神经病,发病率约为1/2500.该病主要呈AD遗传,也可呈AR遗传及XD或XR遗传.据统计,与CMT相关的基因有33个[1],已确定的致病基因至少有27个,其中外周髓鞘蛋白22(peripheral myelin protein 22,PMP22)、髓鞘蛋白零(myelin protein zero,MPZ)和间隙连接蛋白32(connexin-32,Cx32)异常最受关注.近年来在突变基因特征及其致病机制方面取得的研究进展为该病的基因诊断和基因治疗奠定了基础.本文主要就上述内容作一综述.%Charcot-Marie-Tooth disease (CMT) is a kind of common hereditary peripheral neuropathy which incidence is estimated 1/2 500. The genetic pattern of this disease mainly shows autosomal dominant (AD) , also shows autosomal recessive inheritance ( AR) and X-linked dominant ( XD) , or recessive inheritance (XR). It was reported that there were 33 CMT-related genes[1]. Twenty-seven disease-causing genes were defined, including peripheral myelin protein 22 ( PMP22) , myelin protein zero ( MPZ) , and connexin 32 ( Cx32) , which had more relevant reports. In recent years, lots of new disease-causing genes have been defined, which laid the foundation for exploring neural degeneration and the pathogenesis of muscle atrophy and for the prevention or treatment of the disease through gene diagnosis and gene therapy. In this paper, the features of mutation genes and the mechanisms of disease-causing genes in CMT are reviewed.

  16. Clinical research of one family with Charcot-Marie-Tooth disease%一家系人群遗传性神经源性腓骨肌萎缩症的临床研究

    Institute of Scientific and Technical Information of China (English)

    邢军卫; 高颂轶; 刘小红; 谭璐; 张晓莉; 徐曼

    2011-01-01

    目的 探讨婴儿期起病的腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)一家系的遗传方式、临床特征、实验室及相关辅助检查、染色体核型及基因诊断等.方法 按照遗传学标准家系分析纲要对患者家族成员作调查,分析临床特征,做详细的体格检查,部分行血常规、血生化、头颅CT、染色体核型检查.绘制家系发病图谱,并进行遗传学分析和基因诊断.结果 先证者谱系代号为Ⅲ7,男性,5岁半.以发现双下肢进行性变细4年半就诊.家系4代41人中患病3人,死亡1例,均为男性,起病年龄为10月至1岁,所有患者均有肌肉萎缩,肢体无力,腱反射减弱或消失,跨阈步态.症状和体征随着年龄增长进行性加重.无明显智力低下.2名CMT患者及5名家系内表型正常者均发现17p11.2-p12区域内包含PMP22基因的重复突变,其亚型为CMT1A.结论 CMT是一种临床表型相似、由不同遗传方式引起的复杂性遗传性疾病,不同的临床表型由不同的基因突变引起;该家系遗传方式为常染色体显性遗传,临床分型为CMT1A;致病基因为17p11.2-p12区域内包含PMP22基因的重复突变.

  17. Charcot-Marie-Tooth and Related Diseases

    Science.gov (United States)

    ... of France, and Howard Henry Tooth of the United Kingdom. Although most people have never heard of CMT, ... CMT provided by patients and families. (See http://neurology.med. wayne.edu/neurogenetics/na_database. php.) MDA ...

  18. Learning about Charcot-Marie-Tooth Disease

    Science.gov (United States)

    ... function and balance, occasional lower leg and forearm muscle cramping, loss of some normal reflexes, occasional partial sight and/or hearing loss, and, in some individuals, scoliosis (curvature of the ... to the muscles - lose their protective outer coverings, their myelin sheaths. ...

  19. The same mutation Glu208Lys in the GJB1 gene was detected in 2 families with X-linked Charcot-Marie-Tooth Disease%在两个X连锁显性腓骨肌萎缩症家系中发现同一GJB1基因突变Glu208Lys

    Institute of Scientific and Technical Information of China (English)

    宋书娟; 闫明; 王小竹; 章远志; 邹俊华; 钟南

    2007-01-01

    在两个X连锁显性腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)家系中进行了GJB1基因的突变分析.提取基因组DNA,PCR(polymerase chain reaction)反应扩增GJBl基因编码序列,进行单链构象多态性(singlestrand conformational polymorphism,SSCP)分析,对有差异SSCP带型的PCR产物进行测序,结果在两家系中发现同一GJBl基因c.622G→A(GIu208Lys)突变.所发现的突变位点在国内尚未报道.

  20. 小热休克蛋白22基因在腓骨肌萎缩症中的突变分析%Mutation analysis of small heat-shock protein 22 gene in Chinese patients with Charcot-Marie-Tooth disease

    Institute of Scientific and Technical Information of China (English)

    张付峰; 胡正茂; 严新翔; 张如旭; 郭鹏; 唐北沙; 赵国华; 陈彪; 张成; 罗巍; 刘小民; 夏昆; 蔡芳

    2005-01-01

    Objective To study the characteristics of the mutation of small heat-shock protein 22 (HSP22) gene in Chinese patients with Charcot-Marie-Tooth (CMT)disease. Methods A CMT2L proband with 423(G→T) mutation in HSP22 gene had been studied and reported by the present authors. In this study, mutation analysis of HSP22 gene was performed using polymerase chain reaction and DNA direct sequencing in 114 CMT probands. Results In the 114 CMT probands, a 582(C→T)(T194T) samesense mutation was found in two unrelated families. Conclusion The rate of HSP22 gene mutation in Chinese patients with CMT is as low as 0.87%(1/115).%目的探讨小热休克蛋白22(small heat-shock protein 22, HSP22)基因在中国人腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)中的突变特点.方法应用聚合酶链反应和DNA直接测序方法,对1个发现HSP22基因423(G→T)突变的CMT2L家系外的114个CMT家系先证者进行了HSP22基因的突变分析.结果114个先证者中有2例患者在 HSP22基因的第3外显子发生了582(C→T)碱基改变,由于编码的氨基酸未改变,均为色氨酸(Thr),为一种同义突变.结论HSP22基因突变在中国人的腓骨肌萎缩症患者中少见,突变率为0.87%(1/115).

  1. Early-onset osteoarthritis, Charcot-Marie-Tooth like neuropathy, autoimmune features, multiple arterial aneurysms and dissections: an unrecognized and life threatening condition.

    Directory of Open Access Journals (Sweden)

    Mélodie Aubart

    Full Text Available BACKGROUND: Severe osteoarthritis and thoracic aortic aneurysms have recently been associated with mutations in the SMAD3 gene, but the full clinical spectrum is incompletely defined. METHODS: All SMAD3 gene mutation carriers coming to our centre and their families were investigated prospectively with a structured panel including standardized clinical workup, blood tests, total body computed tomography, joint X-rays. Electroneuromyography was performed in selected cases. RESULTS: Thirty-four SMAD3 gene mutation carriers coming to our centre were identified and 16 relatives were considered affected because of aortic surgery or sudden death (total 50 subjects. Aortic disease was present in 72%, complicated with aortic dissection, surgery or sudden death in 56% at a mean age of 45 years. Aneurysm or tortuosity of the neck arteries was present in 78%, other arteries were affected in 44%, including dissection of coronary artery. Overall, 95% of mutation carriers displayed either aortic or extra-aortic arterial disease. Acrocyanosis was also present in the majority of patients. Osteoarticular manifestations were recorded in all patients. Joint involvement could be severe requiring surgery in young patients, of unusual localization such as tarsus or shoulder, or mimicking crystalline arthropathy with fibrocartilage calcifications. Sixty eight percent of patients displayed neurological symptoms, and 9 suffered peripheral neuropathy. Electroneuromyography revealed an axonal motor and sensory neuropathy in 3 different families, very evocative of type II Charcot-Marie-Tooth (CMT2 disease, although none had mutations in the known CMT2 genes. Autoimmune features including Sjogren's disease, rheumatoid arthritis, Hashimoto's disease, or isolated autoantibodies- were found in 36% of patients. INTERPRETATION: SMAD3 gene mutations are associated with aortic dilatation and osteoarthritis, but also autoimmunity and peripheral neuropathy which mimics type II

  2. Silencing of the Charcot-Marie-Tooth disease-associated gene GDAP1 induces abnormal mitochondrial distribution and affects Ca2+ homeostasis by reducing store-operated Ca2+ entry.

    Science.gov (United States)

    Pla-Martín, David; Rueda, Carlos B; Estela, Anna; Sánchez-Piris, Maribel; González-Sánchez, Paloma; Traba, Javier; de la Fuente, Sergio; Scorrano, Luca; Renau-Piqueras, Jaime; Alvarez, Javier; Satrústegui, Jorgina; Palau, Francesc

    2013-07-01

    GDAP1 is an outer mitochondrial membrane protein that acts as a regulator of mitochondrial dynamics. Mutations of the GDAP1 gene cause Charcot-Marie-Tooth (CMT) neuropathy. We show that GDAP1 interacts with the vesicle-organelle trafficking proteins RAB6B and caytaxin, which suggests that GDAP1 may participate in the mitochondrial movement within the cell. GDAP1 silencing in the SH-SY5Y cell line induces abnormal distribution of the mitochondrial network, reduces the contact between mitochondria and endoplasmic reticulum (ER) and alters the mobilization of mitochondria towards plasma membrane upon depletion of ER-Ca(2+) stores. GDAP1 silencing does not affect mitochondrial Ca(2+) uptake, ER-Ca(2+), or Ca(2+) flow from ER to mitochondria, but reduces Ca(2+) inflow through store-operated Ca(2+) entry (SOCE) following mobilization of ER-Ca(2+) and SOCE-driven Ca(2+) entry in mitochondria. Our studies suggest that the pathophysiology of GDAP1-related CMT neuropathies may be associated with abnormal distribution and movement of mitochondria throughout cytoskeleton towards the ER and subplasmalemmal microdomains, resulting in a decrease in SOCE activity and impaired SOCE-driven Ca(2+) uptake in mitochondria.

  3. 中国人中发现一例Charcot-Marie-Tooth病连接蛋白32基因新突变%A new mutation in the connexin 32 gene was found in Charcot-Marie-Tooth disease in Chinese patients

    Institute of Scientific and Technical Information of China (English)

    笪宇威; 沈定国

    2000-01-01

    目的了解中国人进行性腓骨肌萎缩症(Charcot-Marie-Tooth disease, CMT)连接蛋白32(connexin 32,Cx32)基因外显子2的突变情况.方法对6例无亲缘关系的、无重复的CMT1患者和10例无亲缘关系的CMT2患者进行SSCP分析,对有异常者进行测序,根据突变点序列设计合适的内切酶,对50名正常对照进行酶切分析.结果在1例CMT1患者发生了Gly21Asp(62G→A)错义突变.用限制性内切酶H-aeⅡ酶切50名正常对照未见异常,表明该突变为致病性突变.结论 Gly21Asp是未报道过的新型突变,中国人CMT1患者中CMTX患者可能占一定比例.

  4. Mutation analysis of small heat-shock protein 27 gene in Chinese patients with Charcot-Marie-Tooth disease%中国人腓骨肌萎缩症小热休克蛋白27基因突变分析

    Institute of Scientific and Technical Information of China (English)

    刘小民; 唐北沙; 赵国华; 夏昆; 张付峰; 潘乾; 蔡芳; 胡正茂; 张成; 陈彪; 沈璐; 张如旭; 江泓

    2005-01-01

    目的探讨中国人腓骨肌萎缩症(Charcot-Marie-Tooth disease, CMT)小热休克蛋白27基因(small heat-shock protein 27, HSP27)的突变特点.方法应用聚合酶链反应结合DNA序列分析方法,对114个CMT家系的先证者进行 HSP27基因突变研究,并进一步对基因突变家系进行单体型分析.结果在4个常染色体显性遗传CMT2家系中发现一个 HSP27基因错义突变C379T,单体型分析提示这4个家系很可能具有共同祖先.结论中国人CMT患者存在 HSP27基因突变,但突变率较低(0.90%). HSP27基因C397T突变除引起远端型遗传性运动神经病外尚可导致CMT2,进一步证实同一CMT疾病基因的同一突变可引起不同的表现型.

  5. 缝隙连接蛋白B1基因I20T新突变导致伴有短暂性脑白质损害的X连锁Charcot-Marie-Tooth病1型%Transient white matter lesions in X-linked Charcot-Marie-Tooth disease type 1 with novel I20T mutation of gap junction protein beta 1 gene

    Institute of Scientific and Technical Information of China (English)

    栾兴华; 陈彬; 郑日亮; 张巍; 王朝霞; 袁云

    2009-01-01

    目的 报道1个伴有短暂性脑白质损害的X连锁Charcot-Marie-Tooth病1型(CMT1x)家系的临床、影像学和基因改变特点.方法 先证者为14岁男孩,出现短暂发作性言语不能和轻度肢体麻木无力2年5个月.其母亲存在弓形足.对先证者进行头颅MRI、神经电生理检查和腓肠神经活体组织检查;对先证者及其父母,50名女性无周围神经病及脑病对照者进行缝隙连接蛋白B1(GJB1)基因检测.结果 先证者周围神经的运动神经动作电位波幅显著下降,传导速度轻度减慢.听觉和体感诱发电位潜伏期明显延长.MRI显示胼胝体和大脑后部白质对称性异常信号,6个月后病变显著减轻.病理检查提示慢性轴索性周围神经病,电镜检查还可见有髓神经纤维的髓鞘施兰切迹加宽.先证者及其母亲GJB1基因存在I20T突变,其父和50名女性对照者无此突变.结论 伴短暂性脑白质损害的CMT1X可能与GJB1基因I20T新突变有关,其大脑白质的MR1改变具有可逆性.%Objective To describe the clinical, radiological and genetic features in a family with X-linked Charot-Marie-Tooth disease type 1 (CMT1X) with transient white matter lesions.Methods The proband is a 14-year-old boy who presented transient and recurrent dysarthria, mild numbness and weakness of the limbs for 2 years and 5 months.Later he developed leg weakness.His mother only presented pes cavus.MRI, electrophysiology and nerve biopsy were performed in the proband.Gap junction protein beta 1 (GJB1) gene was analyzed by PCR-sequencing on the proband, his parents and 50 non-illness control women.Results Electremyography showed marked reduced amplitude of the distal compound muscle action potentials and mild decrease of conduction velocities.MRI showed bilateral white matter lesions in centrum semiovale and corpus callnsum, which improved significantly after 6 months.Pathological examination revealed chronic axonal neuropathy and widened Schmidt

  6. Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies.

    Directory of Open Access Journals (Sweden)

    Ilaria Vaccari

    2011-10-01

    Full Text Available We previously reported that autosomal recessive demyelinating Charcot-Marie-Tooth (CMT type 4B1 neuropathy with myelin outfoldings is caused by loss of MTMR2 (Myotubularin-related 2 in humans, and we created a faithful mouse model of the disease. MTMR2 dephosphorylates both PtdIns3P and PtdIns(3,5P(2, thereby regulating membrane trafficking. However, the function of MTMR2 and the role of the MTMR2 phospholipid phosphatase activity in vivo in the nerve still remain to be assessed. Mutations in FIG4 are associated with CMT4J neuropathy characterized by both axonal and myelin damage in peripheral nerve. Loss of Fig4 function in the plt (pale tremor mouse produces spongiform degeneration of the brain and peripheral neuropathy. Since FIG4 has a role in generation of PtdIns(3,5P(2 and MTMR2 catalyzes its dephosphorylation, these two phosphatases might be expected to have opposite effects in the control of PtdIns(3,5P(2 homeostasis and their mutations might have compensatory effects in vivo. To explore the role of the MTMR2 phospholipid phosphatase activity in vivo, we generated and characterized the Mtmr2/Fig4 double null mutant mice. Here we provide strong evidence that Mtmr2 and Fig4 functionally interact in both Schwann cells and neurons, and we reveal for the first time a role of Mtmr2 in neurons in vivo. Our results also suggest that imbalance of PtdIns(3,5P(2 is at the basis of altered longitudinal myelin growth and of myelin outfolding formation. Reduction of Fig4 by null heterozygosity and downregulation of PIKfyve both rescue Mtmr2-null myelin outfoldings in vivo and in vitro.

  7. LITAF、RAB7、LMNA和MTMR2基因在中国人腓骨肌萎缩症患者的突变分析%Mutation analysis of LITAF,RAB7,LMNA and MTMR2 genes in Chinese Charcot-Marie-Tooth disease

    Institute of Scientific and Technical Information of China (English)

    张如旭; 唐北沙; 郭鹏; 任志军; 赵国华; 刘三妹; 刘婷; 资晓宏; 胡正茂; 夏昆

    2010-01-01

    为了分析LITAF、RAB7、LMNA和MTMR2基因在中国人腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)的突变特点,文章分别应用PCR结合DNA序列分析方法和PCR-单链构象多态性(PCR-SSCP)结合DNA序列分析方法对6个常染色体显性遗传家系先证者和27个散发病例进行LITAF和RAB7基因突变分析;应用PCR-SSCP结合DNA序列分析方法对14个常染色体遗传的CMT家系先证者和27个散发患者进行LMNA和MTMR2基因突变分析.结果发现:LITAF基因c.269G→A、c.274A→G序列变异和LMNA基因c.1243G→A、c.1910C→T序列变异.未发现RAB7和MTMR2基因的序列变异.其中LITAF基因c.269G→A,LMNA基因c.1243G→A和c.1910C→T为新发现的单核苷酸多态;LITAF基因c.274A→G为已知多态.说明LITAF、RAB7、LMNA和MTMR2基因突变在中国人CMT患者中罕见.

  8. 伴有脑干听觉诱发电位异常的腓骨肌萎缩症发现连接蛋白32基因新突变%A new mutation in the connexin 32 gene of a Chinese family with Charcot-Marie-Tooth disease associated with central conduction slowing

    Institute of Scientific and Technical Information of China (English)

    罗巍; 唐北沙; 赵国华; 夏昆; 羊毅; 萧剑锋; 严新翔; 杨期东; 夏家辉

    2002-01-01

    目的报告一个脑干听觉诱发电位有异常改变的腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)家系,并探讨与连接蛋白32(connexin 32,Cx32)基因突变的关系.方法对整个家系进行临床检查,对先证者进行肌电图及脑干听觉诱发电位检查,并应用聚合酶链式反应-单链构象多态(polymerase chain reaction-single strand conformation polymorphism, PCR-SSCP)技术结合DNA序列分析方法检测了先证者、家系内8人及家系外50名无血缘关系的正常人. 结果先证者肌电图检查示神经传导速度明显减慢,脑干听觉诱发电位示中枢传导延长,该家系中先证者及另3人均出现异常SSCP条带,经测序证实为392T→C(Leu131Pro)突变. 结论 Leu131Pro是未报道过的突变,腓骨肌萎缩症患者可以出现脑干听觉诱发电位异常.

  9. Analysis of the clinical, electrophysiological and histopathological features of Chinese Charcot-Marie Tooth disease patients with small heat-shock protein 27 gene mutation%小热休克蛋白27基因突变所致腓骨肌萎缩症患者的临床、电生理和病理特点

    Institute of Scientific and Technical Information of China (English)

    刘小民; 唐北沙; 赵国华; 夏昆; 张付峰; 严新翔; 肖岚

    2005-01-01

    目的探讨小热休克蛋白27基因(small heat-shock protein 27,Hsp27)突变所致腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)患者的临床、电生理和病理特点.方法对发现Hsp27基因同一突变(C379T)的4个常染色体显性遗传CMT2家系的7例患者的临床表现、电生理和病理检查进行回顾性分析.结果患者主要临床特点为35~60岁发病,平均病程(17.6±6.6)年,发病后平均(12.6±4.9)年需要扶拐杖行走,平均(20.7±5.7)年完全丧失行走能力;患者感觉障碍轻,神经电生理示下肢神经传导速度呈中至重度减慢,但上肢正常或轻度减慢,神经活检证实为慢性轴突性神经病,肌肉活检显示神经原性肌萎缩.结论Hsp27基因C397T突变可引起CMT2表现型,突变家系的临床表现与文献报道的该基因突变CMT2F家系有所不同.

  10. A new mutation in the GJB1 gene of a Chinese family with Charcot-Marie-Tooth disease associated with vocal cord paresis%伴声带麻痹的X连锁腓骨肌萎缩症GJB1基因新突变

    Institute of Scientific and Technical Information of China (English)

    李清华; 蒋静子; 刘开祥; 俸军林; 曾爱源; 李浩; 吴岚; 唐永刚; 陈梅玲; 林小慧

    2010-01-01

    Objective To report an X-linked dominant Charcot-Marie-Tooth disease (CMTX) Chinese family with vocal cord paresis and to identify the mutation of gap junction protein beta 1 gene (GJB1). Methods Part of the family members with dysphagia, dysphonia and lethal respiratory failure were studied through flexible laryngoscope, clinical, brain MRI and electrophysiological examinations. After excluding large fragment tandem duplication containing peripheral myelin protein 22 gene (PMP22), direct sequencing was performed to analyze the mutation of the GJB1 gene in 5 patients including the proband, 5 unaffected family members and 50 unrelated healthy individuals. Results Eight members spanning 3 generations in this family were affected with CMTX characterized by progressive atrophy and weakness of the anterior tibial and peroneal muscles, especially in the proband. Vocal cord paresis was observed through flexible laryngoscope in total of 4 affected members with dysarthria and dysphagia, 2 of them died of severe respiratory failure due to complete bilateral vocal cord involvement. Normal brain MRI was observed in the proband. The electrophysiological data showed predominant demyelization involving the motor and sensory nerves in the proband. DNA sequencing revealed a de novo c. 186 C>G missense mutation in exon 2 of the GJB1 gene, the mutation cosegregated with phenotype. Conclusion Respiratory failure associated with vocal cord involvement may be a rare and severe symptom in CMTX. The present report provides further evidence for clinical and genetic heterogeneity in the X-linked Charcot-Marie-Tooth disease.%目的 报告1个临床可疑的伴声带麻痹的X连锁显性遗传腓骨肌萎缩症(X-1inked Charcot-Marie-Tooth disease,CMTX)家系,并探讨与连接蛋白(gap jurction protein beta 1,GJB1)基因突变的关系.方法 对1个具有声音嘶哑、吞咽困难、致死性呼吸衰竭的临床可疑的CMTX家系进行临床、纤维喉镜、头部MRI及电生理检

  11. Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3

    Science.gov (United States)

    Brewer, Megan H.; Chaudhry, Rabia; Qi, Jessica; Kidambi, Aditi; Drew, Alexander P.; Ryan, Monique M.; Subramanian, Gopinath M.; Young, Helen K.; Zuchner, Stephan; Reddel, Stephen W.; Nicholson, Garth A.; Kennerson, Marina L.

    2016-01-01

    With the advent of whole exome sequencing, cases where no pathogenic coding mutations can be found are increasingly being observed in many diseases. In two large, distantly-related families that mapped to the Charcot-Marie-Tooth neuropathy CMTX3 locus at chromosome Xq26.3-q27.3, all coding mutations were excluded. Using whole genome sequencing we found a large DNA interchromosomal insertion within the CMTX3 locus. The 78 kb insertion originates from chromosome 8q24.3, segregates fully with the disease in the two families, and is absent from the general population as well as 627 neurologically normal chromosomes from in-house controls. Large insertions into chromosome Xq27.1 are known to cause a range of diseases and this is the first neuropathy phenotype caused by an interchromosomal insertion at this locus. The CMTX3 insertion represents an understudied pathogenic structural variation mechanism for inherited peripheral neuropathies. Our finding highlights the importance of considering all structural variation types when studying unsolved inherited peripheral neuropathy cases with no pathogenic coding mutations. PMID:27438001

  12. Balance and muscle power of children with Charcot-Marie-Tooth

    Directory of Open Access Journals (Sweden)

    Tais R. Silva

    2014-08-01

    Full Text Available BACKGROUND: In certain diseases, functional constraints establish a greater relationship with muscle power than muscle strength. However, in hereditary peripheral polyneuropathies, no such relationship was found in the literature. OBJECTIVE: In children with Charcot-Marie-Tooth (CMT, to identify the impact of muscle strength and range of movement on the static/dynamic balance and standing long jump based on quantitative and functional variables. METHOD: The study analyzed 19 participants aged between 6 and 16 years, of both genders and with clinical diagnoses of CMT of different subtypes. Anthropometric data, muscle strength of the lower limbs (hand-held dynamometer, ankle and knee range of movement, balance (Pediatric Balance Scale and standing long jump distance were obtained by standardized procedures. For the statistical analysis, Pearson and Spearman correlation coefficients were used. RESULTS: There was a strong positive correlation between balance and the muscle strength of the right plantar flexors (r=0.61 and dorsiflexors (r=0.59 and a moderate correlation between balance and the muscle strength of inversion (r=0.41 and eversion of the right foot (r=0.44. For the long jump and range of movement, there was a weak positive correlation with right and left plantar flexion (r=0.20 and r=0.12, respectively and left popliteal angle (r=0.25, and a poor negative correlation with left dorsiflexion (r=-0.15. CONCLUSIONS: The data on the patients analyzed suggests that the maintenance of distal muscle strength favors performance during balance tasks, while limitations in the range of movement of the legs seem not to be enough to influence the performance of the horizontal long jump.

  13. Tripod pinch strength and thumb opposition are the major determinants of manual dexterity in CharcoteMarieeTooth disease type 1A

    NARCIS (Netherlands)

    Videler, Annemieke J.; Beelen, Anita; van Schaik, Ivo N.; Verhamme, Camiel; van den Berg, Leonard H.; de Visser, Marianne; Nollet, Frans

    2010-01-01

    Background Clinical features of Charcot-Marie-Tooth disease type 1A (CMT1A) include slowly progressive distal muscle weakness, atrophy and sensory loss. Upper-limb involvement results in reduced manual dexterity interfering with the execution of daily activities. Objective To identify which hand fun

  14. Clinical features and gene mutations of Chinese patients with autosomal dominant Charcot-Marie-Tooth disease%常染色体显性遗传腓骨肌萎缩症的临床与基因突变特点

    Institute of Scientific and Technical Information of China (English)

    郭鹏; 宋福聪; 王相斌; 冯文霞; 胡志强; 唐北沙; 夏昆

    2011-01-01

    Objective To analyze the characteristics of the clinical features and the gene mutations between Chinese patients with autosomal dominant Charcot-Marie-Tooth disease. Methods The clinical manifestations, electrophysiological and pathological investigations of patients with autosomal dominant Charcot-Marie-Tooth were analyzed retrospectively. One hundred and six CMT patients underwent mutation analysis of PMP22 duplication and PMP22, MPZ, SIMPLE, EGR2, RAB7,NEFL,MFN2,Hsp27 and Hsp22. Results CMT1A was caused by PMP22 duplication,and CMT1B was caused by MPZ mutation. In those patients,the age of onset were earlier. The most frequently first symptom was weakness and atrophy in lower limbs with hypesthesia. Physical examination showed distal limb weakness and wasting,and taplipes cavus in all of them. Electromyogram and nerve conduction velocity showed slow nerve conduction. Pathological examination showed demye-lination. CMT2A2 was caused by MFN2 mutation,CMT2F wag caused by Hsp27 mutation,and CMT2L was caused by Hsp22 mutation. Compared with CMT1 ,patients of CMT2 were less frequent,the age of onset were later,motor disability was more sever than sensory disability. Electromyogram and nerve conduction velocity was normal. Pathological examination showed axonal denaturation. Conclusions In this study, the results of the mutation screening were consistent with the clinical features. Mutation screening has the character of high accuracy,little harm and can help to diagnosis earlier,so it suggestes to be performed widely in the clinic especially to the patients who has family history or to the lineal relatives.%目的:探讨常染色体显性遗传腓骨肌萎缩症(CMT)患者的临床与基因突变的特点。方法:对43个常染色体显性遗传CMT家系共106例患者的临床表现、电生理和病理特点进行回顾性分析,并进行PMP22的大片段重复突变和PMP22、MPZ、SIMPLE、EGR2、RAB7、NEFL、MFN2、Hsp27及Hsp22

  15. Lower extremity muscles activity in standing and sitting position with use of sEMG in patients suffering from Charcot-Marie-Tooth syndrome.

    Science.gov (United States)

    Kuciel, Natalia Maria; Konieczny, Grzegorz Krzysztof; Oleksy, Łukasz; Wrzosek, Zdzisława

    2016-01-01

    There is very limited, evidenced data about movement possibilities in patients with high level of lower limb muscles atrophy and fatigue in patients suffering from Charcot-Marie-Tooth syndrome. Patient (age 46) suffering from Charcot-Marie-Tooth disease for 30 years with multiple movement restrictions and muscles atrophy above knees took part into the study. Tests were performed for 8 muscles of the lower limb and pelvis. Muscles electrical activity was tested in sitting and standing position (for knees extended and hyperextended). In the right leg rectus femoris, vastus lateralis obliquus, gluteus medius and semitendinosus muscles activated at first and were working the longest time. The highest activity was observed in standing position with knees extended. In the left leg rectus femoris and biceps femoris muscles activated at first and biceps femoris was working the longest time. Activity level in left lower limb is much lower than in the right one. Muscles weakness is asymmetric. Left leg is much weaker and engages antagonists and synergists muscles to compensate weaker rectus femoris, vastus medialis obliquus and vastus lateralis obliquus.

  16. Auditory Function in Children with Charcot-Marie-Tooth Disease

    Science.gov (United States)

    Rance, Gary; Ryan, Monique M.; Bayliss, Kristen; Gill, Kathryn; O'Sullivan, Caitlin; Whitechurch, Marny

    2012-01-01

    The peripheral manifestations of the inherited neuropathies are increasingly well characterized, but their effects upon cranial nerve function are not well understood. Hearing loss is recognized in a minority of children with this condition, but has not previously been systemically studied. A clear understanding of the prevalence and degree of…

  17. Causes of Charcot-Marie-Tooth Disease (CMT)

    Science.gov (United States)

    ... axons , extend from sensory nerve cells in the body's periphery back toward the spinal cord, and from muscle-controlling nerve cells in the spinal cord out toward the muscles. Axons transmit electrical signals for sensation and movement to and from the ...

  18. Genetics Home Reference: Charcot-Marie-Tooth disease

    Science.gov (United States)

    ... SBF2 (CMT4B2), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), FGD4 (CMT4H), and FIG4 (CMT4J). Intermediate forms ... MED25 MFN2 MPZ MTMR2 NDRG1 NEFL PMP22 PRPS1 PRX RAB7A SBF2 SH3TC2 TRPV4 YARS Related Information What ...

  19. Improving molecular diagnosis of Chinese patients with Charcot-Marie-Tooth by targeted next-generation sequencing and functional analysis.

    Science.gov (United States)

    Li, Li-Xi; Zhao, Shao-Yun; Liu, Zhi-Jun; Ni, Wang; Li, Hong-Fu; Xiao, Bao-Guo; Wu, Zhi-Ying

    2016-05-10

    Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy. More than 50 causative genes have been identified. The lack of genotype-phenotype correlations in many CMT patients make it difficult to decide which genes are affected. Recently, targeted next-generation sequencing (NGS) has been introduced as an alternative approach for diagnosis of genetic disorders. Here, we applied targeted NGS in combination with PMP22 duplication/deletion analysis to screen causative genes in 22 Chinese CMT families. The novel variants detected by targeted NGS were then further studied in cultured cells. Of the 22 unrelated patients, 8 had PMP22 duplication. The targeted NGS revealed 10 possible pathogenic variants in 11 patients, including 7 previously reported variants and 3 novel heterozygous variants (GJB1: p.Y157H; MFN2: p.G127S; YARS: p.V293M). Further classification of the novel variants according to American College of Medical Genetics and Genomics (ACMG) standards and guidelines and functional analysis in cultured cells indicated that p.Y157H in GJB1 was pathogenic, p.G127S in MFN2 was likely pathogenic, while p.V293M in YARS was likely benign. Our results suggest the potential for targeted NGS to make a more rapid and precise diagnosis in CMT patients. Moreover, the functional analysis is required when the novel variants are indistinct.

  20. Improving molecular diagnosis of Chinese patients with Charcot-Marie-Tooth by targeted next-generation sequencing and functional analysis

    Science.gov (United States)

    Liu, Zhi-Jun; Ni, Wang; Li, Hong-Fu; Xiao, Bao-Guo; Wu, Zhi-Ying

    2016-01-01

    Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy. More than 50 causative genes have been identified. The lack of genotype-phenotype correlations in many CMT patients make it difficult to decide which genes are affected. Recently, targeted next-generation sequencing (NGS) has been introduced as an alternative approach for diagnosis of genetic disorders. Here, we applied targeted NGS in combination with PMP22 duplication/deletion analysis to screen causative genes in 22 Chinese CMT families. The novel variants detected by targeted NGS were then further studied in cultured cells. Of the 22 unrelated patients, 8 had PMP22 duplication. The targeted NGS revealed 10 possible pathogenic variants in 11 patients, including 7 previously reported variants and 3 novel heterozygous variants (GJB1: p.Y157H; MFN2: p.G127S; YARS: p.V293M). Further classification of the novel variants according to American College of Medical Genetics and Genomics (ACMG) standards and guidelines and functional analysis in cultured cells indicated that p.Y157H in GJB1 was pathogenic, p.G127S in MFN2 was likely pathogenic, while p.V293M in YARS was likely benign. Our results suggest the potential for targeted NGS to make a more rapid and precise diagnosis in CMT patients. Moreover, the functional analysis is required when the novel variants are indistinct. PMID:27027447

  1. Two novel mutations in the GDAP1 and PRX genes in early onset Charcot-Marie-Tooth syndrome.

    Science.gov (United States)

    Auer-Grumbach, M; Fischer, C; Papić, L; John, E; Plecko, B; Bittner, R E; Bernert, G; Pieber, T R; Miltenberger, G; Schwarz, R; Windpassinger, C; Grill, F; Timmerman, V; Speicher, M R; Janecke, A R

    2008-02-01

    Autosomal recessive Charcot-Marie-Tooth syndrome (AR-CMT) is often characterised by an infantile disease onset and a severe phenotype. Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene are thought to be a common cause of AR-CMT. Mutations in the periaxin (PRX) gene are rare. They are associated with severe demyelination of the peripheral nerves and sometimes lead to prominent sensory disturbances. To evaluate the frequency of GDAP1 and PRX mutations in early onset CMT, we examined seven AR-CMT families and 12 sporadic CMT patients, all presenting with progressive distal muscle weakness and wasting. In one family also prominent sensory abnormalities and sensory ataxia were apparent from early childhood. In three families we detected four GDAP1 mutations (L58LfsX4, R191X, L239F and P153L), one of which is novel and is predicted to cause a loss of protein function. In one additional family with prominent sensory abnormalities a novel homozygous PRX mutation was found (A700PfsX17). No mutations were identified in 12 sporadic cases. This study suggests that mutations in the GDAP1 gene are a common cause of early-onset AR-CMT. In patients with early-onset demyelinating AR-CMT and severe sensory loss PRX is one of the genes to be tested.

  2. Mitochondrial defects and neuromuscular degeneration caused by altered expression of Drosophila Gdap1: implications for the Charcot-Marie-Tooth neuropathy.

    Science.gov (United States)

    López Del Amo, Víctor; Seco-Cervera, Marta; García-Giménez, José Luís; Whitworth, Alexander J; Pallardó, Federico V; Galindo, Máximo Ibo

    2015-01-01

    One of the genes involved in Charcot-Marie-Tooth (CMT) disease, an inherited peripheral neuropathy, is GDAP1. In this work, we show that there is a true ortholog of this gene in Drosophila, which we have named Gdap1. By up- and down-regulation of Gdap1 in a tissue-specific manner, we show that altering its levels of expression produces changes in mitochondrial size, morphology and distribution, and neuronal and muscular degeneration. Interestingly, muscular degeneration is tissue-autonomous and not dependent on innervation. Metabolic analyses of our experimental genotypes suggest that alterations in oxidative stress are not a primary cause of the neuromuscular degeneration but a long-term consequence of the underlying mitochondrial dysfunction. Our results contribute to a better understanding of the role of mitochondria in CMT disease and pave the way to generate clinically relevant disease models to study the relationship between mitochondrial dynamics and peripheral neurodegeneration.

  3. Diagnóstico clínico de la enfermedad Charcot-Marie-Tooth

    Directory of Open Access Journals (Sweden)

    Yuselis Pérez Cid

    2014-08-01

    Full Text Available La enfermedad de Charcot-Marie-Tooth es un trastorno polineuropático genéticamente heterogéneo, en la que se han identificado más de 30 genes responsables; sin embargo, el diagnóstico es posible establecerlo sobre las bases de los estudios clínicos y electrofisiológicos. Constituye un reto en la práctica médica de los países del tercer mundo contar con la realización sistemática de estudios genéticos moleculares de las neuropatías hereditarias, por lo que en este trabajo se enfatiza en los estudios clínico-electrofisiológicos para la clasificación de la CMT

  4. Assessment of upper motor neuron dysfunction by triple stimulation technique in patients with Charcot-Marie-Tooth disease%三重刺激技术对腓骨肌萎缩症上运动神经元损害的评估

    Institute of Scientific and Technical Information of China (English)

    徐迎胜; 张朔; 刘小璇; 孙阿萍; 樊东升

    2016-01-01

    目的 对腓骨肌萎缩症(CMT)患者进行三重刺激技术(TST)检测,探索其上运动神经元(UMN)损害的亚临床证据,以期为致病基因的筛选提供依据.方法 分析2013年8月至2015年8月于北京大学第三医院神经内科就诊的经基因检测确诊的CMT患者65例.对其进行临床查体、神经电生理检测,主要观察锥体束征和TST检测(包括经颅磁刺激、外周神经刺激、对冲技术等)结果,计算TST test/TST control波幅比,判断其上运动神经元功能状况.结果 临床查体发现7例患者下肢腱反射亢进,Babinski征阳性,肌张力增高,其中2例合并上肢腱反射亢进,Hoffmann征阳性.10例患者TST test/TST control波幅比下降(其中5例下肢腱反射亢进,Babinski征阳性,2例合并上肢腱反射亢进,Hoffmann征阳性).对应的致病基因:MFN2基因突变5例,BSCL2基因突变1例,3例GJB1基因突变,GDAP基因突变1例.根据临床查体和TST结果,18.5%(12例)的患者存在上运动神经元损害.结论 CMT患者可存在上运动神经元损害,据此可进行相关致病基因检测.%Objective To investigate the presence of upper motor neuron dysfunction in patients with Charcot-Marie-Tooth disease (CMT) by triple stimulation technique (TST) to provide evidence for gene diagnosis.Methods A total of 65 CMT patients confirmed by genetic testing from Peking University Third Hospital between August 2013 and August 2015,underwent physical examination and routine electrophysiological tests and triple stimulation technique.The TST combined transcranial magnetic stimulation (TMS) of the motor cortex with peripheral collision studies.The results were expressed by the TST amplitude ratio (TST test/TST control).Based on the result of physical examination and the ratio of TST,the function of upper motor neuron was assessed.Results All of the CMT patients had typical presentations and were confirmed genetically.Hyperreflexia,Babinski sign and muscular hypertonia were

  5. 腓骨肌萎缩症1型18例电生理分析%Electrophysiological analysis of Charcot-Marie-Tooth disease type

    Institute of Scientific and Technical Information of China (English)

    张家良; 梅翠红

    2006-01-01

    目的 分析腓骨肌萎缩症1型(Charcot-Marie-Tooth病,CMT1)电生理特点.方法 应用肌电图仪检测和分析来自12家系18例CMT1型病人的电生理特征,包括肌电图(EMG)、运动神经传导速度(MCV)和感觉神经传导速度(SCV).结果 15例的病人肌电图上出现纤颤、正相电位,15例病人有运动电位时限延长.正中神经SCV有13例未测出,而对应的MCV只有1例未测出.腓总神经、胫神经的MCV分别有9、10例未测出而正中神经MCV只有1例未测出.结论 电生理特点为下肢神经病变重于上肢,感觉神经病变重于运动神经.感觉、运动神经均受累,不同病人受累程度不一致;CMT1型病人同一家系,表现存在差异.

  6. 剔除小鼠神经微管运动蛋白Kif1b基因导致类似Charcot-Marie-Tooth病动物模型%Neuronal microtubule motor protein Kif1b gene knockout mice as animal model of Charcot-Marie-Tooth disease

    Institute of Scientific and Technical Information of China (English)

    董铭; 于澎; 饶明俐; 田中庸介

    2007-01-01

    目的 研究杂合子小鼠Kif1b基因剔除后导致的表现型,探讨其作为类似Charcot-Marie-Tooth(CMT)病动物模型的可行性.方法 用Southern blotting和PCR检测同源重组和基因型,Western blotting测定杂合子KIF1B蛋白表达量,行为学实验观察其表现型.结果 杂合子Kif1b基因剔除小鼠的KIF1B蛋白表达量减少了一半以上,行为学实验结果表明,杂合子基因剔除小鼠在运动和感觉方面均有异常.Rota-rod实验,Rod walking实验和Wire hanging实验中,野生型小鼠的停留时间均明显长于Kif1b基因剔除小鼠.同时,杂合子Kif1b基因剔除小鼠在热板实验和福尔马林实验中,表现出对温度觉和痛觉反应的迟钝,其反应时间与野生型小鼠相比明显延长,反应强度降低.结论 杂合子Kif1b基因剔除小鼠的表现型与人类腓骨肌萎缩症相似,作为疾病模型具备可行性.

  7. GDAP1 mutations in Italian axonal Charcot-Marie-Tooth patients: Phenotypic features and clinical course.

    Science.gov (United States)

    Pezzini, I; Geroldi, A; Capponi, S; Gulli, R; Schenone, A; Grandis, M; Doria-Lamba, L; La Piana, C; Cremonte, M; Pisciotta, C; Nolano, M; Manganelli, F; Santoro, L; Mandich, P; Bellone, E

    2016-01-01

    Mutations in the ganglioside-induced differentiation associated-protein 1 (GDAP1) gene have been associated with both autosomal recessive (AR) and dominant (AD) Charcot-Marie-Tooth (CMT) axonal neuropathy. The relative frequency of heterozygous, dominant mutations in Italian CMT is unknown. We investigated the frequency of dominant mutations in GDAP1 in a cohort of 109 axonal Italian patients by sequencing genomic DNA and search for copy number variations. We also explored correlations with clinical features. All cases had already been tested for variants in common axonal AD genes. Eight patients (7.3%) harbored five already reported heterozygous mutations in GDAP1 (p.Arg120Gly, p.Arg120Trp, p.His123Arg, p.Gln218Glu, p.Arg226Ser). Mutations had different penetrances in the families; the onset of symptoms is in the first decade and progression is slower than usually seen in GDAP1-related AR-CMT. We show that the relative frequency of mutations in GDAP was slightly higher than those observed in MFN2 and MPZ (7.3% vs 6.3% and 5.0%). The relatively milder clinical features and the quite indolent course observed are relevant for prognostic assessment. On the basis of our experience and the data reported here, we suggest GDAP1 as the first gene that should be analysed in Italian patients affected by CMT2.

  8. 神经超声在Chacot-Marie-Tooth1型和慢性炎性脱髓鞘性多发性神经根神经病鉴别诊断中的价值%The utility of peripheral nerve ultrasound in differentiating Charcot-Marie-Tooth type 1 from chronic inflammatory demyelinating polyradiculoneuropathy

    Institute of Scientific and Technical Information of China (English)

    刘明生; 牛婧雯; 李亦; 吴双; 管宇宙; 崔丽英

    2016-01-01

    CharcotMarie-Tooth type 1 (CMT1) from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).Methods Eighteen patients with CIDP,13 patients with CMT1 and 16 healthy controls were recruited prospectively from Peking Union Medical College Hospital between January 2014 and July 2015 for this study.Ultrasonographic tests were performed via nerve tracing from wrist to axilla on median and ulnar nerve with a 10 MHz linear array probe.The cross sectional areas (CSAs) were measured at 10 defined sites of the nerves,respectively.Results CSAs (mm2) at all sites of median nerve were significantly increased in CMT1 than in CIDP (10.5 ±5.3 vs7.8 ±2.4,10.9 ±3.6 vs 6.8 ±1.9,11.5 ±5.0 vs7.3 ±1.8,13.5 ± 4.4vs7.2±2.5,16.0±4.5vs7.2±2.1,17.1±5.1vs7.0±2.8,21.0±4.5vs9.5±4.8,24.3±6.9 vs 9.5 ±4.3,23.9 ±6.0 vs 10.2 ±4.3,22.4 ±6.7 vs 9.8 ±2.1;t=2.141,4.766,2.935,4.858,6.715,6.602,7.148,7.100,8.078,6.498,respectively,all P < 0.05).CSAs (mm2) at all sites of ulnar nerve were significantly increased in CMT1 than in CIDP (7.9 ± 1.8 vs 4.0 ± 1.3,8.9 ± 2.0 vs 4.9 ± 1.3,13.5±1.9 vs6.5±2.4,15.0±4.3 vs 6.5 ±1.5,15.8 ±4.4 vs 6.8 ±3.3,11.6±2.3 vs6.9± 3.1,10.2±3.2vs7.6±2.8,14.0±3.0vs6.6±2.1,19.2±3.7vs7.6±4.4,18.1±3.6vs6.3± 2.5;t =7.652,7.414,9.194,6.893,6.443,4.766,2.561,7.897,8.113,11.554,respectively,all P < 0.05).CSAs at 8 sites of median nerve and 8 sites of ulnar nerve were significantly increased in CIDP than in healthy controls.Receiver operation characteristic curve analysis revealed that CSA was suited for differentiating CMT1 from CIDP,and the area under curve in 8 sites of median nerve and 9 sites in ulnar nerve was more than 0.9.Conclusions CSAs measured at different sites by peripheral nerve ultrasound in CMT1 were significantly increased than in CIDP.Measurement of CSAs by peripheral nerve ultrasound can be used for differentiating CMTI from CIDP.

  9. Muscle-specific function of the centronuclear myopathy and Charcot-Marie-Tooth neuropathy-associated dynamin 2 is required for proper lipid metabolism, mitochondria, muscle fibers, neuromuscular junctions and peripheral nerves.

    Science.gov (United States)

    Tinelli, Elisa; Pereira, Jorge A; Suter, Ueli

    2013-11-01

    The ubiquitously expressed large GTPase Dynamin 2 (DNM2) plays a critical role in the regulation of intracellular membrane trafficking through its crucial function in membrane fission, particularly in endocytosis. Autosomal-dominant mutations in DNM2 cause tissue-specific human disorders. Different sets of DNM2 mutations are linked to dominant intermediate Charcot-Marie-Tooth neuropathy type B, a motor and sensory neuropathy affecting primarily peripheral nerves, or autosomal-dominant centronuclear myopathy (CNM) presenting with primary damage in skeletal muscles. To understand the underlying disease mechanisms, it is imperative to determine to which degree the primary affected cell types require DNM2. Thus, we used cell type-specific gene ablation to examine the consequences of DNM2 loss in skeletal muscle cells, the major relevant cell type involved in CNM. We found that DNM2 function in skeletal muscle is required for proper mouse development. Skeletal muscle-specific loss of DNM2 causes a reduction in muscle mass and in the numbers of muscle fibers, altered muscle fiber size distributions, irregular neuromuscular junctions (NMJs) and isolated degenerating intramuscular peripheral nerve fibers. Intriguingly, a lack of muscle-expressed DNM2 triggers an increase of lipid droplets (LDs) and mitochondrial defects. We conclude that loss of DNM2 function in skeletal muscles initiates a chain of harmful parallel and serial events, involving dysregulation of LDs and mitochondrial defects within altered muscle fibers, defective NMJs and peripheral nerve degeneration. These findings provide the essential basis for further studies on DNM2 function and malfunction in skeletal muscles in health and disease, potentially including metabolic diseases such as diabetes.

  10. Moléstia de Charcot-Marie-Tooth: conceito clínico-patológico atual

    Directory of Open Access Journals (Sweden)

    José Antonio Levy

    1962-06-01

    Full Text Available Após considerações sobre o quadro anátomo-patológico da moléstia de Charcot-Marie-Tooth, o autor relata 4 casos, chegando à conclusão de que esta moléstia pode ser considerada como uma neuromiopatia em virtude de algumas alterações histopatológicas musculares serem primárias, ao passo que outras são secundárias à lesão do neurônio motor periférico.

  11. A brief review of recent Charcot-Marie-Tooth research and priorities [v1; ref status: indexed, http://f1000r.es/53g

    Directory of Open Access Journals (Sweden)

    Sean Ekins

    2015-02-01

    Full Text Available This brief review of current research progress on Charcot-Marie-Tooth (CMT disease is a summary of discussions initiated at the Hereditary Neuropathy Foundation (HNF scientific advisory board meeting on November 7, 2014. It covers recent published and unpublished in vitro and in vivo research. We discuss recent promising preclinical work for CMT1A, the development of new biomarkers, the characterization of different animal models, and the analysis of the frequency of gene mutations in patients with CMT. We also describe how progress in related fields may benefit CMT therapeutic development, including the potential of gene therapy and stem cell research. We also discuss the potential to assess and improve the quality of life of CMT patients. This summary of CMT research identifies some of the gaps which may have an impact on upcoming clinical trials. We provide some priorities for CMT research and areas which HNF can support. The goal of this review is to inform the scientific community about ongoing research and to avoid unnecessary overlap, while also highlighting areas ripe for further investigation. The general collaborative approach we have taken may be useful for other rare neurological diseases.

  12. Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients.

    Science.gov (United States)

    Rudnik-Schöneborn, S; Tölle, D; Senderek, J; Eggermann, K; Elbracht, M; Kornak, U; von der Hagen, M; Kirschner, J; Leube, B; Müller-Felber, W; Schara, U; von Au, K; Wieczorek, D; Bußmann, C; Zerres, K

    2016-01-01

    We present clinical features and genetic results of 1206 index patients and 124 affected relatives who were referred for genetic testing of Charcot-Marie-Tooth (CMT) neuropathy at the laboratory in Aachen between 2001 and 2012. Genetic detection rates were 56% in demyelinating CMT (71% of autosomal dominant (AD) CMT1/CMTX), and 17% in axonal CMT (24% of AD CMT2/CMTX). Three genetic defects (PMP22 duplication/deletion, GJB1/Cx32 or MPZ/P0 mutation) were responsible for 89.3% of demyelinating CMT index patients in whom a genetic diagnosis was achieved, and the diagnostic yield of the three main genetic defects in axonal CMT (GJB1/Cx32, MFN2, MPZ/P0 mutations) was 84.2%. De novo mutations were detected in 1.3% of PMP22 duplication, 25% of MPZ/P0, and none in GJB1/Cx32. Motor nerve conduction velocity was uniformly 40 m/s in MFN2, and more variable in GJB1/Cx32, MPZ/P0 mutations. Patients with CMT2A showed a broad clinical severity regardless of the type or position of the MFN2 mutation. Out of 75 patients, 8 patients (11%) with PMP22 deletions were categorized as CMT1 or CMT2. Diagnostic algorithms are still useful for cost-efficient mutation detection and for the interpretation of large-scale genetic data made available by next generation sequencing strategies.

  13. Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Ionasescu, V.; Ionasescu, R.; Searby, C. [Univ. of Iowa Hospitals and Clinics, Iowa City, IA (United States)

    1996-06-14

    We studied the relationship between the genotype and clinical phenotype in 27 families with dominant X-linked Charcot-Marie-Tooth (CMTX1) neuropathy. Twenty-two families showed mutations in the coding region of the connexin32 (cx32) gene. The mutations include four nonsense mutations, eight missense mutations, two medium size deletions, and one insertion. Most missense mutations showed a mild clinical phenotype (five out of eight), whereas all nonsense mutations, the larger of the two deletions, and the insertion that produced frameshifts showed severe phenotypes. Five CMTX1 families with mild clinical phenotype showed no point mutations of the cx32 gene coding region. Three of these families showed positive genetic linkage with the markers of the Xq13.1 region. The genetic linkage of the remaining two families could not be evaluated because of their small size. 25 refs., 1 fig., 1 tab.

  14. Disease: H00264 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00264 Charcot-Marie-Tooth disease (CMT); Hereditary motor and sensory neuropathy; ...Peroneal muscular atrophy Charcot-Marie-Tooth disease is a genetically heterogeneous group of inherited peri...52 613353 PMID:18215208 Barisic N, Claeys KG, Sirotkovic-Skerlev M, Lofgren A, Nelis E, De Jonghe P, Timmerman V Charcot-Marie-Too...378 Niemann A, Berger P, Suter U Pathomechanisms of mutant proteins in Charcot-Marie-Tooth disease. Neuromol...ecular Med 8:217-42 (2006) PMID:15518599 Bertorini T, Narayanaswami P, Rashed H Charcot-Marie-Too

  15. Amiotrofia neuro-medular de Charcot-Marie-Tooth associada a artrogripose multipla congenita: registro de um caso e revisão da literatura

    Directory of Open Access Journals (Sweden)

    James Pitagoras de Mattos

    1982-09-01

    Full Text Available Os autores registram a associação da amiotrofia neuro-medular de Charcot-Marie-Tooth com artrogripose múltipla congênita. Mostram as associações com as duas condições em apreço na literatura, assim como acrescentam outras alterações observadas nos diversos exames radiológicos realizados.

  16. SENSITIVITY OF COMPUTER ESTHESIOMETRY ON DISTAL PARTS OF THE UPPER EXTREMITIES AT PATIENTS WITH HEREDITARY NEUROPATHY CHARCOT-MARIE-TOOTH

    Directory of Open Access Journals (Sweden)

    NATALIA SHNAYDER

    2011-11-01

    Full Text Available The purpose: to define the diagnostic importance of computer esthesiometry for use in diagnostics of hereditary neuropathy with primary defeat of myelin sheath of peripheral nerves of the upper extremities. Materials and methods: 47 individuals in a condition of relative health (control group from 21 to 50 years, comparable group % 40 patients from 6 to 81 years, with hereditary neuropathy Charcot%Marie%Tooth (CMT. Vibrating sensitivity was investigated by means of computer vibrometer “Vibrotester MBN” VТ%02%1 (MBN, RF in a wide strip of frequencies of vibration (8, 16, 32, 64, 125, 250, 500 Hz. Statistical data processing of research was lead by means of programs STATISTICA v. 7.0 (StatSoft, USA. Results and discussion: We compared received corridors vibrating sensitivity on the upper extremities for healthy volunteers with those at patients with CMT. Statistically significant increase of vibration sensitivity thresholds in a wide range of vibration frequencies on upper extremities and at patients with CMT versus healthy volunteers is shown. Computer esthesiometry method demonstrates high sensitivity in diagnostics of hereditary neuropathy with primary damage of myelin sheath of peripheral nerves of upper extremities on an example of CMT.

  17. Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

    Science.gov (United States)

    2015-08-24

    Spinal Muscular Atrophy; Charcot-Marie-Tooth Disease; Muscular Dystrophy; Spinal Muscular Atrophy With Respiratory Distress 1; Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Neuromuscular Disease; Peroneal Muscular Atrophy; Fragile X Syndrome

  18. Enfermedad de Charcot Marie Tooth (CMT4A por mutacion en el gen GDAP1: reporte de una familia colombiana

    Directory of Open Access Journals (Sweden)

    Angela Milena Martin

    2015-12-01

    Full Text Available Antecedentes:Las mutaciones del gen GDAP1 son causantes de la enfermedad de Charcot Marie Tooth tanto autosómica dominante como recesiva, y se han reportado más de 40 mutaciones distintas. La mutación recesiva Q163X ha sido descrita en pacientes de ascendencia española y se ha demostrado una mutación fundadora originaria de España en pacientes de origen suramericano. Describimos las características físicas e histológicas y el impacto molecular de la mutación Q163X en una familia colombiana.Objetivo:Se describe el impacto de la mutación Q163X en las características físicas, histológicas y moleculares en una familia colombiana.Métodos:Se describe dos pacientes de sexo femenino, hijas de padres consanguíneos, quienes presentaron inicio de síntomas en los dos primeros años de vida, mostrando deterioro funcional severo, sin evidencia de dismorfía, disfonía o parálisis diafragmática. Los estudios de electrofisiología mostraron una neuropatía sensitiva y motora con patrón axonal. Se solicitó la secuenciación del gen GDAP1, y el estudio identificó una mutación homocigota puntual (c. 487 C>T en el exón 4, causando un codón de parada prematuro (p. Q163X. Este resultado confirma el diagnóstico de Enfermedad de Charcot Marie Tooth, tipo 4A (recesiva, tipo axonal.Resultados:Las pacientes fueron remitidas al servicio de Fisiatría para evaluación de métodos de asistencia para deambulación. Ellas reciben seguimiento por el servicio de Neumología, quienes vigilan la función pulmonar y el desarrollo de parálisis diafragmática. Se brindó asesoramiento genético. La genealogía del paciente, las características fenotípicas y los hallazgos en los estudios electrofisiológicos son herramientas valiosas en el enfoque clínico del paciente con CMT, de forma que se pueda plantear una posible mutación causal. Se debe considerar la presencia de mutaciones en el gen GDAP1 en pacientes de origen suramericano, en especial la

  19. Irmandade afetada pela atrofia muscular peroneal de Charcot-Marie-Tooth com possível variante do fenômeno da antecipação

    Directory of Open Access Journals (Sweden)

    Aguinaldo Gonçalves

    1977-06-01

    Full Text Available Considerando-se a peculiaridade genética da atrofia peroneal de Charcot-Marie-Tooth, é feita a descrição clínica de família com três irmãos afetados, com idade de aparecimento progressivamente antecipada, refletindo possível variante do fenômeno da antecipação, condição inusitada na literatura, não só para esta doença, mas também, de modo geral, em Genética Humana.

  20. Narcolepsy with cataplexy in a child with Charcot-Marie-Tooth disease. Case Report.

    Science.gov (United States)

    Zheng, Feixia; Wang, Shuang

    2016-09-01

    We report an 8-year-old boy diagnosed with both CMT1 and narcolepsy, which were not reported simultaneously presenting in one person. The boy presented with a history of increased suddenly falling frequency and excessive daytime sleepiness for 3 months. CMT1 was diagnosed by electrophysiology and genetic testing. Narcolepsy had not been diagnosed until the frequently falling caused by sudden and transient episodes of legs weakness triggered by emotion was found. Multiple sleep latency test showed multiple sleep onset REM periods with reduced sleep latency. When CMT1 and narcolepsy were coexist in an individual, the latter might be overlooked. Cataplexy caused by narcolepsy might be disregard as distal muscle weakness of CMT1. The daytime sleepiness might also be ignored. Therefore, we recommend that patients with sleep disorders should be queried about the symptoms of narcolepsy.

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

    DEFF Research Database (Denmark)

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

    1995-01-01

    -Sottas disease, is a hypertrophic neuropathy with markedly reduced nerve conduction velocity. HMSN type I is genetically heterogenous with at least four autosomal loci and at least two X-linked loci. The most frequent form, HMSN type Ia, is associated with a specific duplication on chromosome 17, which can...... 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...

  2. Charcot-Marie-Tooth病1X型的临床与分子遗传学研究进展%Advance in Clinical and Molecular Genetics Study of Charcot-Marie-Tooth Disease 1X Type (review)

    Institute of Scientific and Technical Information of China (English)

    乔晓会; 李越星

    2009-01-01

    在Charcot-Marie-Tooth病(CMT)中,1X型发病率居于第2位,它由GJB1基因突变致Connexin32蛋白结构或功能异常,引起细胞间通道缺陷导致发病.文章综述了CMT1X的典型临床特征和分子遗传学进展,总结了CMT发病机制的研究.

  3. Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy [v1; ref status: indexed, http://f1000r.es/33n

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    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

  5. Doença de Charcot-Marie-Tooth associada a malformação de Klippel-Feil: registro de um caso e revisão da literatura

    Directory of Open Access Journals (Sweden)

    Carlos A. de Assis Viegas

    1980-06-01

    Full Text Available Depois de caracterizar a doença de Charcot-Marie-Tooth e a malformação de Klippel-Feil, o autor relata um caso em que ambas estão associadas e procede a uma revisão da literatura pertinente, apresentando múltiplas possibilidades de associação de uma e outra com diversos entidades mórbidas.

  6. Zebrafish as a Model to Investigate Dynamin 2-Related Diseases

    OpenAIRE

    Cinzia Bragato; Germano Gaudenzi; Flavia Blasevich; Giulio Pavesi; Lorenzo Maggi; Michele Giunta; Franco Cotelli; Marina Mora

    2016-01-01

    Mutations in the dynamin-2 gene (DNM2) cause autosomal dominant centronuclear myopathy (CNM) and dominant intermediate Charcot-Marie-Tooth (CMT) neuropathy type B (CMTDIB). As the relation between these DNM2-related diseases is poorly understood, we used zebrafish to investigate the effects of two different DNM2 mutations. First we identified a new alternatively spliced zebrafish dynamin-2a mRNA (dnm2a-v2) with greater similarity to human DNM2 than the deposited sequence. Then we knocked-down...

  7. Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy.

    Science.gov (United States)

    Barneo-Muñoz, Manuela; Juárez, Paula; Civera-Tregón, Azahara; Yndriago, Laura; Pla-Martin, David; Zenker, Jennifer; Cuevas-Martín, Carmen; Estela, Anna; Sánchez-Aragó, María; Forteza-Vila, Jerónimo; Cuezva, José M; Chrast, Roman; Palau, Francesc

    2015-04-01

    Mutations in GDAP1, which encodes protein located in the mitochondrial outer membrane, cause axonal recessive (AR-CMT2), axonal dominant (CMT2K) and demyelinating recessive (CMT4A) forms of Charcot-Marie-Tooth (CMT) neuropathy. Loss of function recessive mutations in GDAP1 are associated with decreased mitochondrial fission activity, while dominant mutations result in impairment of mitochondrial fusion with increased production of reactive oxygen species and susceptibility to apoptotic stimuli. GDAP1 silencing in vitro reduces Ca2+ inflow through store-operated Ca2+ entry (SOCE) upon mobilization of endoplasmic reticulum (ER) Ca2+, likely in association with an abnormal distribution of the mitochondrial network. To investigate the functional consequences of lack of GDAP1 in vivo, we generated a Gdap1 knockout mouse. The affected animals presented abnormal motor behavior starting at the age of 3 months. Electrophysiological and biochemical studies confirmed the axonal nature of the neuropathy whereas histopathological studies over time showed progressive loss of motor neurons (MNs) in the anterior horn of the spinal cord and defects in neuromuscular junctions. Analyses of cultured embryonic MNs and adult dorsal root ganglia neurons from affected animals demonstrated large and defective mitochondria, changes in the ER cisternae, reduced acetylation of cytoskeletal α-tubulin and increased autophagy vesicles. Importantly, MNs showed reduced cytosolic calcium and SOCE response. The development and characterization of the GDAP1 neuropathy mice model thus revealed that some of the pathophysiological changes present in axonal recessive form of the GDAP1-related CMT might be the consequence of changes in the mitochondrial network biology and mitochondria-endoplasmic reticulum interaction leading to abnormalities in calcium homeostasis.

  8. Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy.

    Directory of Open Access Journals (Sweden)

    Manuela Barneo-Muñoz

    2015-04-01

    Full Text Available Mutations in GDAP1, which encodes protein located in the mitochondrial outer membrane, cause axonal recessive (AR-CMT2, axonal dominant (CMT2K and demyelinating recessive (CMT4A forms of Charcot-Marie-Tooth (CMT neuropathy. Loss of function recessive mutations in GDAP1 are associated with decreased mitochondrial fission activity, while dominant mutations result in impairment of mitochondrial fusion with increased production of reactive oxygen species and susceptibility to apoptotic stimuli. GDAP1 silencing in vitro reduces Ca2+ inflow through store-operated Ca2+ entry (SOCE upon mobilization of endoplasmic reticulum (ER Ca2+, likely in association with an abnormal distribution of the mitochondrial network. To investigate the functional consequences of lack of GDAP1 in vivo, we generated a Gdap1 knockout mouse. The affected animals presented abnormal motor behavior starting at the age of 3 months. Electrophysiological and biochemical studies confirmed the axonal nature of the neuropathy whereas histopathological studies over time showed progressive loss of motor neurons (MNs in the anterior horn of the spinal cord and defects in neuromuscular junctions. Analyses of cultured embryonic MNs and adult dorsal root ganglia neurons from affected animals demonstrated large and defective mitochondria, changes in the ER cisternae, reduced acetylation of cytoskeletal α-tubulin and increased autophagy vesicles. Importantly, MNs showed reduced cytosolic calcium and SOCE response. The development and characterization of the GDAP1 neuropathy mice model thus revealed that some of the pathophysiological changes present in axonal recessive form of the GDAP1-related CMT might be the consequence of changes in the mitochondrial network biology and mitochondria-endoplasmic reticulum interaction leading to abnormalities in calcium homeostasis.

  9. Enfermedad de Charcot-Marie-Tooth: Estudio clínico y molecular de los genes GJB-1 y MFN2 en la población española.

    OpenAIRE

    Casasnovas Pons, Carlos

    2010-01-01

    [spa] La enfermedad de Charcot-Marie-Tooth (CMT) es un grupo heterogéneo de enfermedades que afectan el sistema nervioso periférico. Su prevalencia se estima entre los 10 y 30 casos por cada 100,000 habitantes. La clasificación más frecuente empleada en la actualidad combina los hallazgos clínicos con el patrón de herencia y los hallazgos electrofisiológicos o de anatomía patológica.

  10. Charcot-Marie-Tooth病的诊治%Progress of the diagnosis and treatment of Charcot-Marie-Tooth disease

    Institute of Scientific and Technical Information of China (English)

    洪道俊; 张玉生

    2014-01-01

    Charcot-Marie-Tooth病(CMT)是最常见的一种遗传性周围神经病,是一组具有显著临床异质性和遗传异质性的疾病,主要表现为肢体远端肌肉进行性无力和萎缩,伴有轻到中度感觉减退,腱反射减弱和足部畸形等.近20年CMT致病基因的不断被克隆,其疾病分型、临床表型和基因表型的关系发生了巨大变化.本文主要阐述CMT的疾病分型演变、基因诊断策略、临床治疗进展.

  11.  Hypertelorism in Charcot-Marie-Tooth disease 1A from the common PMP22 duplication: A Case Report

    Directory of Open Access Journals (Sweden)

    Josef Finsterer

    2012-03-01

    Full Text Available  The 1.4Mb tandem-duplication in the PMP22 gene at 17p11.2 usually manifests as hereditary sensorimotor polyneuropathy with foot deformity, sensorineural hearing-loss, moderate developmental delay, and gait disturbance. Hypertelorism and marked phenotypic variability within a single family has not been reported. In a single family, the PMP22 tandem-duplication manifested as short stature, sensorimotor polyneuropathy, tremor, ataxia, sensorineural hearing-loss, and hypothyroidism in the 27 years-old index case, as mild facial dysmorphism, muscle cramps, tinnitus, intention tremor, bradydiadochokinesia, and sensorimotor polyneuropathy in the 31 year-old half-brother of the index-patient, and as sensorimotor polyneuropathy and foot deformityin the father of the two. The half-brother additionally presented with hypertelorism, not previously reported in PMP22tandem-duplication carriers. The presented cases show that the tandem-duplication 17p11.2 may present with marked intra-familialphenotype variability and that mild facial dysmorphism with stuck-out ears and hypertelorism may be a rare phenotypic feature of this mutation. The causal relation between facial dysmorphism and the PMP22 tandem-duplication, however, remains speculative.

  12. Thrombotic Microangiopathy in Inverted Formin 2-Mediated Renal Disease

    DEFF Research Database (Denmark)

    Challis, Rachel C; Ring, Troels; Xu, Yaobo;

    2016-01-01

    and her mother also had Charcot-Marie-Tooth disease. Using whole-exome sequencing, we identified a mutation in the inverted formin 2 gene (INF2) in the mutational hotspot for FSGS. Subsequent analysis of the Newcastle aHUS cohort identified another family with a functionally-significant mutation in INF2...

  13. Recent advances in the genetics of hereditary axonal sensory-motor neuropathies type 2.

    Science.gov (United States)

    Ajroud-Driss, Senda; Deng, Han-Xiang; Siddique, Teepu

    2011-06-01

    Hereditary axonal motor and sensory neuropathies or Charcot-Marie-Tooth disease type 2 (CMT2) are characterized clinically by distal muscle weakness and atrophy, sensory loss, and foot deformities. Conduction velocities are usually in the normal range or mildly slowed. The majority of CMT2 are autosomal-dominant but autosomal-recessive forms have been described. The number of genes associated with CMT2 have significantly increased in the past decade, with the gene causing CMT2C/SPSMA being the last one discovered. More than 10 genes are now associated with different subtypes of CMT2, which are classified from CMT2A to CMT2N. These genes have distinct functions, but some appear to be involved in common biological pathways, therefore, providing important clues for understanding the pathogenic mechanism of these heterogeneous disorders.

  14. Classification and molecular diagnostic procedure for Chacort-Marie-Tooth disease%腓骨肌萎缩症的分型与分子诊断流程

    Institute of Scientific and Technical Information of China (English)

    张如旭; 唐北沙

    2012-01-01

    Charcot-Marie-Tooth disease (CMT) is the most common form of hereditary neuropathy with significant clinical and genetic heterogeneity.So far 28 genes have been cloned.The main clinical manifestations of CMT include progressive distal muscle wasting and weakness,impaired distal sensation,and diminishing or loss of tendon reflex.Patients may be classified into demyelinating type (CMT1) and axonal type (CMT2) according to electrophysiological and pathological characteristics.Establishment of a standard diagnostic procedure based on clinical,electrophysiological and pathological findings will enable accurate diagnosis in most CMT patients and provide guidance for gene consulting and prognosis.%腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)是一组最常见的具有高度临床和遗传异质性的周围神经单基因遗传病,目前已有28个疾病基因被克隆.主要临床症状包括进行性对称性肢体远端肌无力和肌萎缩,感觉障碍和腱反射减退或消失.根据电生理和病理特点,CMT可分为脱髓鞘型和轴突型.通过临床表现、电生理病理特点进行临床和遗传学分型,选择可能的疾病基因进行突变分析等一系列具有逻辑性的诊断流程,可明确分子诊断,为疾病预后和遗传咨询提供指导性意见.

  15. 腓骨肌萎缩症的分子遗传学研究%Molecular genetics of Charcot-Marie-Tooth disease

    Institute of Scientific and Technical Information of China (English)

    章远志; Nanbert ZHONG

    2005-01-01

    腓骨肌萎缩症也称为Charcot-Marie-Tooth病(CMT),是一类高发病率的周围神经系统单基因遗传病,可发生于世界范围的各个种族之中,发病率为1/25000遗传方式主要为常染色体显性遗传(AD),也可见常染色体隐性遗传(AR)及X连锁显性或隐性遗传(XD或XR)。即使是同一家庭中的患者,其患病的严重程度也会不同。

  16. Is the extracellular ATP a key in X-linked Charcot-Marie-Tooth disease and in inherited non-syndromic deafness?

    OpenAIRE

    Mas del Molino, Ezequiel

    2011-01-01

    [spa] El ATP es una molécula ampliamente conocida por su papel en muchas funciones como la homeostasis celular, el mantenimiento de gradientes iónicos, el mantenimiento del pH en gránulos secretores, el almacenamiento energético, regulador de la interacción actina-miosina, etc. Además, el ATP puede actuar como molécula señalizadora a través de los receptores purinérgicos P2. De receptores P2 hay de dos tipos, los P2X, que son ionotrópicos, y los P2Y que son metabotrópicos. Los primeros son un...

  17. X-linked Charcot-Marie-Tooth (CMT) neuropathies (CMTX1, CMTX2, CMTX3) show different clinical phenotype and molecular genetics

    Energy Technology Data Exchange (ETDEWEB)

    Ionasescu, V.V.; Searby, C.C.; Ionasescu, R. [Univ. of Iowa Hospitals and Clinics, Iowa City, IA (United States)

    1994-09-01

    The purpose of this study was to compare the X-linked dominant type CMTX1 (20 families) with X-linked recessive types CMTX2 and CMTX3 (2 families). The clinical phenotype was consistent with CMT peripheral neuropathy in all cases including distal weakness, atrophy and sensory loss, pes cavus and areflexia. Additional clinicial involvement of the central nervous system was present in one family with CMTX2 (mental retardation) and one family with CMTX3 (spastic paraparesis). Tight genetic linkage to Xq13.1 was present in 20 families with CMTX1 (Z=34.07 at {theta}=0) for the marker DXS453. Fifteen of the CMTX1 families showed point mutations of the connexin 32 coding region (5 nonsense mutations, 8 missense mutations, 2 deletions). Five CMTX1 neuropathy families showed no evidence of point mutations of the CX32 coding sequence. These findings suggest that the CMTX1 neuropathy genotype in these families may be the result of promoter mutations, 3{prime}-untranslated region mutations or exon/intron splice site mutations or a mutation with a different type of connexin but which has close structural similarities to CX32. No mutations of the CX32 coding region were found in the CMTX2 or CMTX3 families. Linkage to Xq13.1 was excluded in both families. Genetic linkage to Xp22.2 was present in the CMTX2 family (Z=3.54 at {theta}=0) for the markers DXS987 and DXS999. Suggestion of linkage to Xq26 (Z=1.81 at {theta}=0) for the marker DXS86 was present in the CMTX3 family.

  18. Common Membrane Trafficking Defects of Disease Associated Dynamin 2 Mutations

    OpenAIRE

    Liu, Ya-Wen; Lukiyanchuk, Vasyl; Schmid, Sandra L.

    2011-01-01

    Dynamin (Dyn) is a multidomain and multifunctional GTPase best known for its essential role in clathrin-mediated endocytosis (CME). Dyn2 mutations have been linked to two human diseases, Centronuclear Myopathy (CNM) and Charcot-Marie-Tooth (CMT) disease. Paradoxically, although Dyn2 is ubiquitously expressed and essential for embryonic development, the disease-associated Dyn2 mutants are autosomal dominant, but result in slowly progressing and tissue-specific diseases. Thus, although the cell...

  19. Mitochondrial dynamics in mammalian health and disease.

    Science.gov (United States)

    Liesa, Marc; Palacín, Manuel; Zorzano, Antonio

    2009-07-01

    The meaning of the word mitochondrion (from the Greek mitos, meaning thread, and chondros, grain) illustrates that the heterogeneity of mitochondrial morphology has been known since the first descriptions of this organelle. Such a heterogeneous morphology is explained by the dynamic nature of mitochondria. Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. Furthermore, during the last decade, it has been identified that mutations in two mitochondrial fusion genes (MFN2 and OPA1) cause prevalent neurodegenerative diseases (Charcot-Marie Tooth type 2A and Kjer disease/autosomal dominant optic atrophy). In addition, other diseases such as type 2 diabetes or vascular proliferative disorders show impaired MFN2 expression. Altogether, these findings have established mitochondrial dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies.

  20. Mitochondrial Fusion Proteins and Human Diseases

    Directory of Open Access Journals (Sweden)

    Michela Ranieri

    2013-01-01

    Full Text Available Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1 and 2 (MFN2, located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1, in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer’s and Parkinson’s diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion.

  1. Lamin A/C truncation in dilated cardiomyopathy with conduction disease

    Directory of Open Access Journals (Sweden)

    Huber Jill M

    2003-07-01

    Full Text Available Abstract Background Mutations in the gene encoding the nuclear membrane protein lamin A/C have been associated with at least 7 distinct diseases including autosomal dominant dilated cardiomyopathy with conduction system disease, autosomal dominant and recessive Emery Dreifuss Muscular Dystrophy, limb girdle muscular dystrophy type 1B, autosomal recessive type 2 Charcot Marie Tooth, mandibuloacral dysplasia, familial partial lipodystrophy and Hutchinson-Gilford progeria. Methods We used mutation detection to evaluate the lamin A/C gene in a 45 year-old woman with familial dilated cardiomyopathy and conduction system disease whose family has been well characterized for this phenotype 1. Results DNA from the proband was analyzed, and a novel 2 base-pair deletion c.908_909delCT in LMNA was identified. Conclusions Mutations in the gene encoding lamin A/C can lead to significant cardiac conduction system disease that can be successfully treated with pacemakers and/or defibrillators. Genetic screening can help assess risk for arrhythmia and need for device implantation.

  2. 有TIA样表现的Charcot-Marie-Tooth病:病例报告及文献复习%Case report about Charcot-Marie-Tooth disease with manifestation of TIA and literature review

    Institute of Scientific and Technical Information of China (English)

    俞羚; 李建萍; 李焰生

    2007-01-01

    @@ 腓骨肌萎缩症又称为Charcot-Marie-Tooth病(CMT),是人类最常见的遗传性周围神经病,其发病率在美国约为1/2500,国内亦有不少报道.其主要表现为足内侧肌、腓骨肌和大腿肌远端进行性无力和萎缩,典型者呈弓形足和"鹤腿",也可累及手或前臂肌肉,形成爪形手;腱反射(特别是踝反射)减弱或消失;可伴有轻到中度感觉减退,主要累及深感觉.目前将CMT分为CMT1、CMT2、CMT3、CMT4和CMTX等5型.CMTX占其中10%~15%,并不少见,但有类似短暂性缺血发作(TIA)样表现的极少,容易漏诊或误诊.现报道一例初诊为有TIA样表现的CMTX.

  3. 1例腓骨肌萎缩症亚急性进展误诊分析%Analysis on misdiagnosis in one case of charcot marie tooth disease in subacute progress

    Institute of Scientific and Technical Information of China (English)

    郭洁; 王亚萍

    2010-01-01

    @@ 1病例介绍 患者,男性,51岁.主因四肢无力伴麻木进行性加重1年转入我院.患者于入院前1年开始出现四肢无力伴麻木,以双下肢为著,呈进行性加重,经常摔倒,需要轮椅帮助日常活动.当地医院以慢性炎性脱髓鞘性周围神经病(CIDP)收入院.

  4. Molecular genetic analysis of a Chinese family with Charcot-Marie-Tooth disease%一个Charcot-Marie-Tooth病家系的分子遗传学分析

    Institute of Scientific and Technical Information of China (English)

    杨莹韵; 从杨; 孙之星; 田原; 刘辰; 杨威

    2010-01-01

    目的 鉴定一个Charcot-Marie-Tooth病(CMT)家系的致病突变.方法 根据家族史、临床表现和肌电图检查结果判断家系CMT分型.采集16名家系成员外周血,提取基因组DNA.针对CMT1的6个亚型,选择微卫星标记进行连锁分析.针对PMP22基因重复突变,采用实时定量PCR检测家系成员.结果 本家系疾病呈常染色体显性遗传.患者均有青少年发病、缓慢进展的下肢无力症状.部分患者经查体发现下肢腱反射减弱、痛触觉减弱,下肢神经传导速度均小于30 m/s,提示为CMT1型.通过连锁分析排除了CMT1A、CMT1E以外的其他4个亚型,证实患者基因组内PMP22基因存在重复突变.结论 此家系患者表型为CMT1A,其致病突变为染色体17p11.2区域内PMP22基因的重复.

  5. Progress of surgical treatment for foot and ankle deformities due to the Charcot-Marie-Tooth disease%Charcot-Marie-Tooth病足踝畸形与外科治疗进展

    Institute of Scientific and Technical Information of China (English)

    梁喜斌; 秦泗河

    2014-01-01

    Charcot-Marie-Tooth病(CMT)是一种进行性、神经性肌萎缩综合征,是周围神经系统最常见的遗传性疾病,易引起下肢足踝畸形,尤以高弓内翻足多见.由于CMT病涉及多学科,临床表现多样,临床医生对此病的治疗熟悉甚少,使此类患者就医时出现较大困惑.本文参考近年文献,归纳认为对于CMT引起的足踝畸形的外科治疗,应根据患者年龄、畸形类别与程度、肌力失衡的范围及程度、患者对矫形治疗的期望值等因素确定手术指征、制定矫形方案.

  6. Impact of I30T and I30M substitution in MPZ gene associated with Dejerine-Sottas syndrome type B (DSSB): A molecular modeling and dynamics.

    Science.gov (United States)

    Agrahari, Ashish; George Priya Doss, C

    2015-10-01

    Myelin protein zero (MPZ) gene encodes MPZ protein is a vital component of the myelin sheath. Mutationsassociated with MPZ gene leads to severe de-hypomyelination Dejerine-Sottas syndrome type B (DSSB) also termed as Charcot-Marie-Tooth disease (CMT) type 3. In this work, we employed a set of various in silico prediction methods to screen 97 nsSNPs associated with MPZ gene. Based on this, we identified the nsSNPs to be most deleterious and pathogenic associated with DSSB. To get more insight into the mutational effect at three-dimensional structural level, we modeled the homology structure of native type as well as I30T and I30M mutant of MPZ protein using Modeler 9.13 software. Molecular dynamics simulation was initiated to explain the impact of the mutation on its structure and function. The obtained results depict that the protein with I30T mutation had variable structural conformation and dynamic behavior than native and mutant I30M of MPZ protein. We hope our computational insight might be helpful in rationalizing the deleterious mutations in DSSB and the advancement of novel pharmacological strategy.

  7. No mutation was detected in the LMNA gene among sporadic Charcot-Marie-Tooth patients%在散发型腓骨肌萎缩症患者中未检测出LMNA基因突变

    Institute of Scientific and Technical Information of China (English)

    宋书娟; 章远志; 陈彪; 王曼捷; 王越英; 张远锦; 闫明; Nanbert ZHONG

    2006-01-01

    Objective: To intensively investigate sporadic CMT patients, we have analyzed the LMNA gene in this study in a series of 32 unrelated CMT patients. Methods: Twelve exons of the LMNA gene were amplified from genetomic DNA. PCR products of each exon were analyzed by single strand conformational polymorphism (SSCP). Results: No abnormal SSCP pattern, suggesting no mutation in our CMT patients, was detected. Conclusion: The CMT diseases resulted from the mutations of LMNA gene were rare.

  8. Defective membrane remodeling in neuromuscular diseases: insights from animal models.

    Directory of Open Access Journals (Sweden)

    Belinda S Cowling

    Full Text Available Proteins involved in membrane remodeling play an essential role in a plethora of cell functions including endocytosis and intracellular transport. Defects in several of them lead to human diseases. Myotubularins, amphiphysins, and dynamins are all proteins implicated in membrane trafficking and/or remodeling. Mutations in myotubularin, amphiphysin 2 (BIN1, and dynamin 2 lead to different forms of centronuclear myopathy, while mutations in myotubularin-related proteins cause Charcot-Marie-Tooth neuropathies. In addition to centronuclear myopathy, dynamin 2 is also mutated in a dominant form of Charcot-Marie-Tooth neuropathy. While several proteins from these different families are implicated in similar diseases, mutations in close homologues or in the same protein in the case of dynamin 2 lead to diseases affecting different tissues. This suggests (1 a common molecular pathway underlying these different neuromuscular diseases, and (2 tissue-specific regulation of these proteins. This review discusses the pathophysiology of the related neuromuscular diseases on the basis of animal models developed for proteins of the myotubularin, amphiphysin, and dynamin families. A better understanding of the common mechanisms between these neuromuscular disorders will lead to more specific health care and therapeutic approaches.

  9. Mechanisms for Nonrecurrent Genomic Rearrangements Associated with CMT1A or HNPP: Rare CNVs as a Cause for Missing Heritability

    NARCIS (Netherlands)

    F. Zhang; P. Seeman; P. Liu; M.A.J. Weterman; C. Gonzaga-Jauregui; C.F. Towne; S.D. Batish; E. de Vriendt; P. de Jonghe; B. Rautenstrauss; K.H. Krause; M. Khajavi; J. Posadka; A. Vandenberghe; F. Palau; L. van Maldergem; F. Baas; V. Timmerman; J.R. Lupski

    2010-01-01

    Genomic rearrangements involving the peripheral myelin protein gene (PMP22) in human chromosome 17p12 are associated with neuropathy: duplications cause Charcot-Marie-Tooth disease type IA (CMT1A), whereas deletions lead to hereditary neuropathy with liability to pressure palsies (HNPP). Our previou

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

    NARCIS (Netherlands)

    S. Zuchner; P. de Jonghe; A. Jordanova; K.G. Claeys; V. Guergueltcheva; S. Cherninkova; S.R. Hamilton; G. van Stavern; K.M. Krajewski; J. Stajich; I. Tournev; K. Verhoeven; C.T. Langerhorst; M. de Visser; F. Baas; T. Bird; V. Timmerman; M. Shy; J.M. Vance

    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

  11. Disease Mutations in Rab7 Result in Unregulated Nucleotide Exchange and Inappropriate Activation

    Energy Technology Data Exchange (ETDEWEB)

    B McCray; E Skordalakes; J Taylor

    2011-12-31

    Rab GTPases are molecular switches that orchestrate vesicular trafficking, maturation and fusion by cycling between an active, GTP-bound form, and an inactive, GDP-bound form. The activity cycle is coupled to GTP hydrolysis and is tightly controlled by regulatory proteins. Missense mutations of the GTPase Rab7 cause a dominantly inherited axonal degeneration known as Charcot-Marie-Tooth type 2B through an unknown mechanism. We present the 2.8 A crystal structure of GTP-bound L129F mutant Rab7 which reveals normal conformations of the effector binding regions and catalytic site, but an alteration to the nucleotide binding pocket that is predicted to alter GTP binding. Through extensive biochemical analysis, we demonstrate that disease-associated mutations in Rab7 do not lead to an intrinsic GTPase defect, but permit unregulated nucleotide exchange leading to both excessive activation and hydrolysis-independent inactivation. Consistent with augmented activity, mutant Rab7 shows significantly enhanced interaction with a subset of effector proteins. In addition, dynamic imaging demonstrates that mutant Rab7 is abnormally retained on target membranes. However, we show that the increased activation of mutant Rab7 is counterbalanced by unregulated, GTP hydrolysis-independent membrane cycling. Notably, disease mutations are able to rescue the membrane cycling of a GTPase-deficient mutant. Thus, we demonstrate that disease mutations uncouple Rab7 from the spatial and temporal control normally imposed by regulatory proteins and cause disease not by a gain of novel toxic function, but by misregulation of native Rab7 activity.

  12. Mitochondrial Dynamics in Mitochondrial Diseases

    Directory of Open Access Journals (Sweden)

    Juan M. Suárez-Rivero

    2016-12-01

    Full Text Available Mitochondria are very versatile organelles in continuous fusion and fission processes in response to various cellular signals. Mitochondrial dynamics, including mitochondrial fission/fusion, movements and turnover, are essential for the mitochondrial network quality control. Alterations in mitochondrial dynamics can cause neuropathies such as Charcot-Marie-Tooth disease in which mitochondrial fusion and transport are impaired, or dominant optic atrophy which is caused by a reduced mitochondrial fusion. On the other hand, mitochondrial dysfunction in primary mitochondrial diseases promotes reactive oxygen species production that impairs its own function and dynamics, causing a continuous vicious cycle that aggravates the pathological phenotype. Mitochondrial dynamics provides a new way to understand the pathophysiology of mitochondrial disorders and other diseases related to mitochondria dysfunction such as diabetes, heart failure, or Hungtinton’s disease. The knowledge about mitochondrial dynamics also offers new therapeutics targets in mitochondrial diseases.

  13. Inherited demyelinating neuropathies with micromutations of peripheral myelin protein 22 gene.

    Science.gov (United States)

    Taioli, Federica; Cabrini, Ilaria; Cavallaro, Tiziana; Acler, Michele; Fabrizi, Gian Maria

    2011-02-01

    The peripheral myelin protein 22 gene (PMP22) encodes an intrinsic membrane protein of compact myelin. Duplication or deletion of PMP22 causes the most common autosomal dominant neuropathies, Charcot-Marie-Tooth disease type 1A or hereditary neuropathy with liability to pressure palsies. Charcot-Marie-Tooth disease type 1A is a hypertrophic de-remyelinating neuropathy manifesting with peroneal muscular atrophy and uniform, marked, slowing of nerve conduction velocities. Hereditary neuropathy with liability to pressure palsies is a recurrent focal neuropathy with sausage-like myelin thickening (tomacula) and non-uniform nerve conduction velocity changes. Missense or nonsense mutations also cause more severe Charcot-Marie-Tooth disease type 1A forms of infancy or hereditary neuropathy with liability to pressure palsies, but they are presumably very rare. We performed a mutational scanning of PMP22 in 229 index patients (46 familial, 183 isolated) referred for suspected inherited neuropathy. The series included 125 cases with hereditary neuropathy with liability to pressure palsies (mean age 42.5 years), 47 cases with Charcot-Marie-Tooth disease type 1A (motor nerve conduction velocities at median nerve below 38 m/s) (mean age 40.7 years) and 57 cases with Charcot-Marie-Tooth with unknown nerve conduction velocities (mean age 43 years). Preliminary molecular studies ruled out PMP22 duplication or deletion or mutations in a comprehensive panel of Charcot-Marie-Tooth genes. Mutational scanning of PMP22 was done by denaturing high performance liquid chromatography and automated nucleotide sequencing. To investigate the molecular basis of phenotype-to-genotype correlations, we performed a transcriptional analysis of PMP22 using reverse-transcriptase polymerase chain reaction and quantitative real-time polymerase chain reaction in two phenotypically divergent nerve biopsies. Ten patients harboured eight micromutations of PMP22 including four novel changes. In six familial

  14. Organization experience of diagnostic and medicosocial services for patients with Charcot—Marie—Tooth disease in Krasnoyarsk region

    Directory of Open Access Journals (Sweden)

    E. V. Glushchenko

    2012-01-01

    Full Text Available Hereditary neuropathy Charcot-Marie-Tooth (CMT is the most common form of hereditary polyneuropathies. Goal of the study was the development of evidence-based diagnostic and treatment algorithms using patients with CMT (for example, in Krasnoyarsk Territory.Materials and methods: A total of 324 people. (probands and their relatives 1 and 2 lines of kinship. We analyzed 125 (38,5 % clinical cases of CMT, 64/125 (51,2 % clinical cases were include to statistical analysis (probands and their family trees, past the full range of clinical and laboratory findings according to the protocol this study. Age ranged from 6 to 81 years, median age — 30,5 years, including women 24 (37,5 %, median age — 33,5 years; males 40 (62,5 %, median age — 28,5 years. Methods of diagnosis: clinical, genetic, neurophysiological, molecular genetic, assessment of quality of life assessment of anxiety and depression.Results: The family history of CMT noted in 53/57 (93,0 % cases, with a predominance of autosomal dominant type of inheritance —52 (91,2 % cases. As a result of DNA testing duplication of peripheral myelin protein gene (RMR22 on chromosome 17, held 34 survey, this mutation was found in 17 (50,0 % patients. Modified method of computer esthesiometry for CMT diagnosis using domestic diagnostic equipment “Vibrotester-MBN” BT-02-1 has a high sensitivity in the early stages of the disease and can be recommended for more widespread adoption of on par with other subjects of the Russian Federation.

  15. Dejerine-Sottas disease: a case report

    Directory of Open Access Journals (Sweden)

    Jaqueline Luvisotto Marinho

    Full Text Available CONTEXT: Hereditary peripheral neuropathies (hereditary motor-sensory neuropathies or hereditary demyelinating neuropathies are abnormalities of Schwann cells and their myelin sheaths, with peripheral nerve dysfunction. They include Charcot-Marie-Tooth disease, Dejerine-Sottas disease, congenital hypomyelinating neuropathy and hereditary neuropathy with liability to pressure palsy. OBJECTIVE: The objective of the present work was to describe a case of Dejerine-Sottas disease. CASE REPORT: A 9-year-old boy presented progressive slight motor deficit in the lower limbs, particularly in the feet, and generalized hyporeflexia. Electromyography disclosed significant reduction in motor and sensory nerve conduction velocities. Sural nerve biopsy showed axons surrounded by a thin myelin sheath and concentrically arranged cytoplasmic processes of Schwann cells forming onion-bulbs. No axon damage was observed.

  16. Naturally occurring plant polyphenols as potential therapies for inherited neuromuscular diseases.

    Science.gov (United States)

    Fuller, Heidi R; Humphrey, Emma L; Morris, Glenn E

    2013-11-01

    There are several lines of laboratory-based evidence emerging to suggest that purified polyphenol compounds such as resveratrol, found naturally in red grapes, epigallocatechin galate from green tea and curcumin from turmeric, might be useful for the treatment of various inherited neuromuscular diseases, including spinal muscular atrophy, Duchenne muscular dystrophy and Charcot-Marie-Tooth disease. Here, we critically examine the scientific evidence related to the known molecular effects that these polyphenols have on different models of inherited neuromuscular disease, with particular attention to problems with the validity of in vitro evidence. We also present proteomic evidence that polyphenols have in vitro effects on cells related to metal ion chelation in cell-culture media. Although their precise mechanisms of action remain somewhat elusive, polyphenols could be an attractive approach to therapy for inherited neuromuscular disease, especially since they may be safer to use on young children, compared with some of the other drug candidates.

  17. Hereditary peripheral neuropathies of childhood: an overview for clinicians.

    Science.gov (United States)

    Wilmshurst, Jo M; Ouvrier, Robert

    2011-11-01

    This review focuses on the "pure" hereditary peripheral neuropathies where peripheral nerve disease is the main manifestation and does not address neurodegenerative disorders associated with but not dominated by peripheral neuropathy. Aetiologies of childhood-onset peripheral neuropathies differ from those of adult-onset, with more inherited conditions, especially autosomal recessive. Charcot-Marie-Tooth disease is the commonest neuromuscular disorder. The genetic labels of CMT (Charcot-Marie-Tooth) disease types 1-4 are the preferred sub-type terms. Clinical presentations and molecular genetic heterogeneity of hereditary peripheral neuropathies are diverse. For most patients worldwide, diagnostic studies are limited to clinical assessment. Such markers which could be used to identify specific sub-types include presentation in early childhood, scoliosis, marked sensory involvement, respiratory compromise, upper limb involvement, visual or hearing impairment, pyramidal signs and mental retardation. These key markers may assist targeted genetic testing and aid in diagnosing children where DNA testing is not possible.

  18. Computational Analysis Reveals the Association of Threonine 118 Methionine Mutation in PMP22 Resulting in CMT-1A

    Directory of Open Access Journals (Sweden)

    Chundi Vinay Kumar

    2014-01-01

    Full Text Available The T118M mutation in PMP22 gene is associated with Charcot Marie Tooth, type 1A (CMT1A. CMT1A is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of the peripheral nervous system. Mutations in CMT related disorder are seen to increase the stability of the protein resulting in the diseased state. We performed SNP analysis for all the nsSNPs of PMP22 protein and carried out molecular dynamics simulation for T118M mutation to compare the stability difference between the wild type protein structure and the mutant protein structure. The mutation T118M resulted in the overall increase in the stability of the mutant protein. The superimposed structure shows marked structural variation between the wild type and the mutant protein structures.

  19. A Charcot-Marie-Tooth disease resembling to chronic inflammatory demyelinating polyradiculoneuropathy: a report of two cases%慢性炎性脱髓鞘性周围神经病样表现的腓骨肌萎缩症二例

    Institute of Scientific and Technical Information of China (English)

    王毅; 乔凯; 吕传真

    2005-01-01

    目的观察亚急性病程的慢性炎性脱髓鞘性周围神经病(CIDP)样表现的腓骨肌萎缩症(CMT)的临床、病理和电生理特点.方法报道2例亚急性的CIDP样表现的CMT患者的临床、神经电生理及周围神经活检的病理特点.结果 2例证实为17p12重复突变的CMT1A患者,慢性病程中亚急性加重,临床表现类似于CIDP.肌电图示运动神经传导速度(MNCV)减慢、阻滞;神经活检见洋葱头样改变,髓鞘脱失,有炎性细胞的浸润,证明有炎性脱髓鞘的CMT1A存在,且免疫治疗有效.结论慢性病程的CMT1A可有类似于CIDP的病程和临床表现,免疫治疗可改善症状.

  20. 周围髓鞘蛋白22基因重复异常的Charcot-Marie-Tooth病患者临床表型分析%Clinical Phenotype of Peripheral Myelin Protein 22 Gene Duplication Abnormality in Charcot-Marie-Tooth Disease

    Institute of Scientific and Technical Information of China (English)

    叶静; 翟红珍; 廖张原; 李存江

    2009-01-01

    目的 分析Charcot-Marie-Tooth病(CMT)周嗣髓鞘蛋白22(PMP22)基因重复异常患者临床症状、体征和电生理特点.方法 61例CMT患者,14例为有家族史的先证者,47例为散发患者,PCR-双酶切方法检测周围髓鞘蛋白22(PMP22)基因重复异常片断,详细问病史和神经系统查体、部分患者行腰穿和腓肠神经病理检查.结果 检出PMP22基因重复异常患者41例,主要临床特点为以双足背屈力弱为主的双下肢无力,伴双侧小腿为主的四肢远端萎缩,80%伴上肢远端肌萎缩,97%踝反射减弱或消失,68%伴有深浅感觉障碍,少数脑脊液蛋白增高,神经电生理和腓肠神经病理提示为脱髓鞘伴有轴索变性.结论 PMP22基因重复异常的CMT患者的临床表现为以下肢远端肌萎缩和肌无力为主,伴有感觉异常;周围神经髓鞘和轴索均有病变.

  1. Mitochondrial dynamics and inherited peripheral nerve diseases.

    Science.gov (United States)

    Pareyson, Davide; Saveri, Paola; Sagnelli, Anna; Piscosquito, Giuseppe

    2015-06-02

    Peripheral nerves have peculiar energetic requirements because of considerable length of axons and therefore correct mitochondria functioning and distribution along nerves is fundamental. Mitochondrial dynamics refers to the continuous change in size, shape, and position of mitochondria within cells. Abnormalities of mitochondrial dynamics produced by mutations in proteins involved in mitochondrial fusion (mitofusin-2, MFN2), fission (ganglioside-induced differentiation-associated protein-1, GDAP1), and mitochondrial axonal transport usually present with a Charcot-Marie-Tooth disease (CMT) phenotype. MFN2 mutations cause CMT type 2A by altering mitochondrial fusion and trafficking along the axonal microtubule system. CMT2A is an axonal autosomal dominant CMT type which in most cases is characterized by early onset and rather severe course. GDAP1 mutations also alter fission, fusion and transport of mitochondria and are associated either with recessive demyelinating (CMT4A) and axonal CMT (AR-CMT2K) and, less commonly, with dominant, milder, axonal CMT (CMT2K). OPA1 (Optic Atrophy-1) is involved in fusion of mitochondrial inner membrane, and its heterozygous mutations lead to early-onset and progressive dominant optic atrophy which may be complicated by other neurological symptoms including peripheral neuropathy. Mutations in several proteins fundamental for the axonal transport or forming the axonal cytoskeleton result in peripheral neuropathy, i.e., CMT, distal hereditary motor neuropathy (dHMN) or hereditary sensory and autonomic neuropathy (HSAN), as well as in hereditary spastic paraplegia. Indeed, mitochondrial transport involves directly or indirectly components of the kinesin superfamily (KIF5A, KIF1A, KIF1B), responsible of anterograde transport, and of the dynein complex and related proteins (DYNC1H1, dynactin, dynamin-2), implicated in retrograde flow. Microtubules, neurofilaments, and chaperones such as heat shock proteins (HSPs) also have a fundamental

  2. [Hereditary sensory and motor neuropathy and hereditary sensory and autonomic neuropathies: recent advances].

    Science.gov (United States)

    Stojkovic, T

    2011-12-01

    This review summarizes the recent genetic advances in hereditary sensorimotor neuropathy also called Charcot-Marie-Tooth disease. The different new genes discovered in 2010 and their underlying phenotypes will be presented.

  3. Gene expression profiling studies in regenerating nerves in a mouse model for CMT1X: uninjured Cx32-knockout peripheral nerves display expression profile of injured wild type nerves.

    Science.gov (United States)

    Freidin, Mona; Asche-Godin, Samantha; Abrams, Charles K

    2015-01-01

    X-linked Charcot-Marie-Tooth disease (CMT1X) is an inherited peripheral neuropathy caused by mutations in GJB1, the human gene for Connexin32 (Cx32). This present study uses Ilumina Ref8-v2 BeadArray to examine the expression profiles of injured and uninjured sciatic nerves at 5, 7, and 14 days post-crush injury (dpi) from Wild Type (WT) and Cx32-knockout (Cx32KO) mice to identify the genes and signaling pathways that are dysregulated in the absence of Schwann cell Cx32. Given the assumption that loss of Schwann cell Cx32 disrupts the regeneration and maintenance of myelinated nerve leading to a demyelinating neuropathy in CMT1X, we initially hypothesized that nerve crush injury would result in significant increases in differential gene expression in Cx32KO mice relative to WT nerves. However, microarray analysis revealed a striking collapse in the number of differentially expressed genes at 5 and 7 dpi in Cx32KO nerves relative to WT, while uninjured and 14 dpi time points showed large numbers of differentially regulated genes. Further comparisons within each genotype showed limited changes in Cx32KO gene expression following crush injury when compared to uninjured Cx32KO nerves. By contrast, WT nerves exhibited robust changes in gene expression at 5 and 7 dpi with no significant differences in gene expression by 14dpi relative to uninjured WT nerve samples. Taken together, these data suggest that the gene expression profile in uninjured Cx32KO sciatic nerve strongly resembles that of a WT nerve following injury and that loss of Schwann cell Cx32 leads to a basal state of gene expression similar to that of an injured WT nerve. These findings support a role for Cx32 in non-myelinating and regenerating populations of Schwann cells in normal axonal maintenance in re-myelination, and regeneration of peripheral nerve following injury. Disruption of Schwann cell-axonal communication in CMT1X may cause dysregulation of signaling pathways that are essential for the

  4. Diagnosis and new treatments in genetic neuropathies.

    Science.gov (United States)

    Reilly, M M; Shy, M E

    2009-12-01

    The genetic neuropathies are a clinically and genetically heterogeneous group of diseases of which the most common types are Charcot-Marie-Tooth disease (CMT), the hereditary sensory and autonomic neuropathies and the distal hereditary motor neuropathies. More than 30 causative genes have been described, making an accurate genetic diagnosis increasingly possible. Although no specific therapies are yet available, research into their pathogenesis has revolutionised our understanding of the peripheral nervous system and allowed the development of rational approaches to therapy. The first therapeutic trials in CMT are currently underway. This review will suggest an approach to the diagnosis of these disorders and provide an update on new therapies.

  5. Genetic spectrum of hereditary neuropathies with onset in the first year of life.

    Science.gov (United States)

    Baets, Jonathan; Deconinck, Tine; De Vriendt, Els; Zimoń, Magdalena; Yperzeele, Laetitia; Van Hoorenbeeck, Kim; Peeters, Kristien; Spiegel, Ronen; Parman, Yesim; Ceulemans, Berten; Van Bogaert, Patrick; Pou-Serradell, Adolf; Bernert, Günther; Dinopoulos, Argirios; Auer-Grumbach, Michaela; Sallinen, Satu-Leena; Fabrizi, Gian Maria; Pauly, Fernand; Van den Bergh, Peter; Bilir, Birdal; Battaloglu, Esra; Madrid, Ricardo E; Kabzińska, Dagmara; Kochanski, Andrzej; Topaloglu, Haluk; Miller, Geoffrey; Jordanova, Albena; Timmerman, Vincent; De Jonghe, Peter

    2011-09-01

    Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset.

  6. A Clinical Analysis of 36 Nervous System Disease Patients Acompanying Auditory Neuropathy%伴发神经系统疾病的听神经病36例临床分析

    Institute of Scientific and Technical Information of China (English)

    王锦玲; 王剑; 石力; 薛飞; 吴保仁; 高磊; 谢娟; 韩丽萍

    2011-01-01

    neuropathy (AN) and the relations between them. Methods The clinical data of 36 syndromic AN patients were retrospectively examined and ten typical patients were described in this study. Results Thirty-six nervous system disease patients consisted of Friedreich ataxia (5 patients), Charcot-Marie-Tooth disease (4 patients), Refsum disease (1 patient), optic atrophy (9 patients), pelvic limb peripheral neuropathy (9 patients), multiple sclerosis (2 patients), chronic inflammatory demyelinating polyneuropathy (CIDP, 1 patient), subacute combined degeneration of the spinal cord (2 patients), motor neuron disease (1 patient), hypoxic ischemic encephalopathy (1 patient), and erythromelalgia (1 patient). Twenty-three out of 36 patients developed more than one type of nervous system diseases. Twenty-two (61.11 %) patients appeared to have hearing loss and poor speech recognition abilities as the first symptoms while the other patients (39%) showed the features of peripheral neuropathy firstly, including the numbness of lower limb, difficulty or weakness in walking, and visual impairment. Seven patients had family hereditary history. According to etiological factors,neurological examinations showed various findings as presented in this paper.Fourteen out of 26 patients who received vestibular caloric tests showed canal paresis, and vestibular evoked myogenic potentials(VEMP) wave could not be observed in 9 out of 13 patients. All the audiological diagnostic results were within the AN diagnostic criteria. Conclusion AN may be accompanied with nervous system diseases in that most are peripheral and hereditary neuropathy. Most patients appeared to have hearing loss, difficulty in walking or visual impairment. The audiological tests showed that they all had the characteristics of auditory neuropathy. The hearing disorder may be before or late during the course of nervous system disease. AN symptoms may indicate that the primary neurological disorders have affected the auditory nerve.

  7. Episodic central nervous system symptoms with reversible white matter involvement in Chinese patients with X-linked Charcot-Marie-Tooth disease and literatures review%伴一过性中枢神经障碍的3个X连锁显性夏科-马里-图斯病家系的临床和遗传学研究及文献复习

    Institute of Scientific and Technical Information of China (English)

    张海华; 高利国; 王静敏; 高志杰; 姜玉武; 王爽; 熊晖; 常杏芝; 吴晔

    2013-01-01

    Objective To analyze the phenotype and genotype of CMTX1 patients with episodic transient reversible white matter involvement,and delineate the features of brain MRI in the episode and the possible mechanisms.Method Three Chinese probands and their family members were sequenced in the coding regions of GJB1.With the other 16 reported CMTX1 patients with episodic transient reversible white matter involvement,the clinical feature of the episodic central nervous system symptoms and the genotypes were reviewed.Result Missense mutations in GJB1 were identified in all 3 probands.In 19 patients with transient reversible white matter involvement,the episodes were manifested as weakness of the limbs,dysarthria,and dysphagia,without disturbance of consciousness or seizures.The episodes lasted for 13 hours (10 min-72 hours) with complete remission in all patients; There were multiple episodes in 9 patients.During the episode,brain MRI showed symmetrical high signals in T2 weighted,Flair and DWI images in periventricular white matter,with predominance in posterior region including splenium of corpus callosum.These changes in imaging were most prominent during or within 1 week after the clinical episode.Significant improvements occurred within 1 month,with complete remission within 4-6 months.No specific locations of mutant amino acids in GJB1 protein were found in these patients with episodic transient reversible white matter involvement.Conclusion Episodic transient reversible white matter involvement may present in a small number of patients with CMTX1.Transient edema of oligodendrocytes due to the dysfunction of gap junction may be involved in the pathogenesis.There is no correlation between the location of the mutant amino acids in GJB1 and the occurrence of the episodes.%目的 分析伴有短暂可逆性脑白质病变的X连锁显性夏科-马里-图斯病(CMTX1)患者临床和头颅核磁(MRI)特点及可能的发生机制,探讨GJB1基因型与患者脑白质病变的相关关系.方法 以临床诊断为CMTX1且伴短暂可逆性脑白质病变的3个先证者及其家庭成员为研究对象,对其进行GJB1基因检测分析.并收集国际已报道的16例患者,对连同本研究3例共19例进行临床特征及突变类型的总结分析.结果 3例先证者均发现GJB1基因编码区的错义突变.19例伴短暂可逆性脑白质病变的CMXT1患者发作期表现为:四肢无力、构音障碍、吞咽困难等,无意识障碍及惊厥;平均发作持续时间13 h(10 min~72 h),发作均可自行完全缓解;9例病程中有多次发作;发作期头颅MRI表现为脑室周围白质对称性长T1、长T2、Flair高信号,DWI高信号,后头部显著,常累及胼胝体压部,发作期及发作后1周内脑白质异常最为明显,1个月明显好转,4~6个月完全恢复.发生可逆性脑白质病变的CMTX1患者的突变位点在GJB1蛋白上无特定分布区域.结论 少数CMTX1患者可出现短暂可逆性的脑白质病变,推测可能与细胞间通道功能障碍导致胶质细胞一过性水肿有关.GJB1基因型与患者是否出现脑白质病变临床表型无明确相关性.

  8. Association of PRPS1 Mutations with Disease Phenotypes

    Directory of Open Access Journals (Sweden)

    Rahul Mittal

    2015-01-01

    Full Text Available Phosphoribosylpyrophosphate synthetase 1 (PRPS1 codes for PRS-I enzyme that catalyzes the first step of nucleotide synthesis. PRPS1 gene mutations have been implicated in a number of human diseases. Recently, new mutations in PRPS1 have been identified that have been associated with novel phenotypes like diabetes insipidus expanding the spectrum of PRPS1-related diseases. The purpose of this review is to evaluate current literature on PRPS1-related syndromes and summarize potential therapies. The overexpression of PRPS1 results in PRS-I superactivity resulting in purine overproduction. Patients with PRS-I superactivity demonstrate uric acid overproduction, hypotonia, ataxia, neurodevelopment abnormalities, and postlingual hearing impairment. On the other hand, decreased activity leads to X-linked nonsyndromic sensorineural deafness (DFNX-2, Charcot-Marie-Tooth disease-5 (CMTX5, and Arts syndrome depending on the residual activity of PRS-I. Mild PRS-I deficiency (DFNX-2 results in non-syndromic progressive hearing loss whereas moderate PRS-I deficiency (CMTX5 and severe PRS-I deficiency (Arts syndrome present with peripheral or optic neuropathy, prelingual progressive sensorineural hearing loss, and central nervous system impairment. Currently, purine replacement via S-adenosylmethionine (SAM supplementation in patients with Arts syndrome appears to improve their condition. This suggests that SAM supplementation can alleviate symptoms of PRPS1 deficient patients and open new avenues of therapeutic intervention.

  9. Additive reductions in zebrafish PRPS1 activity result in a spectrum of deficiencies modeling several human PRPS1-associated diseases

    Science.gov (United States)

    Pei, Wuhong; Xu, Lisha; Varshney, Gaurav K.; Carrington, Blake; Bishop, Kevin; Jones, MaryPat; Huang, Sunny C.; Idol, Jennifer; Pretorius, Pamela R.; Beirl, Alisha; Schimmenti, Lisa A.; Kindt, Katie S.; Sood, Raman; Burgess, Shawn M.

    2016-01-01

    Phosphoribosyl pyrophosphate synthetase-1 (PRPS1) is a key enzyme in nucleotide biosynthesis, and mutations in PRPS1 are found in several human diseases including nonsyndromic sensorineural deafness, Charcot-Marie-Tooth disease-5, and Arts Syndrome. We utilized zebrafish as a model to confirm that mutations in PRPS1 result in phenotypic deficiencies in zebrafish similar to those in the associated human diseases. We found two paralogs in zebrafish, prps1a and prps1b and characterized each paralogous mutant individually as well as the double mutant fish. Zebrafish prps1a mutants and prps1a;prps1b double mutants showed similar morphological phenotypes with increasingly severe phenotypes as the number of mutant alleles increased. Phenotypes included smaller eyes and reduced hair cell numbers, consistent with the optic atrophy and hearing impairment observed in human patients. The double mutant also showed abnormal development of primary motor neurons, hair cell innervation, and reduced leukocytes, consistent with the neuropathy and recurrent infection of the human patients possessing the most severe reductions of PRPS1 activity. Further analyses indicated the phenotypes were associated with a prolonged cell cycle likely resulting from reduced nucleotide synthesis and energy production in the mutant embryos. We further demonstrated the phenotypes were caused by delays in the tissues most highly expressing the prps1 genes. PMID:27425195

  10. A duplicated PLP gene causing Pelizaeus-Merzbacher disease detected by comparative multiplex PCR

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, K.; Sugiyama, N.; Kawanishi, C. [Yokohama City Univ., Yokohama (Japan)] [and others

    1996-07-01

    Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder caused by abnormalities in the proteolipid protein (PLP) gene, which is essential for oligodendrocyte differentiation and CNS myelin formation. Although linkage analysis has shown the homogeneity at the PLP locus in patients with PMD, exonic mutations in the PLP gene have been identified in only 10% - 25% of all cases, which suggests the presence of other genetic aberrations, including gene duplication. In this study, we examined five families with PMD not carrying exonic mutations in PLP gene, using comparative multiplex PCR (CM-PCR) as a semiquantitative assay of gene dosage. PLP gene duplications were identified in four families by CM-PCR and confirmed in three families by densitometric RFLP analysis. Because a homologous myelin protein gene, PMP22, is duplicated in the majority of patients with Charcot-Marie-Tooth 1A, PLP gene overdosage may be an important genetic abnormality in PMD and affect myelin formation. 38 ref., 5 figs., 2 tabs.

  11. Molecular genetics and mechanisms of disease in distal hereditary motor neuropathies: insights directing future genetic studies.

    Science.gov (United States)

    Drew, A P; Blair, I P; Nicholson, G A

    2011-11-01

    The distal hereditary motor neuropathies (dHMNs) are a clinically and genetically heterogeneous group of disorders that primarily affect motor neurons, without significant sensory involvement. New dHMN genes continue to be identified. There are now 11 causative genes described for dHMN, and an additional five genetic loci with unidentified genes. This genetic heterogeneity has further delineated the classification of dHMN, which was previously classified according to mode of inheritance, age at onset, and additional complicating features. Some overlap between phenotypically distinct forms of dHMN is also apparent. The mutated genes identified to-date in dHMN include HSPB1, HSPB8, HSPB3, DCTN1, GARS, PLEKHG5, BSCL2, SETX, IGHMBP2, ATP7A and TRPV4. The pathogenesis of mutations remains to be fully elucidated, however common pathogenic mechanisms are emerging. These include disruption of axonal transport, RNA processing defects, protein aggregation and inclusion body formation, disrupted calcium channel activity, and loss of neuroprotective signalling. Some of these dHMN genes are also mutated in Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). This review examines the growing number of identified dHMN genes, discusses recent insights into the functions of these genes and possible pathogenic mechanisms, and looks at the increasing overlap between dHMN and the other neuropathies CMT2 and SMA.

  12. Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders.

    Science.gov (United States)

    Al-Maawali, Almundher; Dupuis, Lucie; Blaser, Susan; Heon, Elise; Tarnopolsky, Mark; Al-Murshedi, Fathiya; Marshall, Christian R; Paton, Tara; Scherer, Stephen W; Roelofsen, Jeroen; van Kuilenburg, André B P; Mendoza-Londono, Roberto

    2015-03-01

    PRPS1 codes for the enzyme phosphoribosyl pyrophosphate synthetase-1 (PRS-1). The spectrum of PRPS1-related disorders associated with reduced activity includes Arts syndrome, Charcot-Marie-Tooth disease-5 (CMTX5) and X-linked non-syndromic sensorineural deafness (DFN2). We describe a novel phenotype associated with decreased PRS-1 function in two affected male siblings. Using whole exome and Sanger sequencing techniques, we identified a novel missense mutation in PRPS1. The clinical phenotype in our patients is characterized by high prenatal maternal α-fetoprotein, intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis. Additional phenotypic features include macular coloboma-like lesions with retinal dystrophy, severe short stature and diabetes insipidus. Exome sequencing of the two affected male siblings identified a shared putative pathogenic mutation c.586C>T p.(Arg196Trp) in the PRPS1 gene that was maternally inherited. Follow-up testing showed normal levels of hypoxanthine in urine samples and uric acid levels in blood serum. The PRS activity was significantly reduced in erythrocytes of the two patients. Nucleotide analysis in erythrocytes revealed abnormally low guanosine triphosphate and guanosine diphosphate. This presentation is the most severe form of PRPS1-deficiency syndrome described to date and expands the spectrum of PRPS1-related disorders.

  13. Japanese neuropathy patients with peripheral myelin protein-22 gene aneuploidy

    Energy Technology Data Exchange (ETDEWEB)

    Lebo, R.V.; Li, L.Y.; Flandermeyer, R.R. [Univ. of California, San Francisco, CA (United States)] [and others

    1994-09-01

    Peripheral myelin protein (PMP-22) gene aneuploidy results in Charcot-Marie-Tooth disease Type 1A (CMT1A) and the Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) in Japanese patients as well as Caucasian Americans. Charcot-Marie-Tooth disease (CMT), the most common genetic neuropathy, results when expression of one of at least seven genes is defective. CMT1A, about half of all CMT mutations, is usually associated with a duplication spanning the peripheral myelin protein-22 gene on distal chromosome band 17p11.2. Autosomal dominant HNPP (hereditary pressure and sensory neuropathy, HPSN) results from a deletion of the CMT1A gene region. Multicolor in situ hybridization with PMP-22 gene region probe characterized HNPP deletion reliably and detected all different size duplications reported previously. In summary, 72% of 28 Japanese CMT1 (HMSNI) patients tested had the CMT1A duplication, while none of the CMT2 (HMSNII) or CMT3 (HMSNIII) patients had a duplication. Three cases of HNPP were identified by deletion of the CMT1A gene region on chromosome 17p. HNPP and CMT1A have been reported to result simultaneously from the same unequal recombination event. The lower frequency of HNPP compared to CMT1A suggests that HNPP patients have a lower reproductive fitness than CMT1A patients. This result, along with a CMT1A duplication found in an Asian Indian family, demonstrates the broad geographic distribution and high frequency of PMP-22 gene aneuploidy.

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

    NARCIS (Netherlands)

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

    2010-01-01

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

  15. A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy.

    NARCIS (Netherlands)

    Weterman, M.A.J.; Sorrentino, V.; Kasher, P.R.; Jakobs, M.E.; Engelen, B.G.M. van; Fluiter, K.; Wissel, M.B. de; Sizarov, A.; Nurnberg, G.; Nurnberg, P.; Zelcer, N.; Schelhaas, H.J.; Baas, F.

    2012-01-01

    Despite the high number of genes identified in hereditary polyneuropathies/Charcot-Marie-Tooth (CMT) disease, the genetic defect in many families is still unknown. Here we report the identification of a new gene for autosomal dominant axonal neuropathy in a large three-generation family. Linkage ana

  16. Studies of cellular radiosensitivity in hereditary disorders of nervous system and muscle

    Energy Technology Data Exchange (ETDEWEB)

    Brennan, S.; Lewis, P.D. (Royal Postgraduate Medical School, London (UK))

    1983-12-01

    Skin fibroblasts from patients with familial dysautonomia, Duchenne muscular dystrophy and Charcot-Marie-Tooth disease show normal sensitivity to ionising radiation, as measured by post-irradiation clonal growth. Previous reports of cellular hypersensitivity to ionising radiation and other DNA-damaging agents in familial dysautonomia and Duchenne muscular dystrophy have not been confirmed.

  17. Comparison of CMT1A and CMT2: similarities and differences.

    NARCIS (Netherlands)

    Bienfait, H.M.; Verhamme, C.; Schaik, I.N. van; Koelman, J.H.; Visser, B.W. de; Haan, R.J. de; Baas, F.; Engelen, B.G.M. van; Visser, M. de

    2006-01-01

    To evaluate the clinical and electrophysiological similarities and differences between two large groups of patients with Charcot-Marie-Tooth disease, i.e. CMT1A and CMT2, we performed a post hoc comparison of clinical and electrophysiological data.Most CMT1A and CMT2 patients had the classical CMT p

  18. Oral high dose ascorbic acid treatment for one year in young CMT1A patients: a randomised, double-blind, placebo-controlled phase II trial

    NARCIS (Netherlands)

    Verhamme, C.; de Haan, R.J.; Vermeulen, M.; Baas, F.; de Visser, M.; van Schaik, I.N.

    2009-01-01

    ABSTRACT: BACKGROUND: High dose oral ascorbic acid substantially improved myelination and locomotor function in a Charcot-Marie-Tooth type 1A mouse model. A phase II study was warranted to investigate whether high dose ascorbic acid also has such a substantial effect on myelination in Charcot-Marie-

  19. The proteolipid protein gene: Double, double, . . . and trouble

    Energy Technology Data Exchange (ETDEWEB)

    Hodes, M.E.; Dlouhy, S.R. [Indiana Univ. School of Medicine, Indianapolis, IN (United States)

    1996-07-01

    That more of a good thing may be too much has been apparent at least since the discovery that Down syndrome is caused by three copies of chromosome 21 instead of the normal two. Duplications of myelin genes also lead to trouble. An extra dose of PMP22, the gene for a protein of peripheral nervous system myelin, causes Charcot-Marie Tooth type 1A disease (CMT1A). Increased dosage of the proteolipid protein gene, PLP, which encodes the chief protein of CNS myelin, can cause Pelizaeus-Merzbacher disease (PMD). The work of Inoue et al. is of particular importance because they found the duplication in four of five families with {open_quotes}classical{close_quotes} PMD, whereas other changes in PLP, such as missense mutations, are found in no more than one in four or five patients with the disease. 27 refs.

  20. CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis.

    Science.gov (United States)

    Genin, Emmanuelle C; Plutino, Morgane; Bannwarth, Sylvie; Villa, Elodie; Cisneros-Barroso, Eugenia; Roy, Madhuparna; Ortega-Vila, Bernardo; Fragaki, Konstantina; Lespinasse, Françoise; Pinero-Martos, Estefania; Augé, Gaëlle; Moore, David; Burté, Florence; Lacas-Gervais, Sandra; Kageyama, Yusuke; Itoh, Kie; Yu-Wai-Man, Patrick; Sesaki, Hiromi; Ricci, Jean-Ehrland; Vives-Bauza, Cristofol; Paquis-Flucklinger, Véronique

    2016-01-01

    CHCHD10-related diseases include mitochondrial DNA instability disorder, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum, late-onset spinal motor neuropathy (SMAJ), and Charcot-Marie-Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the "mitochondrial contact site and cristae organizing system" (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization. Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle. CHCHD10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mtDNA instability. Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release.

  1. [Hereditary neuropathies].

    Science.gov (United States)

    Vallat, Jean-Michel; Calvo, Judith; Ghorab, Karima; Tazir, Meriem

    2008-11-15

    Although there are many human hereditary neuropathies, most of them with the exception of Charcot-Marie-Tooth disease or hereditary sensorimotor neuropathy, are rare. Irrespective of their type, the mode of transmission may be autosomal dominant or recessive, or X-linked. The most difficult to diagnose, however, are the sporadic forms. It is customary to distinguish the cases in which the neuropathy is the sole clinical expression from multisystemic diseases where neuropathy is one component of multi-organ involvement. The complexity and the multiplicity of genes involved and the lack of understanding of their exact functions hinder logical presentation of these hereditary neuropathies. For understandable technical reasons, the stage of specific treatment, namely the repair of the mutated gene, has yet to be attained.

  2. Structure and chromosomal localization of the gene encoding the human myelin protein zero (MPZ)

    Energy Technology Data Exchange (ETDEWEB)

    Hayasaka, Kiyoshi; Himoro, Masato; Takada, Goro (Akita Univ. School of Medicine, Akita (Japan)); Wang, Yimin; Takata, Mizuho; Minoshima, Shinsei; Shimizu, Nobuyoshi; Miura, Masayuki; Uyemura, Keiichi (Keio Univ. School of Medicine, Tokyo (Japan))

    1993-09-01

    The authors describe the cloning, characterization, and chromosomal mapping of the human myelin protein zero (MPZ) gene (a structural protein of myelin and an adhesive glycoprotein of the immunoglobulin superfamily). The gene is about 7 kb long and consists of six exons corresponding of the functional domains. All exon-intron junction sequences conform to the GT/AG rule. The 5[prime]-flanking region of the gene has a TA-rich element (TATA-like box), two CAAT boxes, and a single defined transcription initiation site detected by the primer extension method. The gene for human MPZ was assigned to chromosome 1q22-q23 by spot blot hybridization of flow-sorted human chromosomes and fluorescence in situ hybridization. The localization of the MPZ gene coincides with the locus for Charcot-Marie-Tooth disease type 1B, determined by linkage analysis. 20 refs., 3 figs., 1 tab.

  3. Physical and genetic mapping of the CMT4A locus and exclusion of PMP-2 as the defect in CMT4A

    Energy Technology Data Exchange (ETDEWEB)

    Othmane, K.B.; Loeb, D.; Roses, A.D.; Pericak-Vance, M.A.; Vance, J.M. [Duke Univ. Medical Center, Durham, NC (United States)] [and others

    1995-07-20

    We have previously localized one form of the autosomal recessive Charcot-Marie-Tooth disease type 4 (CMT4A) to a 5-cM region of chromosome 8q13-q21. We now report the formation of a 7-Bp YAC contig spanning the region. This contig was used to map nine additional microsatellites and six STSs to this region, and subsequent haplotype analysis has narrowed the CMT4A flanking interval to less than 1 cM. In addition, using SSCP and our physical map, we have demonstrated that the myelin protein PMP-2, mapped by FISH to this region, is not the defect in CMT4A. 27 refs., 3 figs., 1 tab.

  4. 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...

  5. Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction

    Directory of Open Access Journals (Sweden)

    Antonio eZorzano

    2015-06-01

    Full Text Available Mitochondrial dynamics is a term that encompasses the movement of mitochondria along the cytoskeleton, regulation of their architecture, and connectivity mediated by tethering and fusion/fission. The importance of these events in cell physiology and pathology has been partially unraveled with the identification of the genes responsible for the catalysis of mitochondrial fusion and fission. Mutations in two mitochondrial fusion genes (MFN2 and OPA1 cause neurodegenerative diseases, namely Charcot-Marie Tooth type 2A and autosomal dominant optic atrophy. Alterations in mitochondrial dynamics may be involved in the pathophysiology of prevalent neurodegenerative conditions. Moreover, impairment of the activity of mitochondrial fusion proteins dysregulates the function of hypothalamic neurons, leading to alterations in food intake and in energy homeostasis. Here we review selected findings in the field of mitochondrial dynamics and their relevance for neurodegeneration and hypothalamic dysfunction.

  6. IgM MGUS anti-MAG neuropathy with predominant muscle weakness and extensive muscle atrophy.

    Science.gov (United States)

    Kawagashira, Yuichi; Kondo, Naohide; Atsuta, Naoki; Iijima, Masahiro; Koike, Haruki; Katsuno, Masahisa; Tanaka, Fumiaki; Kusunoki, Susumu; Sobue, Gen

    2010-09-01

    We report a patient with anti-myelin-associated glycoprotein (MAG) neuropathy, predominantly exhibiting severe motor symptoms, accompanied by extensive muscle atrophy mimicking Charcot-Marie-Tooth disease. Nerve conduction studies revealed mild retardation of motor conduction velocities and significant prolongation of distal latency. Sural nerve biopsy revealed widely spaced myelin and positive staining of myelinated fibers with an IgM antibody. Predominant motor symptoms with muscle atrophy can be one of the clinical manifestations of anti-MAG neuropathy.

  7. 腓骨肌萎缩症并发高弓内翻足的评估与治疗进展

    Institute of Scientific and Technical Information of China (English)

    赵宏谋; 俞光荣

    2010-01-01

    @@ 腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)是最常见的遗传性神经功能障碍性疾病(Hereditary motor-sensory neuropathies,HMSN),主要表现为非代谢紊乱的遗传性神经疾病,发生率为10~40/100 000~([1、2]).

  8. Oral high dose ascorbic acid treatment for one year in young CMT1A patients: a randomised, double-blind, placebo-controlled phase II trial

    Directory of Open Access Journals (Sweden)

    de Visser Marianne

    2009-11-01

    Full Text Available Abstract Background High dose oral ascorbic acid substantially improved myelination and locomotor function in a Charcot-Marie-Tooth type 1A mouse model. A phase II study was warranted to investigate whether high dose ascorbic acid also has such a substantial effect on myelination in Charcot-Marie-Tooth type 1A patients and whether this treatment is safe. Methods Patients below age 25 years were randomly assigned to receive placebo or ascorbic acid (one gram twice daily in a double-blind fashion during one year. The primary outcome measure was the change over time in motor nerve conduction velocity of the median nerve. Secondary outcome measures included changes in minimal F response latencies, compound muscle action potential amplitude, muscle strength, sensory function, Charcot-Marie-Tooth neuropathy score, and disability. Results There were no significant differences between the six placebo-treated (median age 16 years, range 13 to 24 and the five ascorbic acid-treated (19, 14 to 24 patients in change in motor nerve conduction velocity of the median nerve (mean difference ascorbic acid as opposed to placebo treatment of 1.3 m/s, confidence interval -0.3 to 3.0 m/s, P = 0.11 or in change of any of the secondary outcome measures over time. One patient in the ascorbic acid group developed a skin rash, which led to discontinuation of the study medication. Conclusion Oral high dose ascorbic acid for one year did not improve myelination of the median nerve in young Charcot-Marie-Tooth type 1A patients. Treatment was relatively safe. Trial registration Current Controlled Trials ISRCTN56968278, ClinicalTrials.gov NCT00271635.

  9. Yeast Interacting Proteins Database: YGR185C, YPL013C [Yeast Interacting Proteins Database

    Lifescience Database Archive (English)

    Full Text Available associated with Charcot-Marie-Tooth (CMT) neuropathies Rows with this bait as bait (1) Rows with this bait ... anticodon; mutations in human ortholog YARS are associated with Charcot-Marie-Tooth (CMT) neuropathies Rows

  10. NDRG1的功能及其与癌症的关系%The function of NDRG1 and its relationship with cancer

    Institute of Scientific and Technical Information of China (English)

    赵妍; 白翠红

    2011-01-01

    细胞生长、分化和多种应激的情况都可以影响NDRG1(N-myc downstream-regulated gene 1)蛋白的表达水平.NDRG1在许多细胞的正常生理功能中起着重要作用,NDRG1的缺乏可能导致多种疾病,如4D型CMTD(夏-马-图三氏病进行性神经性肌萎缩,Charcot-Marie-Tooth disease)的发生与施万细胞中NDRG1的缺失有关.在多种癌细胞系中,NDRG1的转录和翻译与肿瘤的分化和转移有关.在缺氧环境中,NDRG1的表达水平上调,而且在许多肿瘸细胞中都存在缺氧的现象,这使得NDRG1与缺氧和癌症之间存在着复杂的关系.NDRG1与癌症的关系使得NDRG1可能作为肿瘤演进的标识和癌症诊断的辅助工兵.%The expression of NDRG1 (N-myc downstream-regulated gene 1 )protein is affected by cell growth, cell differentiation and a wide variety of stress.NDRGl plays an important role in the physiologic function of cells. The deficiency of NDRG1 may cause many diseases. The probable cause of Charcot-Marie-Tooth type 4D disease is the deficiency of NDRG1 in Schwann cell. The transcrip tion and translation of NDRG1 correlate with cell differentiation and metastasis in various cancer cell lines. Because it is strongly up-reg ulated under hypoxic condition, and this condition is prevalent in solid tumors, its regulation is a little complicated. NDRG1 gene may be a marker of tumor progression and an efficient diagnostic tool in many types of cancers.

  11. Contribución del estudio neurofisiológico al diagnóstico y control evolutivo de la enfermedad de Charcot-Marie-Tooth en la provincia de Las Palmas

    OpenAIRE

    Navarro Rivero, Beatriz

    2015-01-01

    Programa de doctorado: Patología Quirúrgica [ES]En la presente tesis se estudian los diferentes tipos gnéticos de CMT en la provincia de Las Palmas mediante un estudio transversal, descriptivo y retrospectivo entre los años 2008-2012; valorando la importancia del estudio neurofisiológico y su posible correlación de los parámetros neurofiosológicos con diferentes nervios respecto a discapacidad clínica, tiempos de evolución de la enfer...

  12. Function Over Form: Modeling Groups of Inherited Neurological Conditions in Zebrafish.

    Science.gov (United States)

    Kozol, Robert A; Abrams, Alexander J; James, David M; Buglo, Elena; Yan, Qing; Dallman, Julia E

    2016-01-01

    Zebrafish are a unique cell to behavior model for studying the basic biology of human inherited neurological conditions. Conserved vertebrate genetics and optical transparency provide in vivo access to the developing nervous system as well as high-throughput approaches for drug screens. Here we review zebrafish modeling for two broad groups of inherited conditions that each share genetic and molecular pathways and overlap phenotypically: neurodevelopmental disorders such as Autism Spectrum Disorders (ASD), Intellectual Disability (ID) and Schizophrenia (SCZ), and neurodegenerative diseases, such as Cerebellar Ataxia (CATX), Hereditary Spastic Paraplegia (HSP) and Charcot-Marie Tooth Disease (CMT). We also conduct a small meta-analysis of zebrafish orthologs of high confidence neurodevelopmental disorder and neurodegenerative disease genes by looking at duplication rates and relative protein sizes. In the past zebrafish genetic models of these neurodevelopmental disorders and neurodegenerative diseases have provided insight into cellular, circuit and behavioral level mechanisms contributing to these conditions. Moving forward, advances in genetic manipulation, live imaging of neuronal activity and automated high-throughput molecular screening promise to help delineate the mechanistic relationships between different types of neurological conditions and accelerate discovery of therapeutic strategies.

  13. Function Over Form: Modeling Groups of Inherited Neurological Conditions in Zebrafish

    Science.gov (United States)

    Kozol, Robert A.; Abrams, Alexander J.; James, David M.; Buglo, Elena; Yan, Qing; Dallman, Julia E.

    2016-01-01

    Zebrafish are a unique cell to behavior model for studying the basic biology of human inherited neurological conditions. Conserved vertebrate genetics and optical transparency provide in vivo access to the developing nervous system as well as high-throughput approaches for drug screens. Here we review zebrafish modeling for two broad groups of inherited conditions that each share genetic and molecular pathways and overlap phenotypically: neurodevelopmental disorders such as Autism Spectrum Disorders (ASD), Intellectual Disability (ID) and Schizophrenia (SCZ), and neurodegenerative diseases, such as Cerebellar Ataxia (CATX), Hereditary Spastic Paraplegia (HSP) and Charcot-Marie Tooth Disease (CMT). We also conduct a small meta-analysis of zebrafish orthologs of high confidence neurodevelopmental disorder and neurodegenerative disease genes by looking at duplication rates and relative protein sizes. In the past zebrafish genetic models of these neurodevelopmental disorders and neurodegenerative diseases have provided insight into cellular, circuit and behavioral level mechanisms contributing to these conditions. Moving forward, advances in genetic manipulation, live imaging of neuronal activity and automated high-throughput molecular screening promise to help delineate the mechanistic relationships between different types of neurological conditions and accelerate discovery of therapeutic strategies. PMID:27458342

  14. A 1.5-Mb cosmid contig of the CMT1A duplication/HNPP deletion critical region in 17p11.2-p12

    Energy Technology Data Exchange (ETDEWEB)

    Murakami, Tatsufumi; Lupski, J.R. [Baylor College of Medicine, Houston, TX (United States)

    1996-05-15

    Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a 1.5-Mb tandem duplication in chromosome 17p11.2-p12, and hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a 1.5-Mb deletion at this locus. Both diseases appear to result from an altered copy number of the peripheral myelin protein-22 gene, PMP22, which maps within the critical region. To identify additional genes and characterize chromosomal elements, a 1.5-Mb cosmid contig of the CMT1A duplication/HNPP deletion critical region was assembled using a yeast artificial chromosome (YAC)-based isolation and binning strategy. Whole YAC probes were used for screening a high-density arrayed chromosome 17-specific cosmid library. Selected cosmids were spotted on dot blots and assigned to bins defined by YACs. This binning of cosmids facilitated the subsequent fingerprint analysis. The 1.5-Mb region was covered by 137 cosmids with a minimum overlap set of 52 cosmids assigned to 17 bins and 9 contigs. 20 refs., 2 figs.

  15. The Effect of a Novel c.820C>T (Arg274Trp) Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient

    Science.gov (United States)

    Kawalec, Maria; Kabzińska, Dagmara; Kochański, Andrzej; Krzyśko, Krystiana A.; Zabłocka, Barbara

    2017-01-01

    Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant axonal peripheral neuropathy caused by mutations in the mitofusin 2 gene (MFN2). Mitofusin 2 is a GTPase protein present in the outer mitochondrial membrane and responsible for regulation of mitochondrial network architecture via the fusion of mitochondria. As that fusion process is known to be strongly dependent on the GTPase activity of mitofusin 2, it is postulated that the MFN2 mutation within the GTPase domain may lead to impaired GTPase activity, and in turn to mitochondrial dysfunction. The work described here has therefore sought to verify the effects of MFN2 mutation within its GTPase domain on mitochondrial and endoplasmic reticulum morphology, as well as the mtDNA content in a cultured primary fibroblast obtained from a CMT2A patient harboring a de novo Arg274Trp mutation. In fact, all the parameters studied were affected significantly by the presence of the mutant MFN2 protein. However, using the stable model for mitofusin 2 obtained by us, we were next able to determine that the Arg274Trp mutation does not impact directly upon GTP binding. Such results were also confirmed for GTP-hydrolysis activity of MFN2 protein in patient fibroblast. We therefore suggest that the biological malfunctions observable with the disease are not consequences of impaired GTPase activity, but rather reflect an impaired contribution of the GTPase domain to other MFN2 activities involving that region, for example protein-protein interactions. PMID:28076385

  16. High frequency of mutations in codon 98 of the peripheral myelin protein Po gene in 20 French CMT1 patients

    Energy Technology Data Exchange (ETDEWEB)

    Rougher, H.; LeGuern, E. Gouider, R. [and others

    1996-03-01

    Charcot-Marie-Tooth disease, characterized by distal muscle weakness and amyotrophy, decreased or absent tendon reflexes, and high arched feet, is the most common inherited peripheral neuropathy, with a prevalence of 1 in 2,500. Two types of CMT have been distinguished on the basis of nerve conduction velocities. CMT type 1 is the most frequent, with markedly slowed velocities ({<=}40 m/s) associated with hypertrophic onion bulb changes on nerve biopsy. Autosomal dominant CMT1 is genetically heterogeneous: CMT1A is caused by a 1.5-Mb duplication in 17p11.2 and, more rarely, by a point mutation in tha PMP22 (peripheral myelin protein, 22 kD) gene located in the duplicated region; CMT1B results from mutations in the Po (peripheral myelin protein zero) gene in 1q22-23. Forty-five percent (7/16) of the published mutations associated with CMT1 occur in exon 3 of Po. In order to determine the cause of CMT1 in 20 unrelated patients without 17p11.2 duplications, mutations were sought in exon 3 of Po with three techniques: nonradioactive SSCP, automated sequencing, and PCR enzymatic restriction. 18 refs., 2 figs.

  17. Phenotype expression in women with CMT1X.

    LENUS (Irish Health Repository)

    Siskind, Carly E

    2011-06-01

    Charcot-Marie-Tooth disease type 1X (CMT1X) is the second most common inherited peripheral neuropathy. Women with CMT1X typically have a less severe phenotype than men, perhaps because of X-inactivation patterns. Our objective was to determine the phenotype of women with CMT1X and whether X-inactivation patterns in white blood cells (WBCs) differ between females with CMT1X and controls. Thirty-one women with CMT1X were evaluated using the CMT neuropathy score (CMTNS) and the CMT symptom score in cross-sectional and longitudinal analyses. Lower scores correspond to less disability. WBCs were analyzed for X-inactivation pattern by androgen receptor X-inactivation assay in 14 patients and 23 controls. The 31 women\\'s mean CMTNS was 8.35. Two-thirds of the cohort had a mild CMTNS (mean 4.85) and one-third had a moderate CMTNS (mean 14.73). Three patients had a CMTNS of 0. The pattern of X-inactivation did not differ between the affected and control groups. Women with CMT1X presented with variable impairment independent of age, type of mutation, or location of mutation. No evidence supported the presence of a gap junction beta-1 (GJB1) mutation affecting the pattern of X-inactivation in blood. Further studies are planned to determine whether X-inactivation is the mechanism for CMT1X females\\' variable phenotypes.

  18. Mitochondrial dysfunction in neuromuscular disorders.

    Science.gov (United States)

    Katsetos, Christos D; Koutzaki, Sirma; Melvin, Joseph J

    2013-09-01

    This review deciphers aspects of mitochondrial (mt) dysfunction among nosologically, pathologically, and genetically diverse diseases of the skeletal muscle, lower motor neuron, and peripheral nerve, which fall outside the traditional realm of mt cytopathies. Special emphasis is given to well-characterized mt abnormalities in collagen VI myopathies (Ullrich congenital muscular dystrophy and Bethlem myopathy), megaconial congenital muscular dystrophy, limb-girdle muscular dystrophy type 2 (calpainopathy), centronuclear myopathies, core myopathies, inflammatory myopathies, spinal muscular atrophy, Charcot-Marie-Tooth neuropathy type 2, and drug-induced peripheral neuropathies. Among inflammatory myopathies, mt abnormalities are more prominent in inclusion body myositis and a subset of polymyositis with mt pathology, both of which are refractory to corticosteroid treatment. Awareness is raised about instances of phenotypic mimicry between cases harboring primary mtDNA depletion, in the context of mtDNA depletion syndrome, and established neuromuscular disorders such as spinal muscular atrophy. A substantial body of experimental work, derived from animal models, attests to a major role of mitochondria (mt) in the early process of muscle degeneration. Common mechanisms of mt-related cell injury include dysregulation of the mt permeability transition pore opening and defective autophagy. The therapeutic use of mt permeability transition pore modifiers holds promise in various neuromuscular disorders, including muscular dystrophies.

  19. Physical and transcriptional map in the CMT 1A region

    Energy Technology Data Exchange (ETDEWEB)

    Chevillard, C.; Passage, E.; Cudrey, C. [INSERM Marseille (France)] [and others

    1994-09-01

    The Charcot-Marie-Tooth disease type 1A (CMT1A) has been mapped to the proximal short arm of chromosome 17. CMT1A is the most frequent of the motor and sensory peripheral neuropathies and is associated with a duplication of a 1.5 Mb fragment in proximal 17p12. Several groups have proposed that the gene coding for peripheral myelin protein-22 (PMP-22) as the candidate gene for CMT1A. We have recently published a {open_quote}MegaYAC{close_quote} contig of 6 Mb which covers the CMT1A critical region. In order to isolate new genes localized in this region, we used a {open_quote}physical trapping {close_quote} strategy derived from the direct cDNA selection technique developed by Parimoo et al. This approach has allowed us to construct cDNA {open_quotes}minilibraries{close_quotes} using YAC DNA from the CMT1A region. One of the clones in these minilibraries has been mapped back to the CMT1A duplication. Other potentially interesting clones are in the process of further characterization. Furthermore, we have mapped several Genethon microsatellites in the 6 Mb YAC contig and some are located in the CMT1A duplicated region. These highly polymorphic markers should prove useful for diagnostic testing in CMT1A.

  20. New mutations in CMT 1 and HNPP

    Energy Technology Data Exchange (ETDEWEB)

    Vandenberghe, A.; Boucherat, M. [Faculty of Pharmacy, Lyon (France); Bonnebouche, C. [Hopital de l`Antiquaille, Lyon (France)] [and others

    1994-09-01

    The majority of mutations in CMT 1 (Charcot-Marie-Tooth disease type 1) are due to a duplication of a 1.5 Mb fragment from chromosome 17 containing the PMP22 myelin gene. In addition, micromutations are found in the genes for PMP22 and myelin Po. We collected data from over one hundred families with a duplication in 17p11.2. In about 10% of these families, a de novo mutation was observed. All parents were clinically examined as normal and correct paternity was confirmed. Some families were informative for polymorphic probes located in the duplicated region, and we could deduce a majority of new mutations to be from paternal origin. HNPP (hereditary neuropathy with liability to pressure palsies) is believed to be the reciprocal product of an unequal crossing over underlying the CMT 1 mutation and is due to a deletion of the 1.5 Mb fragment. One new HNPP mutation was found among 7 deleted HNPP families. This mutation is of paternal origin. Clinically assigned CMT 1 patients without a duplication are screened for micromutations applying the SSCP technique. In one family, a de novo mutation was found in the gene for Po.

  1. Gene Dosage Analysis in a Clinical Environment: Gene-Targeted Microarrays as the Platform-of-Choice

    Directory of Open Access Journals (Sweden)

    Donald R. Love

    2013-03-01

    Full Text Available The role of gene deletion and duplication in the aetiology of disease has become increasingly evident over the last decade. In addition to the classical deletion/duplication disorders diagnosed using molecular techniques, such as Duchenne Muscular Dystrophy and Charcot-Marie-Tooth Neuropathy Type 1A, the significance of partial or whole gene deletions in the pathogenesis of a large number single-gene disorders is becoming more apparent. A variety of dosage analysis methods are available to the diagnostic laboratory but the widespread application of many of these techniques is limited by the expense of the kits/reagents and restrictive targeting to a particular gene or portion of a gene. These limitations are particularly important in the context of a small diagnostic laboratory with modest sample throughput. We have developed a gene-targeted, custom-designed comparative genomic hybridisation (CGH array that allows twelve clinical samples to be interrogated simultaneously for exonic deletions/duplications within any gene (or panel of genes on the array. We report here on the use of the array in the analysis of a series of clinical samples processed by our laboratory over a twelve-month period. The array has proven itself to be robust, flexible and highly suited to the diagnostic environment.

  2. Two patients with duplication of 17p11.2: The reciprocal of the Smith-Magenis syndrome deletion?

    Energy Technology Data Exchange (ETDEWEB)

    Brown, A. [Greenwood Genetic Center, SC (United States)]|[Clemson Univ., SC (United States); Phelan, M.C.; Rogers, R.C. [Greenwood Genetic Center, SC (United States)] [and others

    1996-05-17

    J.M. and H.G. are two unrelated male patients with developmental delay. Cytogenetic analysis detected a duplication of 17p11.2 in both patients. The extent of the duplicated region was determined using single copy DNA probes: cen-D17S58-D17S29-D17S258-D17S71-D17S445-D17S122-tel. Four of the six markers, D17S29, D17S258, D17S71, and D17S445, were duplicated by dosage analysis. Fluorescent in situ hybridization (FISH) analysis of H.G., using cosmids for locus D17S29, confirmed the duplication in 17p11.2. Because the deletion that causes the Smith-Magenis syndrome involves the same region of 17p11.2 as the duplication in these patients, the mechanism may be similar to that proposed for the reciprocal deletion/ duplication event observed in Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and Charcot-Marie-Tooth Type 1A disease (CMT1A). 30 refs., 3 figs., 1 tab.

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

    Directory of Open Access Journals (Sweden)

    Cheng-Tsung Hsiao

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

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

    Science.gov (United States)

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

    2011-03-01

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

  5. Experimental therapeutics in hereditary neuropathies: the past, the present, and the future.

    Science.gov (United States)

    Herrmann, David N

    2008-10-01

    Hereditary neuropathies represent approximately 40% of undiagnosed neuropathies in a tertiary clinic setting. The Charcot-Marie-Tooth neuropathies (CMT) are the most common. Mutations in more than 40 genes have been identified to date in CMT. Approximately 50% of CMT cases are accounted for by CMT type 1A, due to a duplication within the peripheral myelin protein 22 gene (PMP22). Mutations in the gap junction beta 1 gene (GJB1), the myelin protein zero gene (MPZ), and the mitofusin 2 gene (MFN2) account for a substantial proportion of other genetically definable CMT. Some 15% of demyelinating CMT and 70% of axonal CMT await genetic clarification. Other hereditary neuropathies include the hereditary sensory and autonomic neuropathies, the familial amyloid polyneuropathies, and multisystem disorders (e.g., lipid storage diseases and inherited ataxias) that have peripheral neuropathy as a major or minor component. This review surveys the challenges of developing effective therapies for hereditary neuropathies in terms of past, present, and future experimental therapeutics in CMT.

  6. Correcting mitochondrial fusion by manipulating mitofusin conformations

    Science.gov (United States)

    Franco, Antonietta; Kitsis, Richard N.; Fleischer, Julie A.; Gavathiotis, Evripidis; Kornfeld, Opher S.; Gong, Guohua; Biris, Nikolaos; Benz, Ann; Qvit, Nir; Donnelly, Sara K; Chen, Yun; Mennerick, Steven; Hodgson, Louis; Mochly-Rosen, Daria; Dorn, Gerald W

    2017-01-01

    Summary Mitochondria are dynamic organelles, remodeling and exchanging contents during cyclic fusion and fission. Genetic mutations of mitofusin (Mfn) 2 interrupt mitochondrial fusion and cause the untreatable neurodegenerative condition, Charcot Marie Tooth disease type 2A (CMT2A). It has not been possible to directly modulate mitochondrial fusion, in part because the structural basis of mitofusin function is incompletely understood. Here we show that mitofusins adopt either a fusion-constrained or fusion-permissive molecular conformation directed by specific intramolecular binding interactions, and demonstrate that mitofusin-dependent mitochondrial fusion can be regulated by targeting these conformational transitions. Based on this model we engineered a cell-permeant minipeptide to destabilize fusion-constrained mitofusin and promote the fusion-permissive conformation, reversing mitochondrial abnormalities in cultured fibroblasts and neurons harboring CMT2A gene defects. The relationship between mitofusin conformational plasticity and mitochondrial dynamism uncovers a central mechanism regulating mitochondrial fusion whose manipulation can correct mitochondrial pathology triggered by defective or imbalanced mitochondrial dynamics. PMID:27775718

  7. Nuclear export of L-periaxin, mediated by its nuclear export signal in the PDZ domain.

    Directory of Open Access Journals (Sweden)

    Yawei Shi

    Full Text Available Myelinating Schwann cells specifically express L-periaxin (L-PRX in the mammalian peripheral nervous system. Several loss-of-function mutations in periaxin have been described and linked to autosomal recessive Dejerine Sottas neuropathy and to demyelinating Charcot-Marie-Tooth disease. The localization of L-periaxin is developmentally regulated in the nucleus and the plasma membrane of Schwann cells. In this study, L-periaxin, which contains a PDZ domain, a nuclear localization signal (NLS domain, a repeat domain, and an acidic domain, was localized in the cytoplasm of RSC96 cells. By contrast, a mutant L-periaxin with a deleted PDZ domain was localized mainly in the nucleus of RSC96 cells. After a nuclear cyclin A1, which is localized exclusively in the nucleus, was fused with the PDZ domain, cyclinA1was found in the cytoplasm of RSC96 cells. Treatment with leptomycin B (LMB, a specific inhibitor of nuclear export mediated by leucine-rich nuclear export signal (NES, also causes nuclear accumulation of wild-type L-periaxin. Double leucine mutation (L83, 85Q in the putative NES in the PDZ domain prevented L-periaxin nuclear export and induced nuclear accumulation. These results suggested that the localization of L-periaxin in the cytoplasm is supported by NES in the PDZ domain.

  8. [The study of distal sensitive conduction in the child: some observations (author's transl)].

    Science.gov (United States)

    Touraine, A; Parain, D

    1981-11-01

    The sensitive potential of the median nerve is evoked by stimulating the second and third fingers while being recorded percutaneously at the wrist. Three parameters are calculated on control subjects: amplitude, duration and velocity, which is obtained from the negative peak latency. These parameters have been measured on children with Charcot-Marie-Tooth's disease. Friedreich's ataxia and Fukuyama's disease. The results are in good agreement with the literature. The interest of this investigation for early diagnosis of the disease and its classification is emphasized.

  9. [Developments in hereditary neuropathies].

    Science.gov (United States)

    Dubourg, O

    2012-12-01

    Hereditary sensorimotor neuropathies, or Charcot-Marie-Tooth disease (CMT) comprise a group of diseases with heterogeneous clinical, electrophysiological and genetic expression. They are classified by the mode of inheritance (autosomal dominant, X-linked dominant, autosomal recessive) and their electrophysiological characteristics taking into account the speed of motor conduction of the median nerve (demyelinating, intermediary and axonal forms). Certain purely motor forms are called spinal CMT or hereditary distal motor neuropathy, or distal spinal amyotrophy. CMT involving an important sensorial component, trophic disorders, or signs of dysautonomia are included in the classification of hereditary sensory and autonomic neuropathies.

  10. 节段性运动神经传导测定在慢性炎性脱髓鞘性多发性神经根神经病和腓骨肌萎缩症1型之间的差异%Difference of segmental motor nerve conduction study between chronic inflammatory demyelinating polyradiculoneuropathy and Clarcot-Marie-Tooth type 1

    Institute of Scientific and Technical Information of China (English)

    刘明生; 崔丽英; 冯新红; 管宇宙; 李本红; 杜华

    2010-01-01

    目的 探讨节段性运动神经传导测定在慢性炎性脱髓鞘性多发性神经根神经病(chronic inflammatory demyelinating polyradiculoneuropathy,CIDP)和腓骨肌萎缩症1型(Charcot-MarieTooth type1,CMT1)鉴别诊断中的价值.方法 收集16例CIDP和13例CMT1患者,进行节段性运动神经传导测定,比较两组远端运动潜伏期、运动神经传导速度,以及近端和远端比较复合肌肉动作电位波幅、面积和时限变化的差异.结果 CIDP和CMT1患者远端运动潜伏期分别为(5.6±3.4)、(9.3±2.1)ms(t=5.347,P=0.000),运动传导速度分别为(31.1±14.3)、(22.2±5.8)m/s(t=6.369,P=0.000),近端和远端比较波幅下降百分比M5o分别为29.7%和4.9%(Z=7.141,P=0.000).在CIDP患者,所有测定神经中40.3%(25/62)远端潜伏期正常,18.1%(26/144)的神经节段传导速度正常,而在CMT1中所有测定神经的远端潜伏期均延长,所有测定节段的传导速度均减慢.在CIDP患者29.2%的神经节段可见传导阻滞或异常波形离散,而在CMT1仅有3.0%的节段可见传导阻滞(x2=20.829,P=0.000).结论 当针对CIDP和CMT1进行鉴别时,如果节段性运动神经传导测定发现传导阻滞和异常波形离散、不同神经节段传导速度下降程度差别较大,可以支持 CIDP的诊断.%Objective to assess the utility of segmental motor nerve conduction study in differential diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy(CIDP)and Charcot-Marie-Tooth type 1(CMT1).Methods A segmental motor nerve conduction study was performed on 16 patients with CIDP and 13 patients with CMT1.Distal motor latency,motor nerve conduction velocity,the changes of amplitude,area and duration of compound motor action potential over conventional segment were compared between the groups.Results Distal motor latency was (5.6±3.4) ms in CIDP and (9.3±2.1) ms in CMT1(t=5.347 P=0.000),motor nerve conduction velocity was (31.1±14.3) m/s in CIDP and(22.2±5.8)m/s(t=6.369,P=0

  11. [Clinical practice of hereditary motor neuropathy (HMN) and hereditary sensory and autonomic neuropathy (HSAN)].

    Science.gov (United States)

    Takashima, Hiroshi

    2014-01-01

    Inherited neuropathy is a genetically and clinically heterogeneous group of neuropathies, the main category becomes Charcot-Marie-Tooth neuropathy (CMT), also known as hereditary motor and sensory neuropathy (HMSN), distal hereditary motor neuropathy (dHMN), and hereditary sensory autonomic neuropathy (HSAN). At least 80 genes have been associated with CMT, HMN or HSAN, a precise molecular diagnosis is often needed to make a clinical diagnosis accurately, enable genetic counseling of the patient and understanding of their molecular mechanisms. To identify the mutation in each patient, using a high-throughput NGS, we established a diagnostic procedure involving screening of disease causing genes in CMT, HMN or HSAN.

  12. Sciatic nerve tumor and tumor-like lesions - uncommon pathologies

    Energy Technology Data Exchange (ETDEWEB)

    Wadhwa, Vibhor; Thakkar, Rashmi S.; Carrino, John A.; Chhabra, Avneesh [Johns Hopkins University School of Medicine, Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD (United States); Maragakis, Nicholas; Hoeke, Ahmet; Sumner, Charlotte J.; Lloyd, Thomas E. [Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD (United States); Belzberg, Allan J. [Johns Hopkins University School of Medicine, Department of Neurosurgery, Baltimore, MD (United States)

    2012-07-15

    Sciatic nerve mass-like enlargement caused by peripheral nerve sheath tumors or neurocutaneous syndromes such as neurofibromatosis or schwannomatosis has been widely reported. Other causes of enlargement, such as from perineuroma, fibromatosis, neurolymphoma, amyloidosis, endometriosis, intraneural ganglion cyst, Charcot-Marie-Tooth disease, and chronic inflammatory demyelinating polyneuropathy are relatively rare. High-resolution magnetic resonance imaging (MRI) is an excellent non-invasive tool for the evaluation of such lesions. In this article, the authors discuss normal anatomy of the sciatic nerve and MRI findings of the above-mentioned lesions. (orig.)

  13. Lack of on-going adaptations in the soleus muscle activity during walking in patients affected by large-fiber neuropathy

    DEFF Research Database (Denmark)

    Nazarena, Mazzaro; Grey, Michael James; Sinkjær, Thomas;

    2005-01-01

    applied during the stance phase of the gait cycle to mimic the normal variability of the ankle trajectory during walking. Patients with demyelination of large sensory fibers (Charcot-Marie-Tooth type 1A and antibodies to myelin-associated glycoprotein neuropathy) and age-matched controls participated...... in this study. The patients had absent light-touch sense in the toes and feet and absent quadriceps and Achilles tendon reflexes, indicating functional loss of large sensory fibers. Moreover, their soleus stretch reflex response consisted of a single electromyographic (EMG) burst with delayed onset and longer...... duration (P

  14. Small Heat Shock Proteins and Distal Hereditary Neuropathies.

    Science.gov (United States)

    Nefedova, V V; Muranova, L K; Sudnitsyna, M V; Ryzhavskaya, A S; Gusev, N B

    2015-12-01

    Classification of small heat shock proteins (sHsp) is presented and processes regulated by sHsp are described. Symptoms of hereditary distal neuropathy are described and the genes whose mutations are associated with development of this congenital disease are listed. The literature data and our own results concerning physicochemical properties of HspB1 mutants associated with Charcot-Marie-Tooth disease are analyzed. Mutations of HspB1, associated with hereditary motor neuron disease, can be accompanied by change of the size of HspB1 oligomers, by decreased stability under unfavorable conditions, by changes in the interaction with protein partners, and as a rule by decrease of chaperone-like activity. The largest part of these mutations is accompanied by change of oligomer stability (that can be either increased or decreased) or by change of intermonomer interaction inside an oligomer. Data on point mutation of HspB3 associated with axonal neuropathy are presented. Data concerning point mutations of Lys141 of HspB8 and those associated with hereditary neuropathy and different forms of Charcot-Marie-Tooth disease are analyzed. It is supposed that point mutations of sHsp associated with distal neuropathies lead either to loss of function (for instance, decrease of chaperone-like activity) or to gain of harmful functions (for instance, increase of interaction with certain protein partners).

  15. PMP22 and its related diseases%PMP22及其相关疾病

    Institute of Scientific and Technical Information of China (English)

    郭家松; 李俊

    2010-01-01

    由基因突变引起的外周神经病统称为Charcot-Marie-Tooth(CMT)病,它是最常见的遗传性神经系统疾病之一,发病率为1/2 500.目前已知有超过53个染色体位点和35个特定基因与CMT有关,但是大部分CMT都是由周围髓鞘蛋白22(PMP22)基因变异所引起的.该文重点对PMP22的生物学及相关疾病的病理生理学进行综述.

  16. Detection of tandam duplications and implications for linkage analysis

    Energy Technology Data Exchange (ETDEWEB)

    Matise, T.C.; Weeks, D.E. (Univ. of Pittsburgh, PA (United States)); Chakravarti, A. (Case Western Reserve Univ., Cleveland, OH (United States)); Patel, P.I.; Lupski, J.R. (Baylor College of Medicine, Houston, TX (United States)); Nelis, E.; Timmerman, V.; Van Broeckhoven, C. (Univ. of Antwerp (Belgium))

    1994-06-01

    The first demonstration of an autosomal dominant human disease caused by segmental trisomy came in 1991 for Charcot-Marie-Tooth disease type 1A (CMT1A). For this disorder, the segmental trisomy is due to a large tandem duplication of 1.5 Mb of DNA located on chromosome 17p11.2-p12. The search for the CMT1A disease gene was misdirected and impeded because some chromosome 17 genetic markers that are linked to CMT1A lie within this duplication. To better understand how such a duplication might affect genetic analyses in the context of disease gene mapping, the authors studied the effects of marker duplication on transmission probabilities of marker alleles, on linkage analysis of an autosomal dominant disease, and on tests of linkage homogeneity. They demonstrate that the undetected presence of a duplication distorts transmission ratios, hampers fine localization of the disease gene, and increases false evidence of linkage heterogeneity. In addition, they devised a likelihood-based method for detecting the presence of a tandemly duplicated marker when one is suspected. They tested their methods through computer simulations and on CMT1A pedigrees genotyped at several chromosome 17 markers. On the simulated data, the method detected 96% of duplicated markers (with a false-positive rate of 5%). On the CMT1A data the method successfully identified two of three loci that are duplicated (with no false positives). This method could be used to identify duplicated markers in other regions of the genome and could be used to delineate the extent of duplications similar to that involved in CMT1A. 18 refs., 5 figs., 6 tabs.

  17. The role of aberrant mitochondrial bioenergetics in diabetic neuropathy.

    Science.gov (United States)

    Chowdhury, Subir K Roy; Smith, Darrell R; Fernyhough, Paul

    2013-03-01

    ataxia, Charcot-Marie-Tooth disease type 2 and human immunodeficiency virus-associated distal-symmetric neuropathy.

  18. The Role of Mitochondrial Dynamics in Neurodegeneration%线粒体动力学改变在神经变性疾病中的地位

    Institute of Scientific and Technical Information of China (English)

    李文伟; 朱敏; 吕传真

    2011-01-01

    Mitochondria are highly dynamic organelles, which undergo continuous cycles of fission and fusion. Mitochondria! Dynamics (fission and fusion) plays important roles in maintaining neuronal func tions, including biogenesis, mitochondrial distribution and cell injury or death. Mfnl/2 and Opal medi ate mitochondria! Fusion, whereas Drpl and Fisl regulate mitochondrial fission. Mutations of Opal cause autosomal dominant optic atrophy, and mutations of Mfn2 lead to Charcot-Marie-Tooth disease type 2A. Moreover, increasing evidences show that abnormal mitochondrial dynamics are involved in pathogenesis of late-onset neurodegenerative disorders, such as Alzheimers disease, Parkinsons disease and Hunting tons disease. This paper reviews the current advances of abnormal mitochondrial dynamics relevant to neuronal loss in neurodegenerative diseases.%线粒体是一种处于高度运动状态的细胞器,频繁地出现分裂和融合,线粒体分裂和融合的动态过程被称为线粒体动力学.对于神经元来说,线粒体的动力学过程具有十分重要的生物学意义.已知线粒体融合介导蛋白的功能缺失性突变可以导致常染色体显性遗传性视神经萎缩和Charcot-Marie-Tooth病等神经变性疾病.近来发现,在迟发性神经变性疾病中,线粒体动力学的改变也具有重要地位.本文将在线粒体动力学的分子调控以及与细胞死亡的关系、在神经变性疾病中的地位等方面综述这一领域的最新进展.

  19. Genetic and physical mapping of the genomic region spanning CMT4A

    Energy Technology Data Exchange (ETDEWEB)

    Othmane, K.B.; Loeb, D.; Roses, A.D. [Duke Univ. Medical Center, Durham, NC (United States)] [and others

    1994-09-01

    Autosomal recessive Charcot-Marie-Tooth disease (CMT4) is a severe childhood neuropathy classified into three types: A, B, and C. We previously mapped CMT4A to chromosome 8q13-q21 in four large Tunisian families. Analysis of recombination events suggested the order: cent.-D8S279-(D8S286,D8S164, CMT4A)-D8S84-tel. Families with types B and C were subsequently typed and linkage for these types was excluded for the CMT4A region and other known CMT loci. Recently, the gene for a major peripheral myelin protein (PMP2) was mapped by FISH to chromosome 8q21-q22 and therefore appeared to be a strong candidate gene for CMT4A. We used SSCP analysis, DNA sequencing, FISH and YAC mapping analysis, and demonstrated that PMP2 is not the defect in CMT4A. Using physical mapping data, we sublocalized a new genethon marker (D8S548) to the CMT4A region between D8S286 and D8S164. All affected CMT4A patients were homozygotes for this polymorphic microsatellite as expected from its physical localization. We screened the CEPH megabase YAC library using the closest markers; over 30 YACs were isolated and characterized by PFGE. FISH analysis revealed about 16% chimeras. The YACs span the 8 cM region between D8S279 and PMP2 (mapped distal to D8S84), with a current 1 cM gap between D8S164 and D8S84. We are currently using Alu-PCR and vectorette to develop end clones in order to identify new YACs in the region and further close this gap. Alu-PCR fragments have identified several new microsatellites in the region which can be used for additional mapping of the CMT4A gene.

  20. Reactivation of Lysosomal Ca2+ Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells.

    Science.gov (United States)

    Zou, Jianlong; Hu, Bo; Arpag, Sezgi; Yan, Qing; Hamilton, Audra; Zeng, Yuan-Shan; Vanoye, Carlos G; Li, Jun

    2015-04-29

    Loss of function of FIG4 leads to Charcot-Marie-Tooth disease Type 4J, Yunis-Varon syndrome, or an epilepsy syndrome. FIG4 is a phosphatase with its catalytic specificity toward 5'-phosphate of phosphatidylinositol-3,5-diphosphate (PI3,5P2). However, the loss of FIG4 decreases PI3,5P2 levels likely due to FIG4's dominant effect in scaffolding a PI3,5P2 synthetic protein complex. At the cellular level, all these diseases share similar pathology with abnormal lysosomal storage and neuronal degeneration. Mice with no FIG4 expression (Fig4(-/-)) recapitulate the pathology in humans with FIG4 deficiency. Using a flow cytometry technique that rapidly quantifies lysosome sizes, we detected an impaired lysosomal fission, but normal fusion, in Fig4(-/-) cells. The fission defect was associated with a robust increase of intralysosomal Ca(2+) in Fig4(-/-) cells, including FIG4-deficient neurons. This finding was consistent with a suppressed Ca(2+) efflux of lysosomes because the endogenous ligand of lysosomal Ca(2+) channel TRPML1 is PI3,5P2 that is deficient in Fig4(-/-) cells. We reactivated the TRPML1 channels by application of TRPML1 synthetic ligand, ML-SA1. This treatment reduced the intralysosomal Ca(2+) level and rescued abnormal lysosomal storage in Fig4(-/-) culture cells and ex vivo DRGs. Furthermore, we found that the suppressed Ca(2+) efflux in Fig4(-/-) culture cells and Fig4(-/-) mouse brains profoundly downregulated the expression/activity of dynamin-1, a GTPase known to scissor organelle membranes during fission. This downregulation made dynamin-1 unavailable for lysosomal fission. Together, our study revealed a novel mechanism explaining abnormal lysosomal storage in FIG4 deficiency. Synthetic ligands of the TRPML1 may become a potential therapy against diseases with FIG4 deficiency.

  1. Detection of mosaicism in a CMT1a patient using FISH

    Energy Technology Data Exchange (ETDEWEB)

    Sourour, E.; Thompson, P.; MacMillan, J.; Upadhyaya, M. [Institute of Medical Genetics, Cardiff (United Kingdom)

    1994-09-01

    Charcot-Marie-Tooth disease type 1 (CMT1) is the most common hereditary motor and sensory neuropathy, and is characterized by peroneal muscular atrophy, pes cavus, loss of deep tendon reflexes and reduced motor nerve conduction velocities. CMT1a segregates as an autosomal dominant condition and shows complete linkage and association with a large submicroscopic duplication on chromosome 17p11.2-p12. We have detected a mosaicism in the father of an affected CMT1a patient. The affected individuals in this family were found to be homozygous with DNA markers YAW409, p132GBRI which are duplicated in CMT1a patients. FISH analysis with YAC clone (Y49H7), carried on 45 interphases from the affected father, revealed that the duplication was only present in 24 of these interphases. However, this duplication was found in all 50 interphases screened from the father`s affected son and, as expected, none of the 50 interphases derived from a non-CMT case had any evidence of this duplication. The affected father had had difficulty with his balance from age 40, with numerous falls. His median and motor nerve conduction velocities were normal. There was no obvious history fo the disorder in the previous generations. The affected boy had foot drop prior to his 10th birthday. He had loss of sensation in his feet and sensorineural deafness from childhood and had a median motor conduction velocity of 33 meters/second. The findings based on FISH analysis suggest that the mosaicism may have occurred early in embryogenesis leading to the disease in the father.

  2. The modified ultrasound pattern sum score mUPSS as additional diagnostic tool for genetically distinct hereditary neuropathies.

    Science.gov (United States)

    Grimm, Alexander; Rasenack, Maria; Athanasopoulou, Ioanna M; Dammeier, Nele Maria; Lipski, Christina; Wolking, Stefan; Vittore, Debora; Décard, Bernhard F; Axer, Hubertus

    2016-02-01

    The objective of this study is to evaluate the nerve ultrasound characteristics in genetically distinct inherited neuropathies, the value of the modified ultrasound pattern sum score (mUPSS) to differentiate between the subtypes and the correlation of ultrasound with nerve conduction studies (NCS), disease duration and severity. All patients underwent a standardized neurological examination, ultrasound, and NCS. In addition, genetic testing was performed. Consequently, mUPSS was applied, which is a sum-score of cross-sectional areas (CSA) at predefined anatomical points in different nerves. 31 patients were included (10xCharcot-Marie-Tooth (CMT)1a, 3xCMT1b, 3xCMTX, 9xCMT2, 6xHNPP [Hereditary neuropathy with liability to pressure palsies]). Generalized, homogeneous nerve enlargement and significantly increased UPS scores emphasized the diagnosis of demyelinating neuropathy, particularly CMT1a and CMT1b. The amount of enlargement did not depend on disease duration, symptom severity, height and weight. In CMTX the nerves were enlarged, as well, however, only in the roots and lower limbs, most prominent in men. In CMT2 no significant enlargement was detectable. In HNPP the CSA values were increased at entrapped sites, and not elsewhere. However, a distinction from CMT1, which also showed enlarged CSA values at entrapment sites, was only possible by calculating the entrapment ratios and entrapment score. The mUPSS allowed distinction between CMT1a (increased UPS scores, entrapment ratios 1.4), while CMT1b and CMTX showed intermediate UPS types and entrapment ratios neuropathies. The modified UPSS is a quantitative tool, which may provide useful information for diagnosis, differentiation and follow-up evaluation in addition to NCS and molecular testing.

  3. Clinical and Genetic Characteristics Analysis of Auditory Neuropathy Acompanying Peripheral Nervous System Disease%以听神经病为首发病伴周围神经病家系的听力学及遗传学特征分析

    Institute of Scientific and Technical Information of China (English)

    齐悦; 兰兰; 史伟; 张秋静; 纵亮; 李娜; 王大勇; 李倩; 王秋菊

    2012-01-01

    目的 分析以听神经病为首发病伴周围神经病家系的临床听力学及遗传学特征.方法 对3个以听神经病为首发病伴周围神经病的家系进行病史采集、专科体检、听力学检查及相关的神经系统检查,从患者的临床表型、听力学检测、家系谱图及家系遗传学特征进行分析.结果 3个家系中的患者均以听神经病为首发病,其中,2个家系中的患者伴发Charcot-Marie-Tooth(CMT)综合征、1个家系中的患者伴发运动神经元病.3个家系中患者的表型特点均为青少年期发病的低频下降为主的双侧感音神经性聋,多伴局部感觉及运动障碍.家系谱分析显示两个伴发CMT综合征家系分别具有常染色体隐性及X连锁隐性遗传特征,而伴发运动神经元病家系则表现出常染色体隐性遗传特征.结论 部分听神经病可表现为周围神经病的首发病,青少年期发病,双耳低频下降型感音神经性聋;具有为常染色体隐性或X连锁隐性遗传特征.%Objective To analysis the clinical and genetic characteristics of three Chinese families with auditory neuropathy and peripheral nervous system disease. Methods The three Chinese families with auditory neuropathy and peripheral nervous system disease were investigated by history collectioning, physical examinationing, audiologi-cal examinationing and drawing the family trees. The systematic examination of audiology including audiological examination, such as pure tone testing, OAE, ABR,and neurologic examination. Results The three families had been diagnosed with bilateral sensorineural hearing loss mainly at low frequency. The hearing loss ranged from mild to serves. Patients all had tinnitus, sensory and movement disorders, partly had ataxia, optic atrophy and other symptoms. Among them, seven of the eight patients accepted systematic examination of audiology. All the audiological diagnostic results showed typical characters of auditory neuropathy

  4. A 1.5 Mb submicroscopic deletion in 17p11.2-p12 is frequently observed in Italian families with hereditary neuropathy with liability to pressure palsies

    Energy Technology Data Exchange (ETDEWEB)

    Lorenzetti, D.; Roa, B.B.; Abbas, N.E. [Baylor College of Medicine, Houston, TX (United States)] [and others

    1994-09-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies that was recently associated with a 1.5 Mb deletion in chromosome 17p11.2-p12. Duplication of the same region is known to be associated with Charcot-Marie-Tooth disease type 1A (CMT1A), a more severe peripheral neuropathy characterized by symmetrically slowed nerve conduction velocity. The CMT1A duplication and HNPP deletion are reciprocal recombination products involving a repeat element (CMT1A-REP) which flanks the 1.5 Mb region involved in the duplication/deletion. Patients from 9 unrelated HNPP Italian families were clinically, electrophysiologically and histologically evaluated. Families were typed with a polymorphic (CA){sub n} repeat and with RFLPs corresponding to loci D17S122, D17S125 and D17S61, which all map within the deleted region. Lack of allelic transmission from affected parent to affected offspring was observed in four informative families, suggesting the presence of deletion. Southern blot analysis of EcoRI digested genomic DNA from HNPP patients and control subjects was performed using a probe mapping within the CMT1A-REP elements. A reduced hybridization signal of a 6.0 kb EcoRI fragment, mapping within the distal CMT1A-REP, was observed in all HNPP patients suggesting the loss of one copy of this fragment in the HNPP-deleted chromosome. PFGE analysis of SacII digested genomic DNA from selected HNPP subjects showed the presence of a junction fragment which has previously been found in association with the 1.5 Mb HNPP deletion. Evidence for deletion could be demonstrated in all 9 families suggesting that the 17p11.2-p12 deletion is commonly associated with HNPP.

  5. A 1.5-Mb deletion in 17p11.2-p12 is frequently observed in Italian families with hereditary neuropathy with liability to pressure palsies

    Energy Technology Data Exchange (ETDEWEB)

    Lorenzetti, D.; Pandolfo, M. [Istituto Nazionale Neurologico, Milan (Italy)]|[Baylor College of Medicine, Houston, TX (United States); Pareyson, D.; Sghirlanzoni, A.; Di Donato, S. [Istituto Nazionale Neurologico, Milan (Italy); Roa, B.B.; Abbas, N.E.; Lupski, J.R. [Baylor College of Medicine, Houston, TX (United States)

    1995-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies. A 1.5-Mb deletion in chromosome 17p11.2-p12 has been associated with HNPP. Duplication of the same 1.5-Mb region is known to be associated with Charcot-Marie-Tooth disease type 1 (CMT1A), a more severe peripheral neuropathy characterized by symmetrically slowed nerve conduction velocity (NCV). The CMT1A duplication and HNPP deletion appear to be the reciprocal products of a recombination event involving a repeat element (CMT1A-REP) that flanks the 1.5-Mb region involved in the duplication/deletion. Patients from nine unrelated Italian families who were diagnosed with HNPP on the basis of clinical, electrophysiological, and histological evaluations were analyzed by molecular methods for DNA deletion on chromosome 17p. In all nine families, Southern analysis using a CMT1A-REP probe detected a reduced hybridization signal of a 6.0-kb EcoRI fragment mapping within the distal CMT1A-REP, indicating deletion of one copy of CMT1A-REP in these HNPP patients. Families were also typed with a polymorphic (CA){sub n} repeat and with RFLPs corresponding to loci D17S122, D17S125, and D17S61, which all map within the deleted region. Lack of allelic transmission from affected parent to affected offspring was observed in four informative families, providing an independent indication for deletion. Furthermore, pulsed-field gel electrophoresis analysis of SacII-digested genomic DNA detected junction fragments specific to the 1.5-Mb HNPP deletion in seven of nine Italian families included in this study. These findings suggest that a 1.5-Mb deletion on 17p11.2-p12 is the most common mutation associated with HNPP. 51 refs., 5 figs., 1 tab.

  6. Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: Implications for testing in the cytogenetics laboratory

    Energy Technology Data Exchange (ETDEWEB)

    Shaffer, L.G.; Kennedy, G.M.; Spikes, A.S. [Baylor College of Medicine, Houston, TX (United States)] [and others

    1997-03-31

    Charcot-Marie-Tooth (CMT) disease type 1A is an inherited peripheral neuropathy characterized by slowly progressive distal muscle wasting and weakness, decreased nerve conduction velocities, and genetic linkage to 17p12. Most (>98%) CMT1A cases are caused by a DNA duplication of a 1.5-Mb region in 17p12 containing the PMP22 gene. The reciprocal product of the CMT1A duplication is a 1.5-Mb deletion which causes hereditary neuropathy with liability to pressure palsies (HNPP). The most informative current diagnostic testing requires pulsed-field gel electrophoresis to detect DNA rearrangement-specific junction fragments. We investigated the use of interphase FISH for the detection of duplications and deletions for these disorders in the clinical molecular cytogenetics laboratory. Established cell lines or blood specimens from 23 individuals with known molecular diagnoses and 10 controls were obtained and scored using a two-color FISH assay. At least 70%, of CMT1A cells displayed three signals consistent with duplications. Using this minimum expected percentile to make a CMT1A duplication diagnosis, all patients with CMT1A showed a range of 71-92% of cells displaying at least three signals. Of the HNPP cases, 88% of cells displayed only one hybridization signal, consistent with deletions. The PMP22 locus from normal control individuals displayed a duplication pattern in {approximately}9% of cells, interpreted as replication of this locus. The percentage of cells showing replication was significantly lower than in those cells displaying true duplications. We conclude that FISH can be reliably used to diagnose CMT1A and HNPP in the clinical cytogenetics laboratory and to readily distinguish the DNA rearrangements associated with these disorders from individuals without duplication or deletion of the PMP22 locus. 43 refs., 4 figs., 2 tabs.

  7. Evidence for involvement of TRE-2 (USP6) oncogene, low-copy repeat and acrocentric heterochromatin in two families with chromosomal translocations.

    Science.gov (United States)

    Ou, Zhishuo; Jarmuz, Małgorzata; Sparagana, Steven P; Michaud, Jacques; Décarie, Jean-Claude; Yatsenko, Svetlana A; Nowakowska, Beata; Furman, Patti; Shaw, Chad A; Shaffer, Lisa G; Lupski, James R; Chinault, A Craig; Cheung, Sau W; Stankiewicz, Paweł

    2006-09-01

    We report clinical findings and molecular cytogenetic analyses for two patients with translocations [t(14;17)(p12;p12) and t(15;17)(p12;p13.2)], in which the chromosome 17 breakpoints map at a large low-copy repeat (LCR) and a breakage-prone TRE-2 (USP6) oncogene, respectively. In family 1, a 6-year-old girl and her 5-year-old brother were diagnosed with mental retardation, short stature, dysmorphic features, and Charcot-Marie-Tooth disease type 1A (CMT1A). G-banding chromosome analysis showed a der(14)t(14;17)(p12;p12) in both siblings, inherited from their father, a carrier of the balanced translocation. Chromosome microarray and FISH analyses revealed that the PMP22 gene was duplicated. The chromosome 17 breakpoint was mapped within an approximately 383 kb LCR17pA that is known to also be the site of several breakpoints of different chromosome aberrations including the evolutionary translocation t(4;19) in Gorilla gorilla. In family two, a patient with developmental delay, subtle dysmorphic features, ventricular enlargement with decreased periventricular white matter, mild findings of bilateral perisylvian polymicrogyria and a very small anterior commissure, a cryptic duplication including the Miller-Dieker syndrome region was identified by chromosome microarray analysis. The chromosome 17 breakpoint was mapped by FISH at the TRE-2 oncogene. Both partner chromosome breakpoints were mapped on the short arm acrocentric heterochromatin within or distal to the rRNA cluster, distal to the region commonly rearranged in Robertsonian translocations. We propose that TRE-2 together with LCR17pA, located approximately 10 Mb apart, also generated the evolutionary gorilla translocation t(4;19). Our results support previous observations that the USP6 oncogene, LCRs, and repetitive DNA sequences play a significant role in the origin of constitutional chromosome aberrations and primate genome evolution.

  8. Functional and comparative genomics analyses of pmp22 in medaka fish

    Directory of Open Access Journals (Sweden)

    Kawarabayasi Yutaka

    2009-06-01

    Full Text Available Abstract Background Pmp22, a member of the junction protein family Claudin/EMP/PMP22, plays an important role in myelin formation. Increase of pmp22 transcription causes peripheral neuropathy, Charcot-Marie-Tooth disease type1A (CMT1A. The pathophysiological phenotype of CMT1A is aberrant axonal myelination which induces a reduction in nerve conduction velocity (NCV. Several CMT1A model rodents have been established by overexpressing pmp22. Thus, it is thought that pmp22 expression must be tightly regulated for correct myelin formation in mammals. Interestingly, the myelin sheath is also present in other jawed vertebrates. The purpose of this study is to analyze the evolutionary conservation of the association between pmp22 transcription level and vertebrate myelin formation, and to find the conserved non-coding sequences for pmp22 regulation by comparative genomics analyses between jawed fishes and mammals. Results A transgenic pmp22 over-expression medaka fish line was established. The transgenic fish had approximately one fifth the peripheral NCV values of controls, and aberrant myelination of transgenic fish in the peripheral nerve system (PNS was observed. We successfully confirmed that medaka fish pmp22 has the same exon-intron structure as mammals, and identified some known conserved regulatory motifs. Furthermore, we found novel conserved sequences in the first intron and 3'UTR. Conclusion Medaka fish undergo abnormalities in the PNS when pmp22 transcription increases. This result indicates that an adequate pmp22 transcription level is necessary for correct myelination of jawed vertebrates. Comparison of pmp22 orthologs between distantly related species identifies evolutionary conserved sequences that contribute to precise regulation of pmp22 expression.

  9. North America and South America (NA-SA) neuropathy project.

    Science.gov (United States)

    Pasnoor, Mamatha; Nascimento, Osvaldo J M; Trivedi, Jaya; Wolfe, Gil I; Nations, Sharon; Herbelin, Laura; de Freitas, M G; Quintanilha, Giseli; Khan, Saud; Dimachkie, Mazen; Barohn, Richard

    2013-08-01

    Peripheral neuropathy is a common neurological disorder. There may be important differences and similarities in the diagnosis of peripheral neuropathy between North America (NA) and South America (SA). Neuromuscular databases were searched for neuropathy diagnosis at two North American sites, University of Kansas Medical Center and University of Texas Southwestern Medical Center, and one South American site, Federal Fluminense University in Brazil. All patients were included into one of the six major categories: immune-mediated, diabetic, hereditary, infectious/inflammatory, systemic/metabolic/toxic (not diabetic) and cryptogenic. A comparison of the number of patients in each category was made between North America and South America databases. Total number of cases in North America was 1090 and in South America was 1034 [immune-mediated: NA 215 (19.7%), SA 191 (18%); diabetic: NA 148 (13.5%), SA 236 (23%); hereditary: NA 292 (26.7%), SA 103 (10%); infectious/inflammatory: NA 53 (4.8%), SA 141 (14%); systemic/metabolic/toxic: NA 71 (6.5%), SA 124 (12%); cryptogenic: NA 311 (28.5%), SA 239 (23%)]. Some specific neuropathy comparisons were hereditary neuropathies [Charcot-Marie-Tooth (CMT) cases] in NA 246/292 (84.2%) and SA 60/103 (58%); familial amyloid neuropathy in SA 31/103 (30%) and none in NA. Among infectious neuropathies, cases of human T-lymphotropic virus type 1 (HTLV-1) neuropathy in SA were 36/141(25%), Chagas disease in SA were 13/141(9%) and none for either in NA; cases of neuropathy due to leprosy in NA were 26/53 (49%) and in SA were 39/141(28%). South American tertiary care centers are more likely to see patients with infectious, diabetic and hereditary disorders such as familial amyloid neuropathies. North American tertiary centers are more likely to see patients with CMT. Immune neuropathies and cryptogenic neuropathies were seen equally in North America and South America.

  10. Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients

    Energy Technology Data Exchange (ETDEWEB)

    Juyal, R.C.; Figuera, L.E.; Hauge, X. [Baylor College of Medicine, Houston, TX (United States)] [and others

    1996-05-01

    Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (1) FISH analysis, (2) PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (3) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS. 49 refs.

  11. Type I Glycogen Storage Disease

    Science.gov (United States)

    ... Baby Boomers Get Tested Core Programs HE Webinar Disney 2014 5 Ways to Love Your Liver Liver ... Drive Away Liver Disease Liver Lowdown Aug 2013 Disney Marathon In The Field Healthy Foods Diet Recommendations ...

  12. Castleman′s disease: Hyaline vascular type

    Directory of Open Access Journals (Sweden)

    Srikanth Shastry

    2014-01-01

    Full Text Available Castleman′s disease is a rare disease of lymph node with two identified forms, the hyaline vascular type and plasma cell type. It presents as localized or systemic lymphadenopathy or even as extranodal mass and may give rise to several differential diagnoses. Castleman′s disease represents a morphologically distinct form of lymph node hyperplasia rather than a neoplasm or a hamartoma. It occurs most commonly in adults but it can also affect children. Here we present a case of Castleman′s disease in a 22 year male patient involving right cervical lymphnode.

  13. Autoimmune diseases associated with neurofibromatosis type 1.

    Science.gov (United States)

    Nanda, Arti

    2008-01-01

    Associations of autoimmune diseases with neurofibromatosis type 1 have been rarely described. In the present report, we describe two patients of neurofibromatosis type 1 having an association with vitiligo in one, and alopecia areata and autoimmune thyroiditis in another. The associations of neurofibromatosis type 1 with vitiligo, alopecia areata, and autoimmune thyroiditis have not been reported earlier. Whether these associations reflect a causal relationship with neurofibromatosis type 1 or are coincidental needs to be settled.

  14. Connexin:a potential novel target for protecting the central nervous system?

    Institute of Scientific and Technical Information of China (English)

    Hong-yan Xie; Yu Cui; Fang Deng; Jia-chun Feng

    2015-01-01

    Connexin subunits are proteins that form gap junction channels, and play an important role in communication between adjacent cells. This review article discusses the function of connexins/hemichannels/gap junctions under physiological conditions, and summarizes the findings re-garding the role of connexins/hemichannels/gap junctions in the physiological and pathological mechanisms underlying central nervous system diseases such as brain ischemia, traumatic brain and spinal cord injury, epilepsy, brain and spinal cord tumor, migraine, neuroautoimmune disease, Alzheimer’s disease, Parkinson’s disease, X-linked Charcot-Marie-Tooth disease, Peli-zaeus-Merzbacher-like disease, spastic paraplegia and maxillofacial dysplasia. Connexins are considered to be a potential novel target for protecting the central nervous system.

  15. Connexin: a potential novel target for protecting the central nervous system?

    Directory of Open Access Journals (Sweden)

    Hong-yan Xie

    2015-01-01

    Full Text Available Connexin subunits are proteins that form gap junction channels, and play an important role in communication between adjacent cells. This review article discusses the function of connexins/hemichannels/gap junctions under physiological conditions, and summarizes the findings regarding the role of connexins/hemichannels/gap junctions in the physiological and pathological mechanisms underlying central nervous system diseases such as brain ischemia, traumatic brain and spinal cord injury, epilepsy, brain and spinal cord tumor, migraine, neuroautoimmune disease, Alzheimer′s disease, Parkinson′s disease, X-linked Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher-like disease, spastic paraplegia and maxillofacial dysplasia. Connexins are considered to be a potential novel target for protecting the central nervous system.

  16. Genetics Home Reference: glycogen storage disease type V

    Science.gov (United States)

    ... storage disease type V glycogen storage disease type V Enable Javascript to view the expand/collapse boxes. ... All Close All Description Glycogen storage disease type V (also known as GSDV or McArdle disease) is ...

  17. Exome sequence analysis suggests genetic burden contributes to phenotypic variability and complex neuropathy

    Science.gov (United States)

    Gonzaga-Jauregui, Claudia; Harel, Tamar; Gambin, Tomasz; Kousi, Maria; Griffin, Laurie B.; Francescatto, Ludmila; Ozes, Burcak; Karaca, Ender; Jhangiani, Shalini; Bainbridge, Matthew N.; Lawson, Kim S.; Pehlivan, Davut; Okamoto, Yuji; Withers, Marjorie; Mancias, Pedro; Slavotinek, Anne; Reitnauer, Pamela J; Goksungur, Meryem T.; Shy, Michael; Crawford, Thomas O.; Koenig, Michel; Willer, Jason; Flores, Brittany N.; Pediaditrakis, Igor; Us, Onder; Wiszniewski, Wojciech; Parman, Yesim; Antonellis, Anthony; Muzny, Donna M.; Katsanis, Nicholas; Battaloglu, Esra; Boerwinkle, Eric; Gibbs, Richard A.; Lupski, James R.

    2015-01-01

    Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ~45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy associated genes in subjects versus controls; confirmed in a second ethnically discrete neuropathy cohort, suggesting mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HMPVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity. PMID:26257172

  18. Genetic disorders producing compressive radiculopathy.

    Science.gov (United States)

    Corey, Joseph M

    2006-11-01

    Back pain is a frequent complaint seen in neurological practice. In evaluating back pain, neurologists are asked to evaluate patients for radiculopathy, determine whether they may benefit from surgery, and help guide management. Although disc herniation is the most common etiology of compressive radiculopathy, there are many other causes, including genetic disorders. This article is a discussion of genetic disorders that cause or contribute to radiculopathies. These genetic disorders include neurofibromatosis, Paget's disease of bone, and ankylosing spondylitis. Numerous genetic disorders can also lead to deformities of the spine, including spinal muscular atrophy, Friedreich's ataxia, Charcot-Marie-Tooth disease, familial dysautonomia, idiopathic torsional dystonia, Marfan's syndrome, and Ehlers-Danlos syndrome. However, the extent of radiculopathy caused by spine deformities is essentially absent from the literature. Finally, recent investigation into the heritability of disc degeneration and lumbar disc herniation suggests a significant genetic component in the etiology of lumbar disc disease.

  19. [The role of the immune system in hereditary demyelinating neuropathies].

    Science.gov (United States)

    Mäurer, M; Toyka, K V; Martini, R

    2005-06-01

    Hereditary neuropathies, e.g., Charcot-Marie-Tooth (CMT) disease, are inherited diseases of the peripheral nervous system causing chronic progressive motor and sensory dysfunction. Most neuropathies are due to mutations in myelin genes such as PMP22, P0, and the gap junction protein Cx32. Myelin mutant mice are regarded as suitable animal models for several forms of hereditary neuropathies and are important neurobiological tools for the evaluation of pathogenetic and therapeutic concepts in hereditary neuropathies. Using these animal models we could recently show that the immune system is involved in the pathogenesis of hereditary neuropathies. Due to the phenotypic similarities we also consider the immune system important for human inherited neuropathies, in particular since several case reports demonstrate a beneficial effect of immune therapies in patients with hereditary neuropathies. In this review we compare findings from animal models and human disease to elucidate the role of the immune system in hereditary neuropathies.

  20. Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

    Directory of Open Access Journals (Sweden)

    Claudia Gonzaga-Jauregui

    2015-08-01

    Full Text Available Charcot-Marie-Tooth (CMT disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼45% (17/37 of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.

  1. Intracellular transport proteins: classification, structure and function of kinesins

    Directory of Open Access Journals (Sweden)

    Agnieszka Chudy

    2011-09-01

    Full Text Available Correct cell functioning, division and morphogenesis rely on efficient intracellular transport. Apart from dyneins and myosins, kinesins are the main proteins responsible for intracellular movement. Kinesins are a large, diverse group of motor proteins, which based on phylogenetic similarity were classified into fourteen families. Among these families, due to the location of their motor domains, three groups have been characterized: N-, C- and M-kinesin. As molecular motors, kinesins transport various molecules and vesicles mainly towards the microtubule plus end (from the cell body participating in anterograde transport, although there are also kinesins involved in retrograde transport (C-kinesins. Kinesins are also involved in spindle formation, chromosome segregation, and spermatogenesis. Because of their great importance for the correct functioning of cells, mutations in kinesin coding genes may lead to such neurodegenerative diseases as dominant hereditary spastic paraplegia or Charcot-Marie-Tooth disease.

  2. The mitochondrial connection in auditory neuropathy.

    Science.gov (United States)

    Cacace, Anthony T; Pinheiro, Joaquim M B

    2011-01-01

    'Auditory neuropathy' (AN), the term used to codify a primary degeneration of the auditory nerve, can be linked directly or indirectly to mitochondrial dysfunction. These observations are based on the expression of AN in known mitochondrial-based neurological diseases (Friedreich's ataxia, Mohr-Tranebjærg syndrome), in conditions where defects in axonal transport, protein trafficking, and fusion processes perturb and/or disrupt mitochondrial dynamics (Charcot-Marie-Tooth disease, autosomal dominant optic atrophy), in a common neonatal condition known to be toxic to mitochondria (hyperbilirubinemia), and where respiratory chain deficiencies produce reductions in oxidative phosphorylation that adversely affect peripheral auditory mechanisms. This body of evidence is solidified by data derived from temporal bone and genetic studies, biochemical, molecular biologic, behavioral, electroacoustic, and electrophysiological investigations.

  3. Expressing hNF-LE397K results in abnormal gaiting in a transgenic model of CMT2E

    Science.gov (United States)

    Dale, Jeffrey M.; Villalon, Eric; Shannon, Stephen G.; Barry, Devin M.; Markey, Rachel M.; Garcia, Virginia B.; Garcia, Michael L.

    2012-01-01

    Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gaiting, exacerbation of neuropathy, sensory defects, and deafness. We generated a novel line of CMT2E mice expressing a hNF-LE397K transgene, which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons, and decreased nerve conduction velocity. In this study, we demonstrated that hNF-LE397K mice developed abnormal gait of the hind limbs. The identification of severe gaiting defects in combination with previously observed muscle atrophy, reduced axon caliber, and decreased nerve conduction velocity suggests that hNF-LE397K mice recapitulate many of clinical signs associated with CMT2E. Therefore, hNF-LE397K mice provide a context for potential therapeutic intervention. PMID:22288874

  4. Correlation between muscle atrophy on MRI and manual strength testing in hereditary neuropathies.

    Science.gov (United States)

    del Porto, Lana A; Nicholson, Garth A; Ketheswaren, Pon

    2010-07-01

    MRI shows areas where muscle has been replaced by fat, a process which occurs in neuropathies. The purpose of this study was to investigate the usefulness of MRI in assessing disease severity in Charcot-Marie-Tooth (CMT) and hereditary motor neuropathy (HMN) compared to manual muscle testing (MMT). MRI and MMT correlated well (Spearman's rank correlation coefficient 0.910, 0.789-1.0). MRI was useful to document the extent and pattern of muscle atrophy and fat replacement and to determine the level of denervation. In addition, nerve length dependent denervation was confirmed in both CMT and HMN. MRI will be useful to confirm MMT findings and may be helpful for diagnosis of early or subclinical disease, as well as to further investigate the mechanisms of hereditary neuropathies.

  5. Type 2 Gaucher Disease (Acute Infantile Gaucher Disease or Neuropathic Type

    Directory of Open Access Journals (Sweden)

    Mohammad Mehdi TAGHDIRI

    2012-12-01

    Full Text Available How to Cite this Article: Taghdiri MM. Type 2 Gaucher Disease (Acute Infantile Gaucher Disease or Neuropathic Type. Iran J Child Neurol Autumn 2012; 6:4 (suppl. 1:12. Pls see PDF. 

  6. Surgery for gastroesophageal reflux disease with Gaucher disease type 2.

    Science.gov (United States)

    Kubo, Hiroyuki; Shimono, Ryuichi; Tanaka, Aya; Fujii, Takayuki; Yasuda, Saneyuki; Koyano, Kosuke; Jinnai, Wataru; Kondo, Sonoko; Kondo, Takeo; Kusaka, Takashi

    2016-07-01

    Gaucher disease, the most common lysosomal storage disease, is sometimes complicated with gastroesophageal reflux disease (GERD). The present patient was a 136-day-old Japanese boy with Gaucher disease type 2. Enzyme replacement therapy and chemical chaperone therapy were successful for the skin disorders, joint contractures, hepatosplenomegaly and thrombocytopenia, but he also had GERD. Accordingly, a Nissen fundoplication with gastrostomy was performed. There was no vulnerability of organs, easy bleeding or difficulty of maintaining the visual field because of hepatosplenomegaly during operation. In the perioperative period, there was no prolonged wound healing or infection. GERD was improved. In the near future, the number of long-term survivors of Gaucher disease will increase due to improvements in medical therapy. Therefore, it is expected that the number of patients requiring fundoplication will also increase. In patients with successful medical therapy, surgical fundoplication can be safely and effectively performed.

  7. Pregnancies in glycogen storage disease type Ia

    NARCIS (Netherlands)

    Martens, Danielle H. J.; Rake, Jan Peter; Schwarz, Martin; Ullrich, Kurt; Weinstein, David A.; Merkel, Martin; Sauer, Pieter J. J.; Smit, G. Peter A.

    2008-01-01

    OBJECTIVE: Reports on pregnancies in women with glycogen storage disease type Ia (GSD-Ia) are scarce. Because of improved life expectancy, pregnancy is becoming an important issue. We describe 15 pregnancies by focusing on dietary treatment, biochemical parameters, and GSD-Ia complications. STUDY DE

  8. Respiratory muscle weakness in peripheral neuropathies.

    Science.gov (United States)

    Burakgazi, Ahmet Z; Höke, Ahmet

    2010-12-01

    Common peripheral neuropathies do not usually cause diaphragmatic weakness and subsequent respiratory compromise. However, respiratory involvement is relatively common in Guillain-Barré syndrome (GBS). Experience in GBS has led to a standardized approach to manage respiratory problems in peripheral neuropathies. Diaphragmatic weakness is not common in chronic inflammatory demyelinating polyneuropathy and extremely rare in multifocal motor neuropathy. The linkage has been described between certain subtypes of Charcot-Marie-Tooth (CMT) disease such as CMT2C and CMT4B1 and diaphragmatic weakness. A correlation usually has not been found between electrophysiologic findings and clinical respiratory signs or spirometric abnormalities in peripheral neuropathies except in amplitudes of evoked phrenic nerve responses. Careful and frequent assessment of respiratory function by a qualified team of healthcare professionals and physicians is essential. Criteria established for mechanical ventilation in GBS cases may be applied to other peripheral neuropathies with respiratory compromise as necessary.

  9. Small heat shock protein Hsp27 is required for proper heart tube formation.

    Science.gov (United States)

    Brown, Daniel D; Christine, Kathleen S; Showell, Christopher; Conlon, Frank L

    2007-11-01

    The small heat shock protein Hsp27 has been shown to be involved in a diverse array of cellular processes, including cellular stress response, protein chaperone activity, regulation of cellular glutathione levels, apoptotic signaling, and regulation of actin polymerization and stability. Furthermore, mutation within Hsp27 has been associated with the human congenital neuropathy Charcot-Marie Tooth (CMT) disease. Hsp27 is known to be expressed in developing embryonic tissues; however, little has been done to determine the endogenous requirement for Hsp27 in developing embryos. In this study, we show that depletion of XHSP27 protein results in a failure of cardiac progenitor fusion resulting in cardia bifida. Furthermore, we demonstrate a concomitant disorganization of actin filament organization and defects in myofibril assembly. Moreover, these defects are not associated with alterations in specification or differentiation. We have thus demonstrated a critical requirement for XHSP27 in developing cardiac and skeletal muscle tissues.

  10. Peripheral neuropathy in mitochondrial disorders.

    Science.gov (United States)

    Pareyson, Davide; Piscosquito, Giuseppe; Moroni, Isabella; Salsano, Ettore; Zeviani, Massimo

    2013-10-01

    Why is peripheral neuropathy common but mild in many mitochondrial disorders, and why is it, in some cases, the predominant or only manifestation? Although this question remains largely unanswered, recent advances in cellular and molecular biology have begun to clarify the importance of mitochondrial functioning and distribution in the peripheral nerve. Mutations in proteins involved in mitochondrial dynamics (ie, fusion and fission) frequently result in a Charcot-Marie-Tooth phenotype. Peripheral neuropathies with different phenotypic presentations occur in mitochondrial diseases associated with abnormalities in mitochondrial DNA replication and maintenance, or associated with defects in mitochondrial respiratory chain complex V. Our knowledge of mitochondrial disorders is rapidly growing as new nuclear genes are identified and new phenotypes described. Early diagnosis of mitochondrial disorders, essential to provide appropriate genetic counselling, has become crucial in a few treatable conditions. Recognising and diagnosing an underlying mitochondrial defect in patients presenting with peripheral neuropathy is therefore of paramount importance.

  11. An oral Na(V)1.8 blocker improves motor function in mice completely deficient of myelin protein P-0

    DEFF Research Database (Denmark)

    Rosberg, Mette R.; Alvarez Herrero, Susana; Krarup, Christian

    2016-01-01

    -/-, a CMT model with a much more severe neuropathy. We found that the progressive impairment of motor performance from 1 to 4 months of age in P0-/- could be acutely reversed by C31 treatment. The effect was associated with an improvement of the amplitude of the plantar CMAP evoked by tibial nerve...... stimulation. The corresponding motor nerve excitability studies by “threshold tracking” showed changes after C31 consistent with attenuation of a resting membrane depolarization. Our data suggest that the depolarizing motor conduction failure in P0-/- could be acutely improved by C31. This provides proof......Mice deficient of myelin protein P0 are established models of demyelinating Charcot-Marie-Tooth (CMT) disease. Dysmyelination in these mice is associated with an ectopic expression of the sensory neuron specific sodium channel isoform NaV1.8 on motor axons. We reported that in P0+/−, a model of CMT...

  12. Analysis of dynein intermediate chains, light intermediate chains and light chains in a cohort of hereditary peripheral neuropathies.

    Science.gov (United States)

    Tey, Shelisa; Ahmad-Annuar, Azlina; Drew, Alexander P; Shahrizaila, Nortina; Nicholson, Garth A; Kennerson, Marina L

    2014-10-01

    The cytoplasmic dynein heavy chain (DYNC1H1) gene has been increasingly associated with neurodegenerative disorders including axonal Charcot-Marie-Tooth disease (CMT2), intellectual disability and malformations of cortical development. In addition, evidence from mouse models (Loa, catabolite repressor-activator (Cra) and Sprawling (Swl)) has shown that mutations in Dync1h1 cause a range of neurodegenerative phenotypes with motor and sensory neuron involvement. In this current study, we examined the possible contribution of other cytoplasmic dynein subunits that bind to DYNC1H1 as a cause of inherited peripheral neuropathy. We focused on screening the cytoplasmic dynein intermediate, light intermediate and light chain genes in a cohort of families with inherited peripheral neuropathies. Nine genes were screened and ten variants were detected, but none was identified as pathogenic, indicating that cytoplasmic dynein intermediate, light intermediate and light chains are not a cause of neuropathy in our cohort.

  13. Acquired versus familial demyelinative neuropathies in children.

    Science.gov (United States)

    Miller, R G; Gutmann, L; Lewis, R A; Sumner, A J

    1985-01-01

    The electrophysiologic differences between chronic acquired demyelinative neuropathy and the demyelinative form of Charcot-Marie-Tooth disease have recently been reported. The present report extends these observations to include the genetically determined demyelinating neuropathies seen in metachromatic leukodystrophy, Krabbe's leukodystrophy, and Cockayne's syndrome. The electrophysiologic features of metachromatic leukodystrophy (five patients), Krabbe's (four patients), and Cockayne's syndrome (three patients) were all similar. There was uniform slowing of conduction (both in different nerves and in different nerve segments), and conduction block was not seen. These findings are consistent with a uniform degree of demyelination in multiple nerves and throughout the entire length of individual axons. Thus, uniform slowing of nerve conduction constitutes strong evidence for a familial demyelinative neuropathy, as opposed to the multifocal slowing seen in acute and chronic acquired demyelinative neuropathy.

  14. Type I Gaucher disease: extraosseous extension of skeletal disease

    Energy Technology Data Exchange (ETDEWEB)

    Poll, L.W.; Koch, J.A.; Moedder, U. [Department of Diagnostic Radiology, Heinrich Heine University Duesseldorf (Germany); vom Dahl, S.; Haeussinger, D. [Department of Internal Medicine, Divison of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Duesseldorf (Germany); Sarbia, M. [Department of Pathology, Heinrich Heine University Duesseldorf (Germany); Niederau, C. [Department of Internal Medicine, St.-Josef Hospital Oberhausen, Oberhausen (Germany)

    2000-01-01

    Objective. To investigate the frequency and morphology of extraosseous extension in patients with Gaucher disease type I.Design and patients. MRI examinations of the lower extremities were analyzed in 70 patients with Gaucher disease type I. Additionally, the thoracic spine and the midface were investigated on MRI in two patients.Results. Four cases are presented in which patients with Gaucher disease type I and severe skeletal involvement developed destruction or protrusion of the cortex with extraosseous extension into soft tissues. In one patient, Gaucher cell deposits destroyed the cortex of the mandible and extended into the masseter muscle. In the second patient, multiple paravertebral masses with localized destruction of the cortex were apparent in the thoracic spine. In the third and fourth patient, cortical destruction with extraosseous tissue extending into soft tissues was seen in the lower limbs.Conclusions. Extraosseous extension is a rare manifestation of Gaucher bone disease. While an increased risk of cancer, especially hematopoietic in origin, is known in patients with Gaucher disease, these extraosseous benign manifestations that may mimic malignant processes should be considered in the differential diagnosis of extraosseous extension into soft tissues. A narrow neck of tissue was apparent in all cases connecting bone and extraosseous extensions. (orig.)

  15. Microtubule dynamics in the peripheral nervous system: A matter of balance.

    Science.gov (United States)

    Almeida-Souza, Leonardo; Timmerman, Vincent; Janssens, Sophie

    2011-11-01

    The special architecture of neurons in the peripheral nervous system, with axons extending for long distances, represents a major challenge for the intracellular transport system. Two recent studies show that mutations in the small heat shock protein HSPB1, which cause an axonal type of Charcot-Marie-Tooth (CMT) neuropathy, affect microtubule dynamics and impede axonal transport. Intriguingly, while at presymptomatic age the neurons in the mutant HSPB1 mouse show a hyperstable microtubule network, at postsymptomatic age, the microtubule network completely lost its stability as reflected by a marked decrease in tubulin acetylation levels. We here propose a model explaining the role of microtubule stabilization and tubulin acetylation in the pathogenesis of HSPB1 mutations.

  16. Peptide mimetic of the S100A4 protein modulates peripheral nerve regeneration and attenuates the progression of neuropathy in myelin protein P0 null mice

    DEFF Research Database (Denmark)

    Moldovan, Mihai; Pinchenko, Volodymyr; Dmytriyeva, Oksana

    2013-01-01

    We recently found that S100A4, a member of the multifunctional S100 protein family, protects neurons in the injured brain and identified two sequence motifs in S100A4 mediating its neurotrophic effect. Synthetic peptides encompassing these motifs stimulated neuritogenesis and survival in vitro...... and survival of myelinated axons. H3 accelerated electrophysiological, behavioral and morphological recovery after sciatic nerve crush while transiently delaying regeneration after sciatic nerve transection and repair. On the basis of the finding that both S100A4 and H3 increased neurite branching in vitro......, these effects were attributed to the modulatory effect of H3 on initial axonal sprouting. In contrast to the modest effect of H3 on the time course of regeneration, H3 had a long-term neuroprotective effect in the myelin protein P0 null mice, a model of dysmyelinating neuropathy (Charcot-Marie-Tooth type 1...

  17. Development profile in a patient with monosomy 10q and Dup(17p) associated with a peripheral neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Pellegrino, J.E.; Spinner, N.B.; Zackai, E.H. [Childrens Hospital of Philadelphia, PA (United States)] [and others

    1996-02-02

    We report on a patient with dup(17p) and monosomy (10q) resulting from a familial translocation. Manifestations typical of both syndromes were present. The overall development of this patient was better by comparison with similar reported cases of either anomaly. Our evaluation detected severe gross motor delay and signs of a demyelinating peripheral neuropathy. This patient is trisomic for the region of 17p which includes the peripheral myelin protein-22 (PMP-22) gene, known to be duplicated in Charcot-Marie-Tooth neuropathy type 1A (CMT1A). Our analysis in this patient suggests that trisomy for the PMP-22 gene led to the demyelinating neuropathy and contributed to his severe motor development delay. 33 refs., 3 figs., 1 tab.

  18. Blood type biochemistry and human disease.

    Science.gov (United States)

    Ewald, D Rose; Sumner, Susan C J

    2016-11-01

    Associations between blood type and disease have been studied since the early 1900s when researchers determined that antibodies and antigens are inherited. In the 1950s, the chemical identification of the carbohydrate structure of surface antigens led to the understanding of biosynthetic pathways. The blood type is defined by oligosaccharide structures, which are specific to the antigens, thus, blood group antigens are secondary gene products, while the primary gene products are various glycosyltransferase enzymes that attach the sugar molecules to the oligosaccharide chain. Blood group antigens are found on red blood cells, platelets, leukocytes, plasma proteins, certain tissues, and various cell surface enzymes, and also exist in soluble form in body secretions such as breast milk, seminal fluid, saliva, sweat, gastric secretions, urine, and amniotic fluid. Recent advances in technology, biochemistry, and genetics have clarified the functional classifications of human blood group antigens, the structure of the A, B, H, and Lewis determinants and the enzymes that produce them, and the association of blood group antigens with disease risks. Further research to identify differences in the biochemical composition of blood group antigens, and the relationship to risks for disease, can be important for the identification of targets for the development of nutritional intervention strategies, or the identification of druggable targets. WIREs Syst Biol Med 2016, 8:517-535. doi: 10.1002/wsbm.1355 For further resources related to this article, please visit the WIREs website.

  19. Type 1 diabetes: A predictable disease

    Institute of Scientific and Technical Information of China (English)

    Kimber M Simmons; Aaron W Michels

    2015-01-01

    Type 1 diabetes (T1D) is an autoimmune disease characterizedby loss of insulin producing beta cells andreliance on exogenous insulin for survival. T1D is one ofthe most common chronic diseases in childhood and theincidence is increasing, especially in children less than 5years of age. In individuals with a genetic predisposition,an unidentified trigger initiates an abnormal immuneresponse and the development of islet autoantibodiesdirected against proteins in insulin producing beta cells.There are currently four biochemical islet autoantibodiesmeasured in the serum directed against insulin, glutamicdecarboxylase, islet antigen 2, and zinc transporter 8.Development of islet autoantibodies occurs before clinicaldiagnosis of T1D, making T1D a predictable disease in anindividual with 2 or more autoantibodies. Screening forislet autoantibodies is still predominantly done throughresearch studies, but efforts are underway to screenthe general population. The benefits of screening forislet autoantibodies include decreasing the incidenceof diabetic ketoacidosis that can be life threatening,initiating insulin therapy sooner in the disease process,and evaluating safe and specific therapies in largerandomized clinical intervention trials to delay or preventprogression to diabetes onset.

  20. Bullous Skin Diseases: Classical Types of Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Jan Damoiseaux

    2013-01-01

    Full Text Available The prototypic bullous skin diseases, pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid, are characterized by the blister formation in the skin and/or oral mucosa in combination with circulating and deposited autoantibodies reactive with (hemidesmosomes. Koch’s postulates, adapted for autoimmune diseases, were applied on these skin diseases. It appears that all adapted Koch’s postulates are fulfilled, and, therefore, these bullous skin diseases are to be considered classical autoimmune diseases within the wide and expanding spectrum of autoimmune diseases.

  1. Niemann-Pick disease type C

    OpenAIRE

    Vanier Marie T

    2010-01-01

    Abstract Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in...

  2. Localized Castleman disease of plasma cell type in the abdomen

    Institute of Scientific and Technical Information of China (English)

    LU Zhi-hua; WU Mei

    2011-01-01

    Castleman disease is a relatively rare entity,with the hyaline-vascular type the predominant form.Although the plasma cell type is uncommon,it still comprises approximately 10% of cases of localized diseases.In addition,the abdomen is a rare site for involvement and localized Castleman disease of the plasma cell type in the abdomen is rare.The radiologic features of localized plasma cell type in the abdomen are mostly limited to case reports.In addition to the conventional imaging findings,we present some new imaging findings of localized plasma cell type in the abdomen.

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

    Science.gov (United States)

    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

  4. [Autoimmune diseases in type 1A diabetes mellitus].

    Science.gov (United States)

    Ferreira-Hermosillo, Aldo; Molina-Ayala, Mario Antonio

    2015-08-01

    Type 1A diabetes (DM1A) is an autoimmune disease that comprises 10% of patients with diabetes mellitus. Its frequency is gradually increasing in countries like Mexico. Patients with DM1A commonly have hypothyroidism, Addison disease, celiac disease and less common diseases such as polyglandular syndrome. These diseases are related to susceptibility genes such as HLA, CTLA-4 and PTPN22, which induce central and peripheral immunologic tolerance. This review article emphasizes the importance of searching other autoimmune diseases in patients with DM1A, to improve their prognosis and quality of life.

  5. Transitional type of Castleman's disease manifested as the POEMS syndrome

    Directory of Open Access Journals (Sweden)

    Tomić Ilija

    2004-01-01

    Full Text Available Background. Castleman’s disease is an atypical lymphoproliferative disorder characterized by angiofollicular hyperplasia of lymph nodes. Histologically it can be classified into a hyaline-vascular type, plasma-cell type, and transitional (mixed-cell type, while clinically localized type has been classified as unicentric, or generalized (multicentric form of the disease. Case report. This paper presents a 21 years old male patient with multicentric Castleman’s disease, a transitional (mixed-cell type. The disease was manifested by fever, generalized enlargement of peripherial lymph nodes, breast glands enlargement, hyperemia of the face, and weakness of the lower extremities. We found mediastinal lymphadenopathy, pleural and pericardial effusions, sensorimotor peripherial neuropathy and polyclonal hypergammaglobulinemia. The simultaneous presence of these manifestations of the disease (sensomotor peripheral neuropathy, lymphadenopathy, effusions endocrinopathy, polyclonal gammaglobulinemia and skin changes is indentified as POEMS syndrome. The diagnosis of Castleman’s disease was based on the results of histopathologic analysis of mediastinal lymph node biopsies after thoracotomy. The patient was treated with corticosteroids (prednisone 80 mg daily for 2 weeks followed by 60 mg daily. A partial response was achieved after 4 months of treatment. Conclusion. A transitional type of multicentric Castleman’s disease may be present itself as POEMS syndrome. The effect of corticosteroid therapy in this form of the disease is unpredictable.

  6. Surgical treatment of unicentric plasma cell histological type Castleman's disease

    Directory of Open Access Journals (Sweden)

    Marić Nebojša

    2011-01-01

    Full Text Available Introduction. Castleman’s disease or angiofollicular lymph hyperplasia is a rare disease with two identified clinical forms. Unicentric or localized form is characterized by isolated growth of lymph nodes, most often in mediastinum, and multicentric form is expressed as systemic disease with spread lymphadenopathy, organomegaly and presence of general symptoms of the disease. Histological types are hyalovascular, plasma-cell and transitive (mixed cell. Case report. This case report shows a woman, 59 years old, with unicentric form of plasma-cell type of Castleman’s disease. Unicentric form is usually shown as hyalovascular histological type, extremely rare as plasma-cell type, and transitive (mixed cell type was never described in literature as localized clinical form. The disease was manifested with chest pain, loss of body weight, exhaustion and weakness of legs. Further diagnostic procedures found the presence of enlarged lymph nodes paratracheally right, in a close contact with vena cava superior. The disease was confirmed by histopathological analysis of bioptated mediastinal lymph node after mediastinoscopy. Surgical treatment included extirpation of enlarged lymph nodes. After the regular postoperative condition, a full therapy effect was confirmed. Conclusion. Unicentric form of Castleman’s disease is expressed with enlarged lymph nodes on predilected places, usually in mediastinum. Surgical treatment is best method for the management of the disease and brings a full recovery of patient.

  7. An autosomal locus causing autoimmune disease: Autoimmune polyglandular disease type I assigned to chromosome 21

    NARCIS (Netherlands)

    J. Aaltonen (Johanna); P. Björses (Petra); L.A. Sandkuijl (Lodewijk); J. Perheentupa (Jaakko); L. Peltonen (Leena Johanna)

    1994-01-01

    textabstractAutoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease characterized by a variable combination of the failure of the endocrine glands. The pathogenesis of this unique autoimmune disease is unknown; unlike many other autoimmune diseases, APECED does

  8. Niemann-Pick disease type C

    Directory of Open Access Journals (Sweden)

    Vanier Marie T

    2010-06-01

    Full Text Available Abstract Niemann-Pick C disease (NP-C is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood. The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period, gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period, and ataxia not unfrequently following initial psychiatric disturbances (adult form. The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype. Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential

  9. Niemann-Pick disease type C.

    Science.gov (United States)

    Vanier, Marie T

    2010-06-03

    Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120,000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include

  10. Infantile Onset Glycogen Storage Disease Type 2: Case Report

    Directory of Open Access Journals (Sweden)

    Serkan Bilge Koca

    2014-08-01

    Full Text Available Glycogen storage disease type 2 (Pompe’s disease is an autosomal recessive, fatal glycogen storage disease presenting with hypotonia and muscle weakness. It is known that deficiency of lysosomal acid alpha-glucosidase (acid maltase leads to progressive generalised myopathy, cardiomyopathy and death in early infancy because of respiratory muscle weakness. Excessive undegradable intracellular glycogen deposition plays a role in the pathogenesis of the disease. Here we report a 3.5 month-old girl presenting with respiratory failure due to pneumonia and hypotonia, who was later diagnosed as Pompe disease.

  11. Genetics Home Reference: glycogen storage disease type I

    Science.gov (United States)

    ... Wolfsdorf JI, Watson MS; American College of Medical Genetics and Genomics. Diagnosis and management of glycogen storage disease type ... practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014 Nov;16(11):e1. Citation ...

  12. Radiographic findings in type 3 b Gaucher disease

    Energy Technology Data Exchange (ETDEWEB)

    Hill, S.C. [Diagnostic Radiology Department, National Institutes of Health, Bethesda, MD (United States); Damaska, B.M. [Diagnostic Radiology Department, National Institutes of Health, Bethesda, MD (United States); Tsokos, M. [Laboratory of Pathology, National Institutes of Health, Bethesda, MD (United States); Kreps, C. [Developmental and Metabolic Neurology Branch, National Institutes of Health, Bethesda, MD (United States); Brady, R.O. [Developmental and Metabolic Neurology Branch, National Institutes of Health, Bethesda, MD (United States); Barton, N.W. [Developmental and Metabolic Neurology Branch, National Institutes of Health, Bethesda, MD (United States)

    1996-12-01

    The purpose of this paper is to describe the radiographic findings in type 3 b Gaucher disease, a chronic neuronopathic form of the illness with severe systemic manifestations. Between 1980 and 1985 17 consecutive patients were evaluated with radiography of the chest, long bones and spine, CT of the head and chest, abdominal sonography, and MRI of the head, abdomen and spine. Clinical manifestations were severe, and led to death from hepatic, pulmonary or cardiac failure in nine patients. Type 3 b Gaucher disease shares the same spectrum of radiographic findings observed in type 1 disease, but the systemic manifestations are more severe. Pulmonary infiltrates, thoracic lymph node enlargement, vertebral compression fractures and osteonecrosis of the long bones occur much more frequently in patients with type 3 b disease. (orig.). With 7 figs., 2 tabs.

  13. The clinical management of Type 2 Gaucher disease.

    Science.gov (United States)

    Weiss, Karin; Gonzalez, Ashley N; Lopez, Grisel; Pedoeim, Leah; Groden, Catherine; Sidransky, Ellen

    2015-02-01

    Gaucher disease, the inherited deficiency of the enzyme glucocerebrosidase, is the most common of the lysosomal storage disorders. Type 2 Gaucher disease, the most severe and progressive form, manifests either prenatally or in the first months of life, followed by death within the first years of life. The rarity of the many lysosomal storage disorders makes their diagnosis a challenge, especially in the newborn period when the focus is often on more prevalent illnesses. Thus, a heightened awareness of the presentation of these rare diseases is necessary to ensure their timely consideration. This review, designed to serve as a guide to physicians treating newborns and infants with Gaucher disease, discusses the presenting manifestations of Type 2 Gaucher disease, the diagnostic work-up, associated genotypes and suggestions for management. We also address the ethical concerns that may arise with this progressive and lethal disorder, since currently available treatments may prolong life, but do not impact the neurological manifestations of the disease.

  14. Interferon Type I Driven Immune Activation in Generalized Autoimmune Diseases

    NARCIS (Netherlands)

    Z. Brkić (Zana)

    2013-01-01

    textabstractThis thesis describes research performed on several generalized autoimmune diseases with the main focus on primary Sjögren’s syndrome. Interferon type I has been implicated in the pathogenesis of these diseases and will be introduced in this chapter together with other important immune f

  15. [Periodontal disease in children with diabetes mellitus type 1].

    Science.gov (United States)

    Tuleutaeva, S; Ashirbekova, Z; Manapova, D; Almurat, S; Kharchenko, V

    2014-10-01

    The aim of the article was to study the occurrence of periodontal diseases in children with type I diabetes mellitus. The examination of 78 children revealed periodontal diseases in 40 children with type I diabetes. OHI-S, CPITN, PMA indices were determined. Pathological changes in periodontal tissues were revealed in 100% of cases. The following were identified: gingival hemorrhage (100%), over - and under-gingival dental tartar (100%), inflammation of gingival papilla (87,5%) marginal (80%) and alveolar gingiva (55%). Spread of periodontal disease among children with I type diabetes is characterized as high and is equal to 100%. Degree of periodontal sickness is evaluated as average and is M=2,28; SD=0,47 according to CPITN index. Treatment and preventive measures should be carried out taking into account major somatic disease.

  16. A probable new type of osteopenic bone disease

    Energy Technology Data Exchange (ETDEWEB)

    Widhe, Torulf L. [Department of Orthopaedics, Huddinge University Hospital (Sweden)

    2002-06-01

    A probable new type of osteopenic bone disease in two sisters and one female cousin is described. In infancy, the radiological findings were osteopenia, coxa vara, periosteal cloaking, bowing of the long bones, and flaring of the metaphyses. During growth, spinal pathology developed with compression of the vertebral bodies and scoliosis in one girl and kyphosis in another. All three children had genu valgum and two developed severe S-shaped bowing of the tibiae. Growth was stunted. Inheritance of this disorder is probably recessive. Type I and III collagen biosynthesis was normal. This condition is probably a hitherto undescribed form of osteogenesis imperfecta type III or a new bone disease. (orig.)

  17. Molecular characterization of infants with type 2 Gaucher disease

    Energy Technology Data Exchange (ETDEWEB)

    Stubblefield, B.; Martin, B.M.; Ginns, E.I. [Clinical Neuroscience Branch, Bethseda, MD (United States)] [and others

    1994-09-01

    Type 2 (acute neuronopathic) Gaucher disease was previously thought to be stereotypic in presentation with neurologic deterioration and death by age 2-3 years. However, the generation of a null allele knock-out Gaucher mouse led to the recognition of a subset of type 2 patients who die as neonates. To better understand this subgroup we studied DNA, RNA and residual enzyme activity in fibroblasts from neonatal type 2 Gaucher patients, {open_quotes}classic{close_quotes} type 2 patients, type 1 and type 3 patients and normal individuals. Mutational analysis revealed genotypic heterogeneity in each group. One patient with severe neonatal Gaucher disease and hydrops fetalis was homoallelic for a complex allele including mutations L44P, A456P and V460V, while others had different or unknown alleles. Northern blots demonstrated that transcription was intact even in the neonatal lethal patients. However, the more severe type 2 patients had virtually no protein on Western, indicating that the transcript is either not appropriately translated or results in an unstable protein. Thus type 2 Gaucher disease exhibits more phenotypic, genotypic and biochemical heterogeneity than previously appreciated.

  18. Muscle fiber-type distribution, fiber-type-specific damage, and the Pompe disease phenotype.

    Science.gov (United States)

    van den Berg, L E M; Drost, M R; Schaart, G; de Laat, J; van Doorn, P A; van der Ploeg, A T; Reuser, A J J

    2013-09-01

    Pompe disease is a lysosomal storage disorder caused by acid α-glucosidase deficiency and characterized by progressive muscle weakness. Enzyme replacement therapy (ERT) has ameliorated patients' perspectives, but reversal of skeletal muscle pathology remains a challenge. We studied pretreatment biopsies of 22 patients with different phenotypes to investigate to what extent fiber-type distribution and fiber-type-specific damage contribute to clinical diversity. Pompe patients have the same fiber-type distribution as healthy persons, but among nonclassic patients with the same GAA mutation (c.-32-13T>G), those with early onset of symptoms tend to have more type 2 muscle fibers than those with late-onset disease. Further, it seemed that the older, more severely affected classic infantile patients and the wheelchair-bound and ventilated nonclassic patients had a greater proportion of type 2x muscle fibers. However, as in other diseases, this may be caused by physical inactivity of those patients.

  19. Basal Cell Carcinoma in Type 2 Segmental Darier's Disease

    Directory of Open Access Journals (Sweden)

    Lynne Robertson

    2012-01-01

    Full Text Available Background. Darier's disease (DD, also known as Keratosis Follicularis or Darier-White disease, is a rare disorder of keratinization. DD can present as a generalized autosomal dominant condition as well as a localized or segmental postzygotic condition (Vázquez et al., 2002. Clinical features of DD include greasy, warty papules and plaques on seborrheic areas, dystrophic nails, palmo-plantar pits, and papules on the dorsum of the hands and feet. Objective. We report a case of basal cell carcinoma developing in a patient with type 2 segmental DD. Conclusion. According to the current literature, Type 2 segmental disease is a rare presentation of Darier's disease with only 8 previous cases reported to date. In addition, nonmelanoma skin cancer (NMSC arising from DD is rarely reported; however, there may be an association between DD and risk of carcinogenesis.

  20. Type A Behaviours and Heart Disease: Epidemiological and Experimental Foundations

    Directory of Open Access Journals (Sweden)

    Paul Bennett

    1990-01-01

    Full Text Available This paper critically examines three strands of evidence that concern the relationship between type A behaviours and coronary heart disease; prospective epidemiological studies of healthy populations, studies of those at high risk for coronary heart disease, and angiographic studies of atherosclerosis. The first of these would seem to provide the strongest test. Methodological and conceptual issues mean that the results of studies using the other methods should be interpreted with care. It is concluded that there is relatively strong evidence of an association between Type A behaviour as measured by Structured Interview and coronary heart disease. Hostility and anger appear to be the most powerful determinants of CHD. However, it is likely that they interact with other type A behaviours and related environmental factors in determining risk.

  1. Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease

    OpenAIRE

    Mistry, Pramod K.; LIU, Jun; Sun, Li; Chuang, Wei-Lien; Yuen, Tony; Yang, Ruhua; Lu, Ping; Zhang, Kate; Li, Jianhua; Keutzer, Joan; Stachnik, Agnes; Mennone, Albert; Boyer, James L; Jain, Dhanpat; Brady, Roscoe O

    2014-01-01

    Type 1 Gaucher disease (GD1) is a rare autosomal recessive disorder caused by inherited mutations in the glucocerebrosidase (GBA1) gene. This disease results in a marked accumulation of glycosphingolipid substrates, causing visceromegaly, cytopenia, and osteopenia. Here, we have rescued this clinical phenotype in GD1 mice by genetically deleting Gba2, a gene encoding a downstream extralysosomal enzyme, GBA2. We also report that sphingosine production in GD1 patients may contribute to the low-...

  2. The saccadic and neurological deficits in type 3 Gaucher disease.

    Directory of Open Access Journals (Sweden)

    William Benko

    Full Text Available Our objective was to characterize the saccadic eye movements in patients with type 3 Gaucher disease (chronic neuronopathic in relationship to neurological and neurophysiological abnormalities. For approximately 4 years, we prospectively followed a cohort of 15 patients with Gaucher type 3, ages 8-28 years, by measuring saccadic eye movements using the scleral search coil method. We found that patients with type 3 Gaucher disease had a significantly higher regression slope of duration vs amplitude and peak duration vs amplitude compared to healthy controls for both horizontal and vertical saccades. Saccadic latency was significantly increased for horizontal saccades only. Downward saccades were more affected than upward saccades. Saccade abnormalities increased over time in some patients reflecting the slowly progressive nature of the disease. Phase plane plots showed individually characteristic patterns of abnormal saccade trajectories. Oculo-manual dexterity scores on the Purdue Pegboard test were low in virtually all patients, even in those with normal cognitive function. Vertical saccade peak duration vs amplitude slope significantly correlated with IQ and with the performance on the Purdue Pegboard but not with the brainstem and somatosensory evoked potentials. We conclude that, in patients with Gaucher disease type 3, saccadic eye movements and oculo-manual dexterity are representative neurological functions for longitudinal studies and can probably be used as endpoints for therapeutic clinical trials.ClinicalTrials.gov NCT00001289.

  3. RENAL COMPLICATIONS IN GLYCOGEN-STORAGE-DISEASE TYPE-I

    NARCIS (Netherlands)

    REITSMABIERENS, WCC

    1993-01-01

    Deficiency of the enzyme glucose-6-phosphatase is the biochemical defect in glycogen storage disease type I (GSD I). Normally this enzyme is present in the liver, intestine and kidneys. The lack of the enzyme in the kidney makes it obvious that glycogen storage will not be restricted to the liver bu

  4. Acute type II cryoglobulinaemic vasculitis mimicking atherosclerotic peripheral vascular disease.

    LENUS (Irish Health Repository)

    Saeed, A

    2012-01-31

    Atherosclerotic peripheral vascular disease is a common presenting cause for digital ischaemia in life long smokers. Acute severe Type II Cryoglobulinaemic vasculitis is a rare yet important cause, which may present with similar clinical features and which if undiagnosed may be rapidly fatal. Following the instigation of therapy with intravenous methylprednisolone and cyclophosphamide this patient made an excellent recovery.

  5. Relationship between Genomic Types of Escherichia coli and Clinical Diseases

    Institute of Scientific and Technical Information of China (English)

    Meiying YI; Ruen LIU; Hanju HUANG

    2008-01-01

    In this study, by analysis of genome structures of E. coli, the relationships Between the genomic types of E. coli and the associated diseases were investigated. Samples of sputum, urine and other excretions from patients with different infective diseases were collected. And 62 E. coli strains were isolated from these samples. Intact bacterial genomic DNA was cleaved with I-CeuI, separated by pulsed field gel electrophoresis and then typed on the basis of cleavage map. The results showed that 7 I-CeuI sites were found in all the genome structures of the 62 E. coli, indicating that there were 7 rrn operons in the genomes. The size of genome ranged from 4500 kb to 5000 kb. According to thegenome structures, 62 E. coli strains were divided into 30 genome types. It was concluded that genome structures of E. coli isolated from the patients with different infective diseases varied to some extent, suggesting that some genome types of E. coli were closely related to some infective diseases.

  6. Coxarthritis as the Presenting Symptom of Gaucher Disease Type 1

    Directory of Open Access Journals (Sweden)

    Giacomo Brisca

    2011-01-01

    Full Text Available Gaucher disease (GD type 1 is the most common lysosomal storage disorder due to beta glucocerebrosidase deficiency leading to an abnormal accumulation of its substrate, glucocerebroside, in the mononuclear phagocyte system. The disease presentation is usually characterized by signs and symptoms related to hypersplenism, such as splenomegaly, anaemia, thrombocytopenia and leucopenia. Skeletal disease may occur later for the infiltration of bone marrow by macrophages infiltration and bone resorption: bone involvement may be heterogeneously manifested by symptoms ranging from bone crisis to avascular necrosis, osteoporosis and defect in remodeling of long bones. Herein, we report a patient in whom the osteoarticular involvement has been the only symptom of the disease stressing that this unusual presentation of GD has prompted a wide differential diagnosis with more common forms of coxitis.

  7. [Niemann-Pick type C disease: pathophysiology, diagnosis and treatment].

    Science.gov (United States)

    Ohno, Kousaku

    2016-03-01

    Niemann-Pick type C (NPC) disease is an autosomal recessive neurodegenerative disorder which is caused in 95% by a mutation in the NPC1 gene on chromosome 18 or by NPC2 mutation, encoding for 2 different lysosomal lipid transport proteins. The impaired protein function leads to systemic intralysosomal accumulation of free cholesterol and shingolipids particularly in the CNS. In Japan, currently 34 living NPC patients are known as of December 2015. Considering the prevalence of the disease in the Western countries, the real number of NPC patients is most likely to be five-folds higher. For NPC, treatment methods are established and an approved disease-specific medications are available. It is important that patients early in their disease are referred to expert centers, in order to ensure timely initiation of treatment and to delay the progression of neurological symptoms as a goal.

  8. Consensus guidelines for management of glycogen storage disease type 1b - European Study on Glycogen Storage Disease Type 1

    NARCIS (Netherlands)

    Visser, G; Rake, JP; Labrune, P; Leonard, JV; Moses, S; Ullrich, K; Wendel, U; Smit, GPA

    2002-01-01

    Life expectancy in glycogen storage disease type 1 (GSD-1) has improved considerably. Its relative rarity implies that no metabolic centre has experience of large series of patients and therefore experience with long-term management and follow-up at each centre is limited. There is wide variation in

  9. The Myers-Briggs type indicator and coronary heart disease.

    Science.gov (United States)

    Thorne, B M; Fyfe, J H; Carskadon, T G

    1987-01-01

    Researchers have for many years attempted to establish a relationship between coronary heart disease (CHD) and personality type. In our study, 103 subjects completed Form G of the Myers-Briggs Type Indicator (MBTI). Comparisons were made between 93 CHD patients and an age-appropriate control group (Group C) on each of the four MBTI dimensions: Extraversion-Introversion, Sensing-Intuition, Thinking-Feeling, and Judging-Perceiving. The comparison between CHD patients and Group C showed that CHD patients were significantly more likely to prefer sensing and feeling.

  10. Bone turnover markers in patients with type 1 Gaucher disease

    Directory of Open Access Journals (Sweden)

    Gaetano Giuffrida

    2012-11-01

    Full Text Available Bone complications occur frequently in Gaucher disease (GD and reduce the quality of life of these patients. Skeletal involvement is an important indication for treatment to ameliorate symptoms and reduce the risk of irreversible and debilitating disease. Bone biomarkers have been used to assess disease status and the response to therapy in a number of bone disorders. Here, we examine the literature for evidence of abnormalities in bone turnover markers in patients with type 1 GD to assess whether they might be useful for the assessment of bone involvement in GD. We have found that bone biomarkers in GD show highly variable results which do not currently support their routine use for clinical assessment of bone status, as an indication for therapy initiation, or for monitoring the response to therapy. A greater understanding of bone markers and their relation to the bone manifestations of GD is required.

  11. Pulmonary involvement in siblings with Gaucher disease type III

    Directory of Open Access Journals (Sweden)

    Đorđević Maja

    2011-01-01

    Full Text Available Introduction. Pulmonary involvement has been described in all types of Gaucher disease (GD but it is considered as relatively rare manifestation. There are reports suggesting that homozygosity for L444P mutation in GBA gene is associated with a substantial risk for developing primary pulmonary disease in GD. Case report. We reported sisters with pulmonary involvement in GD type III. Respiratory failure with fatal outcome at 3 years and 4 months of age occurred in K.K. due to pulmonary complications of GD. At the time enzyme replacement therapy (ERT was not available in Serbia. J.K., homozygous for L444P mutation, developed asymptomatic pulmonary involvement at the age of 6 after 2.5 years of ERT. Pulmonary disease in J.K. was verified by high resolution computerized tomography, cytology of bronchoalveolar lavage fluid and histopathology of transbronchial lung biopsy. Conclusion. Primary lung disease in children homoallelic for L444P mutation in GBA gene emerges as a significant clinical manifestation of GD with unclear response to ERT.

  12. Non-diabetic renal disease (NDRD) in patients with type 2 diabetes mellitus (type 2 DM).

    Science.gov (United States)

    Prakash, Jai

    2013-03-01

    In contrast to Type 1 diabetes mellitus (DM), the incidence of non-diabetic renal disease (NDRD) is very high in Type 2 diabetic patients. A wide spectrum of non-diabetic nephropathy (NDN) including both glomerular and tubulointerstitial lesions are reported in patients with Type 2 DM and their precise diagnosis requires histological examination of kidney tissue. Renal biopsy studies suggest that 25-50% of patients with Type 2 diabetes had glomerular lesions unrelated to or in addition to diabetic nephropathy. Histological studies confirm that NDRD can occur in isolated form without diabetic nephropathy or superimposed on diabetic nephropathy. Diabetic nephropathy can occur in absence of retinopathy and chance of getting diabetic and non-diabetic renal lesions are nearly equal in Type 2 diabetic patient in absence of diabetic retinopathy (RP). The presence of RP suggests the concurrence of DN, but does not exclude non-diabetic nephropathy. Clearly, renal biopsy is indicated in proteinuric Type 2 diabetic patients for precise diagnosis of diabetic vs non-diabetic renal disease. Appropriate treatment of NDRD is associated with good clinical outcome. Thus, it is gratifying to treat NDRD in selected patients. Besides, 40 to 60% of ESRD in Type 2 diabetic patients is not caused by diabetic nephropathy.

  13. [Diabetes type 2 and Alzheimer disease - one or two diseases? Mechanisms of association].

    Science.gov (United States)

    Marszałek, Małgorzata

    2013-07-23

    Some epidemiological data and pathophysiological evidence suggest similarities and connection of two amyloidoses: diabetes mellitus type 2, (DM2) (non-insulin dependent diabetes mellitus, NIDDM) and Alzheimer's disease (AD). What they have in common is insulin resistance, neurodegeneration, development and progression of dementia, and the fact that in the course of both diseases fibrillar aggregates of specific proteins are accumulated in affected organs. What is more, experimental evidence also supports the hypothesis that small prefibrillar aggregates that emerge prior to the appearance of mature fibrils are responsible for a key step in development and cytotoxicity of both diseases. They also have similar pathogenic effects. Both peptides possess the common receptor AMY3. More and more evidence is accumulating that key cell regulation processes are similar for both diseases as well. The question is raised: can Alzheimer be a new form of diabetes disease?

  14. Minimal change disease associated with type 1 and type 2 diabetes mellitus.

    Science.gov (United States)

    Moyses Neto, Miguel; Silva, Gyl Eanes Barros; Costa, Roberto S; Romão, Elen A; Vieira Neto, Osvaldo Merege; Dantas, Marcio

    2012-07-01

    A 19-year-old female with type 1 diabetes for four years, and a 73-year-old female with type 2 diabetes for twenty years developed sudden-onset nephrotic syndrome. Examination by light microscopy, immunofluorescence, and electron microscopy (in one case) identified minimal change disease (MCD) in both cases. There was a potential causative drug (meloxicam) for the 73-year-old patient. Both patients were treated with prednisone and responded with complete remission. The patient with type 1 diabetes showed complete remission without relapse, and the patient with type 2 diabetes had two relapses; complete remission was sustained after associated treatment with cyclophosphamide and prednisone. Both patients had two years of follow-up evaluation after remission. We discuss the outcomes of both patients and emphasize the role of kidney biopsy in diabetic patients with an atypical proteinuric clinical course, because patients with MCD clearly respond to corticotherapy alone or in conjunction with other immunosuppressive agents.

  15. Altered expression of type-1 and type-2 cannabinoid receptors in celiac disease.

    Directory of Open Access Journals (Sweden)

    Natalia Battista

    Full Text Available Anandamide (AEA is the prominent member of the endocannabinoid family and its biological action is mediated through the binding to both type-1 (CB1 and type-2 (CB2 cannabinoid receptors (CBR. The presence of AEA and CBR in the gastrointestinal tract highlighted their pathophysiological role in several gut diseases, including celiac disease. Here, we aimed to investigate the expression of CBR at transcriptional and translational levels in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also biopsies from treated celiac patients cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our data show higher levels of both CB1 and CB2 receptors during active disease and normal CBR levels in treated celiac patients. In conclusion, we demonstrate an up-regulation of CB1 and CB2 mRNA and protein expression, that points to the therapeutic potential of targeting CBR in patients with celiac disease.

  16. Type 2 diabetes mellitus and Alzheimer’s disease

    Institute of Scientific and Technical Information of China (English)

    Mario; Barbagallo; Ligia; J; Dominguez

    2014-01-01

    Epidemiological and biological evidences support a link between type 2 diabetes mellitus(DM2) and Alzheimer’s disease(AD). Persons with diabetes have a higher incidence of cognitive decline and an increased risk of developing all types of dementia. Cognitive deficits in persons with diabetes mainly affect the areas of psychomotor efficiency, attention, learning and memory, mental flexibility and speed, and executive function. The strong epidemiological association has suggested the existence of a physiopathological link. The determinants of the accelerated cognitive decline in DM2, however, are less clear. Increased cortical and subcortical atrophy have been evidenced after controlling for diabetic vascular disease and inadequate cerebral circulation. Most recent studies have focused on the role of insulin and insulin resistance as possible links between diabetes and AD. Disturbances in brain insulin signaling mechanisms may contribute to the molecular, biochemical, and histopathological lesions in AD. Hyperglycemia itself is a risk factor for cognitive dysfunction and dementia. Hypoglycemia may also have deleterious effects on cognitive function. Recurrent symptomatic and asymptomatic hypoglycemic episodes have been suggested to cause sub-clinical brain damage, and permanent cognitive impairment. Futuretrials are required to clarify the mechanistic link, to address the question whether cognitive decline may be prevented by an adequate metabolic control, and to elucidate the role of drugs that may cause hypoglycemic episodes.

  17. Glycogen storage disease type I: clinical and laboratory profile

    Directory of Open Access Journals (Sweden)

    Berenice L. Santos

    2014-12-01

    Full Text Available OBJECTIVES: To characterize the clinical, laboratory, and anthropometric profile of a sample of Brazilian patients with glycogen storage disease type I managed at an outpatient referral clinic for inborn errors of metabolism. METHODS: This was a cross-sectional outpatient study based on a convenience sampling strategy. Data on diagnosis, management, anthropometric parameters, and follow-up were assessed. RESULTS: Twenty-one patients were included (median age 10 years, range 1-25 years, all using uncooked cornstarch therapy. Median age at diagnosis was 7 months (range, 1-132 months, and 19 patients underwent liver biopsy for diagnostic confirmation. Overweight, short stature, hepatomegaly, and liver nodules were present in 16 of 21, four of 21, nine of 14, and three of 14 patients, respectively. A correlation was found between height-for-age and BMI-for-age Z-scores (r = 0.561; p = 0.008. CONCLUSIONS: Diagnosis of glycogen storage disease type I is delayed in Brazil. Most patients undergo liver biopsy for diagnostic confirmation, even though the combination of a characteristic clinical presentation and molecular methods can provide a definitive diagnosis in a less invasive manner. Obesity is a side effect of cornstarch therapy, and appears to be associated with growth in these patients.

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

    Science.gov (United States)

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

    2016-08-01

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

  19. The Role of Rab Proteins in Neuronal Cells and in the Trafficking of Neurotrophin Receptors

    Directory of Open Access Journals (Sweden)

    Cecilia Bucci

    2014-10-01

    Full Text Available Neurotrophins are a family of proteins that are important for neuronal development, neuronal survival and neuronal functions. Neurotrophins exert their role by binding to their receptors, the Trk family of receptor tyrosine kinases (TrkA, TrkB, and TrkC and p75NTR, a member of the tumor necrosis factor (TNF receptor superfamily. Binding of neurotrophins to receptors triggers a complex series of signal transduction events, which are able to induce neuronal differentiation but are also responsible for neuronal maintenance and neuronal functions. Rab proteins are small GTPases localized to the cytosolic surface of specific intracellular compartments and are involved in controlling vesicular transport. Rab proteins, acting as master regulators of the membrane trafficking network, play a central role in both trafficking and signaling pathways of neurotrophin receptors. Axonal transport represents the Achilles' heel of neurons, due to the long-range distance that molecules, organelles and, in particular, neurotrophin-receptor complexes have to cover. Indeed, alterations of axonal transport and, specifically, of axonal trafficking of neurotrophin receptors are responsible for several human neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and some forms of Charcot-Marie-Tooth disease. In this review, we will discuss the link between Rab proteins and neurotrophin receptor trafficking and their influence on downstream signaling pathways.

  20. Genetic homogeneity of autoimmune polyglandular disease type I

    Energy Technology Data Exchange (ETDEWEB)

    Bjoerses, P.; Aaltonen, J.; Vikman, A. [Univ. of Helsinki (Finland)] [and others

    1996-10-01

    Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease (MIM 240300) characterized by hypoparathyroidism, primary adrenocortical failure, and chronic mucocutaneous candidiasis. The disease is highly prevalent in two isolated populations, the Finnish population and the Iranian Jewish one. Sporadic cases have been identified in many other countries, including almost all European countries. The APECED locus has previously been assigned to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Locus heterogeneity is a highly relevant question in this disease affecting multiple tissues and with great phenotypic diversity. To solve this matter, we performed linkage and haplotype analyses on APECED families rising from different populations. Six microsatellite markers on the critical chromosomal region of 2.6 cM on 21q22.3 were analyzed. Pair-wise linkage analyses revealed significant LOD scores for all these markers, maximum LOD score being 10.23. The obtained haplotype data and the geographic distribution of the great-grandparents of the Finnish APECED patients suggest the presence of one major, relatively old mutation responsible for {approximately}90% of the Finnish cases. Similar evidence for one founder mutation was also found in analyses of Iranian Jewish APECED haplotypes. These haplotypes, however, differed totally from the Finnish ones. The linkage analyses in 21 non-Finnish APECED families originating from several European countries provided independent evidence for linkage to the same chromosomal region on 21q22.3 and revealed no evidence for locus heterogeneity. The haplotype analyses of APECED chromosomes suggest that in different populations APECED is due to a spectrum of mutations in a still unknown gene on chromosome 21. 21 refs., 3 figs., 3 tabs.

  1. Molecular genetics of distal hereditary motor neuropathies.

    Science.gov (United States)

    Irobi, Joy; De Jonghe, Peter; Timmerman, Vincent

    2004-10-01

    Inherited peripheral neuropathies comprise a wide variety of diseases primarily affecting the peripheral nervous system. The best-known peripheral neuropathy is Charcot-Marie-Tooth disease (CMT) described in 1886 by J.-M. Charcot, P. Marie and H.H. Tooth. In 1980, A.E. Harding and P.K. Thomas showed that in a large group of individuals with CMT, several only had motor abnormalities on clinical and electrophysiological examination, whereas sensory abnormalities were absent. This exclusively motor variant of CMT was designated as spinal CMT or hereditary distal spinal muscular atrophy, and included in the distal hereditary motor neuropathies (distal HMN). The distal HMN are clinically and genetically heterogeneous and are subdivided according to the mode of inheritance, age at onset and clinical evolution. Since the introduction of positional cloning, 12 chromosomal loci and seven disease-causing genes have been identified for autosomal dominant and recessive distal HMN. Most of the genes involved have housekeeping functions, as in RNA processing, translation synthesis, glycosylation, stress response, apoptosis, but also axonal trafficking and editing. Functional characterization of the mutations will help to unravel the cellular processes that underlie the specificity of motor neuropathies leading to neurogenic muscular atrophy of distal limb muscles. Here we review the recent progress of the molecular genetics of distal HMN and discuss the genes implicated.

  2. [Diagnosis of the peripheral hereditary neuropathies and its molecular genetics].

    Science.gov (United States)

    Hernández-Zamora, Edgar; Arenas-Sordo, María de la Luz

    2008-01-01

    Peripheral neuropathies include a wide range of pathological disorders characterized by damage of peripheral nerves. Among them, peripheral hereditary neuropathies are a group of frequent illnesses and early evolution. They have been named hereditary motor and sensory neuropathy (HMSN) or peripheral hereditary neuropathies type Charcot-Marie-Tooth (CMT). The most frequent types are CMT1, CMT2 and CMTX. Approximately 70% of the cases correspond to subtype CMT1A, associated with tandem duplication of a 1.5 Mb DNA fragment on chromosome 17p11.2-p12 that codifies the peripheral myelin protein PMP22. So far, there five different types of CMT (1,2,3,4,X) with approximately 32 subtypes, associated with more than 30 genes. Have been reported genetic heterogeneity and expression variability of the illness makes it necessary to carry on diagnostic strategies that integrate clinical study for determining genetic clinical history, family history, complete physical exploration, muscular strength, physical deformities, reflexes and sensitivity, and molecular studies allow detection of different types of mutations and help establish a correct diagnosis and an adequate genetic counseling.

  3. Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Edvinsson, Marie-Louise; Chen, Qingwen;

    2009-01-01

    pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ETA) and type B (ETB), and angiotensin type 1 (AT1) and type 2 (AT2) receptors expression and function were examined using immunohistochemistry, Western blot and in vitro...... receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions....

  4. Metformin in Patients With Type 2 Diabetes and Kidney Disease

    Science.gov (United States)

    Inzucchi, Silvio E.; Lipska, Kasia J.; Mayo, Helen; Bailey, Clifford J.; McGuire, Darren K.

    2015-01-01

    IMPORTANCE Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. OBJECTIVE To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. EVIDENCE ACQUISITION In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial. RESULTS Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100 000 person-years to 10 per 100 000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus

  5. Charcot-Marine-Tooth CMT-2 Polyneuropathy Syndrome A Case Study.

    Directory of Open Access Journals (Sweden)

    Arbind Kumar Choudhary

    2015-06-01

    Full Text Available Abstract Charcot-Marie-Tooth disease CMT refers to the inherited peripheral neuropathies affect approximately one in 2500 people they are among the most common inherited neurological disorders. The majority of CMT patients have autosomal dominant inheritance although X-linked dominant and autosomal recessive forms also exist. The majority of cases are demyelinating although up to one third appear to be primary axonal or neuronal disorders. A patient of 9-year-old girl visited our hospital because of began to suffer from an insidious onset of progressive distal weakness and numbness and muscle twitching in both in her upper and lower limbs. Nerve conduction studies showed sensory nerve conduction SNCV of bilateral median and ulnar nerve was reduced in upper limb and bilateral sural nerve was reduced in lower limb While in case of motor nerve conduction MNCV bilateral median and ulnar nerve was reduced in upper limb and common peroneal nerve CPN as well as posterior tibial nerve was decreased leg. F response latencies were markedly prolonged in patient. Family history along with electrophysiological studied showed It was typical case of autosomal dominant CMT 2 axonal neuropathy. CMT is currently an untreatable disorder and at the moment the treatment of CMT is only supportive as there are no drugs available that would halt the disease symptoms. The care of a CMT patient is challenging for the health care team.

  6. Cloning, mapping and mutation analysis of human gene GJB5 encoding gap junction protein b-5

    Institute of Scientific and Technical Information of China (English)

    XIA; Jiahui; (夏家辉); ZHENG; Duo; (郑多),; TANG; Dongsheng; (唐冬生); DAI; Heping; (戴和平); PAN; Qian; (潘乾); LONG; Zhigao; (龙志高); LIAO; Xiaodong; (廖晓东)

    2001-01-01

    By homologous EST searching and nested PCR a new human gene GJB5 encoding gap junction protein b-5 was identified. GJB5 was genetically mapped to human chromosome 1p33-p35 by FISH. RT-PCR revealed that it was expressed in skin, placenta and fetal skin. DNA sequencing of GJB5 was carried out in 142 patients with sensorineural hearing impairment and probands of 36 families with genetic diseases, including erythrokeratodermia (5 families), Charcot-Marie-Tooth disease (13), ptosis (4), and retinitis pigmentosa and deafness (14). Two missense mutations (686A→G, H229R; 25C→T, L9F) were detected in two sensorineural hearing impairment families. A heterologous deletion of 18 bp within intron was found in 3 families with heredity hearing impairment, and in one of the 3 families, a missense mutation (R265P) was identified also. But the deletion and missense mutation seemed not segregating with hearing impairment in the family. No abnormal mRNA or mRNA expression was detected in deletion carriers by RT-PCR analysis in skin tissue. Mutation analysis in 199 unaffected individuals revealed that two of them were carriers with the same 18 bp deletion.

  7. Cloning, mapping and mutation analysis of human gene GJB5 encoding gap junction protein b-5

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    By homologous EST searching and nested PCR a new human gene GJB5encoding gap junction protein b-5 was identified. GJB5 was genetically mapped to human chromosome 1p33-p35 by FISH. RT-PCR revealed that it was expressed in skin, placenta and fetal skin. DNA sequencing of GJB5 was carried out in 142 patients with sensorineural hearing impairment and probands of 36 families with genetic diseases, including erythrokeratodermia (5 families), Charcot-Marie-Tooth disease (13), ptosis (4), and retinitis pigmentosa and deafness (14). Two missense mutations (686A→G, H229R; 25C→T, L9F) were detected in two sensorineural hearing impairment families. A heterologous deletion of 18 bp within intron was found in 3 families with heredity hearing impairment, and in one of the 3 families, a missense mutation (R265P) was identified also. But the deletion and missense mutation seemed not segregating with hearing impairment in the family. No abnormal mRNA or mRNA expression was detected in deletion carriers by RT-PCR analysis in skin tissue. Mutation analysis in 199 unaffected individuals revealed that two of them were carriers with the same 18 bp deletion.

  8. Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age.

    Science.gov (United States)

    Eschbach, Judith; Sinniger, Jérôme; Bouitbir, Jamal; Fergani, Anissa; Schlagowski, Anna-Isabel; Zoll, Joffrey; Geny, Bernard; René, Frédérique; Larmet, Yves; Marion, Vincent; Baloh, Robert H; Harms, Matthew B; Shy, Michael E; Messadeq, Nadia; Weydt, Patrick; Loeffler, Jean-Philippe; Ludolph, Albert C; Dupuis, Luc

    2013-10-01

    Mutations in the DYNC1H1 gene encoding for dynein heavy chain cause two closely related human motor neuropathies, dominant spinal muscular atrophy with lower extremity predominance (SMA-LED) and axonal Charcot-Marie-Tooth (CMT) disease, and lead to sensory neuropathy and striatal atrophy in mutant mice. Dynein is the molecular motor carrying mitochondria retrogradely on microtubules, yet the consequences of dynein mutations on mitochondrial physiology have not been explored. Here, we show that mouse fibroblasts bearing heterozygous or homozygous point mutation in Dync1h1, similar to human mutations, show profoundly abnormal mitochondrial morphology associated with the loss of mitofusin 1. Furthermore, heterozygous Dync1h1 mutant mice display progressive mitochondrial dysfunction in muscle and mitochondria progressively increase in size and invade sarcomeres. As a likely consequence of systemic mitochondrial dysfunction, Dync1h1 mutant mice develop hyperinsulinemia and hyperglycemia and progress to glucose intolerance with age. Similar defects in mitochondrial morphology and mitofusin levels are observed in fibroblasts from patients with SMA-LED. Last, we show that Dync1h1 mutant fibroblasts show impaired perinuclear clustering of mitochondria in response to mitochondrial uncoupling. Our results show that dynein function is required for the maintenance of mitochondrial morphology and function with aging and suggest that mitochondrial dysfunction contributes to dynein-dependent neurological diseases, such as SMA-LED.

  9. 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.

    Science.gov (United States)

    Kim, Ji-Yon; Woo, So-Youn; Hong, Young Bin; Choi, Heesun; Kim, Jisoo; Choi, Hyunjung; Mook-Jung, Inhee; Ha, Nina; Kyung, Jangbeen; Koo, Soo Kyung; Jung, Sung-Chul; Choi, Byung-Ok

    2016-01-01

    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.

  10. 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

    Directory of Open Access Journals (Sweden)

    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.

  11. Cryptic Amyloidogenic Elements in the 3′ UTRs of Neurofilament Genes Trigger Axonal Neuropathy

    Science.gov (United States)

    Rebelo, Adriana P.; Abrams, Alexander J.; Cottenie, Ellen; Horga, Alejandro; Gonzalez, Michael; Bis, Dana M.; Sanchez-Mejias, Avencia; Pinto, Milena; Buglo, Elena; Markel, Kasey; Prince, Jeffrey; Laura, Matilde; Houlden, Henry; Blake, Julian; Woodward, Cathy; Sweeney, Mary G.; Holton, Janice L.; Hanna, Michael; Dallman, Julia E.; Auer-Grumbach, Michaela; Reilly, Mary M.; Zuchner, Stephan

    2016-01-01

    Abnormal protein aggregation is observed in an expanding number of neurodegenerative diseases. Here, we describe a mechanism for intracellular toxic protein aggregation induced by an unusual mutation event in families affected by axonal neuropathy. These families carry distinct frameshift variants in NEFH (neurofilament heavy), leading to a loss of the terminating codon and translation of the 3′ UTR into an extra 40 amino acids. In silico aggregation prediction suggested the terminal 20 residues of the altered NEFH to be amyloidogenic, which we confirmed experimentally by serial deletion analysis. The presence of this amyloidogenic motif fused to NEFH caused prominent and toxic protein aggregates in transfected cells and disrupted motor neurons in zebrafish. We identified a similar aggregation-inducing mechanism in NEFL (neurofilament light) and FUS (fused in sarcoma), in which mutations are known to cause aggregation in Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis, respectively. In summary, we present a protein-aggregation-triggering mechanism that should be taken into consideration during the evaluation of stop-loss variants. PMID:27040688

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

    Science.gov (United States)

    Jerath, Nivedita U; Shy, Michael E

    2015-04-01

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

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

    Science.gov (United States)

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

    2016-10-01

    Distinguishing between hereditary and inflammatory neuropathy is usually straightforward on clinical grounds with the help of a family history. There are nevertheless cases where the distinction is less clear. The advent of molecular genetics has in the past several years aided confirmatory diagnosis for an increasing proportion of patients with genetic neuropathy. Various reports have described associations of Charcot-Marie-Tooth disease with a suspected or confirmed inflammatory neuropathy occasionally responding to immunotherapy. Possible predisposition to an inflammatory component was suggested in a subset of patients. Such reports have, however, been relatively few in number, suggesting the rarity of such associations and of such a predisposition if it exists. There have been a number of publications detailing clinical presentations suggestive of inflammatory neuropathy in patients with a known or later proven genetic aetiology, and subsequently felt to be part of the phenotype rather than representing an association. A number of genetically mediated multisystemic diseases with neuropathy have otherwise been reported as mimicking chronic inflammatory demyelinating polyneuropathy (CIDP). The most common example is that of familial amyloid polyneuropathy, of particular concern for the clinician when misdiagnosed as CIDP, in view of the therapeutic implications. We review the literature on reported associations, mimics and misdiagnoses of hereditary and inflammatory neuropathy and attempt to determine a practical approach to the problem in clinical practice using clinical features, electrophysiology, histopathology and targeted early genetic testing. The issue of attempting immunomodulatory therapy is discussed in view of the published literature.

  14. Exercise intolerance in Glycogen Storage Disease Type III

    DEFF Research Database (Denmark)

    Preisler, Nicolai; Pradel, Agnès; Husu, Edith

    2013-01-01

    experience exercise intolerance due to insufficient carbohydrate oxidation in skeletal muscle. Six patients aged 17-36-years were studied. We determined VO 2peak (peak oxygen consumption), the response to forearm exercise, and the metabolic and cardiovascular responses to cycle exercise at 70% of VO 2peak......Myopathic symptoms in Glycogen Storage Disease Type IIIa (GSD IIIa) are generally ascribed to the muscle wasting that these patients suffer in adult life, but an inability to debranch glycogen likely also has an impact on muscle energy metabolism. We hypothesized that patients with GSD IIIa can...... caused exercise intolerance with dynamic skeletal muscle symptoms (excessive fatigue and muscle pain), and hypoglycemia in 4 subjects. In this study we combined anaerobic and aerobic exercise to systematically study skeletal muscle metabolism and exercise tolerance in patients with GSD IIIa. Exercise...

  15. Current view from Alzheimer disease to type 2 diabetes mellitus.

    Science.gov (United States)

    Rasool, Mahmood; Malik, Arif; Qazi, Aamer M; Sheikh, Ishfaq A; Manan, Abdul; Shaheen, Sumaira; Qazi, Mahmood H; Chaudhary, Adeel G; Abuzenadah, Adel M; Asif, Muhammad; Alqahtani, Mohammed H; Iqbal, Zafar; Shaik, Munvar M; Gan, Siew H; Kamal, Mohammad A

    2014-04-01

    Alzheimer's disease (AD) is a neurodegenerative disorder that leads to memory problems. It has been associated with type 2 diabetes mellitus at both the molecular and biochemical level. Pancreatic cells have molecular similarities to the brain at the transcriptomic and proteomic levels. Several genes have been reported to be responsible for both AD and diabetes. Currently, no proper treatment is available but various therapeutic approaches are utilized worldwide for the management of these disorders and may be nanoparticles and herbal treatment of Bacopa monnieri will make promise for the treatment of AD in future. The formation of amyloids in neurons and the formation of amylin in pancreatic cells are potential links between these two disorders, which can be silent killers.

  16. Myocardial dysfunction and cardiovascular disease in type 2 diabetes.

    Science.gov (United States)

    Ofstad, Anne Pernille

    2016-07-01

    Type 2 diabetes mellitus (T2DM) is strongly associated with increased risk of myocardial dysfunction and cardiovascular disease (CVD), two separate conditions which often co-exist and influence each other's course. The prevalence of myocardial dysfunction may be as high as 75% in T2DM populations but is often overlooked due to the initial asymptomatic nature of the disease, complicating co-morbidities such as coronary artery disease (CAD) and obesity, and the lack of consensus on diagnostic criteria. More sensitive echocardiographic applications are furthermore needed to improve detection of early subclinical changes in myocardial function which do not affect conventional echocardiographic parameters. The pathophysiology of the diabetic myocardial dysfunction is not fully elucidated, but involves hyperglycemia and high levels of free fatty acids. It evolves over several years and increases the risk of developing overt HF, and is suggested to at least in part account for the worse outcome seen in T2DM individuals after cardiac events. CAD and stroke are the most frequent CV manifestations among T2DM patients and relate to a large degree to the accelerated atherosclerosis driven by inflammation. Diagnosing CAD is challenging due to the lower sensitivity inherent in the diagnostic tests and there is thus a need for new biomarkers to improve prediction and detection of CAD. It seems that a multi-factorial approach (i.e. targeting several CV risk factors simultaneously) is superior to a strict glucose lowering strategy in reducing risk for macrovascular events, and recent research may even support an effect also on HF outcomes.

  17. Insulin gene polymorphisms in type 1 diabetes, Addison's disease and the polyglandular autoimmune syndrome type II

    Directory of Open Access Journals (Sweden)

    Hahner Stefanie

    2008-07-01

    Full Text Available Abstract Background Polymorphisms within the insulin gene can influence insulin expression in the pancreas and especially in the thymus, where self-antigens are processed, shaping the T cell repertoire into selftolerance, a process that protects from β-cell autoimmunity. Methods We investigated the role of the -2221Msp(C/T and -23HphI(A/T polymorphisms within the insulin gene in patients with a monoglandular autoimmune endocrine disease [patients with isolated type 1 diabetes (T1D, n = 317, Addison's disease (AD, n = 107 or Hashimoto's thyroiditis (HT, n = 61], those with a polyglandular autoimmune syndrome type II (combination of T1D and/or AD with HT or GD, n = 62 as well as in healthy controls (HC, n = 275. Results T1D patients carried significantly more often the homozygous genotype "CC" -2221Msp(C/T and "AA" -23HphI(A/T polymorphisms than the HC (78.5% vs. 66.2%, p = 0.0027 and 75.4% vs. 52.4%, p = 3.7 × 10-8, respectively. The distribution of insulin gene polymorphisms did not show significant differences between patients with AD, HT, or APS-II and HC. Conclusion We demonstrate that the allele "C" of the -2221Msp(C/T and "A" -23HphI(A/T insulin gene polymorphisms confer susceptibility to T1D but not to isolated AD, HT or as a part of the APS-II.

  18. CMT-linked loss-of-function mutations in GDAP1 impair store-operated Ca2+ entry-stimulated respiration

    Science.gov (United States)

    González-Sánchez, Paloma; Pla-Martín, David; Martínez-Valero, Paula; Rueda, Carlos B.; Calpena, Eduardo; del Arco, Araceli; Palau, Francesc; Satrústegui, Jorgina

    2017-01-01

    GDAP1 is an outer mitochondrial membrane protein involved in Charcot-Marie-Tooth (CMT) disease. Lack of GDAP1 gives rise to altered mitochondrial networks and endoplasmic reticulum (ER)-mitochondrial interactions resulting in a decreased ER-Ca2+ levels along with a defect on store-operated calcium entry (SOCE) related to a misallocation of mitochondria to subplasmalemmal sites. The defect on SOCE is mimicked by MCU silencing or mitochondrial depolarization, which prevent mitochondrial calcium uptake. Ca2+ release from de ER and Ca2+ inflow through SOCE in neuroblastoma cells result in a Ca2+-dependent upregulation of respiration which is blunted in GDAP1 silenced cells. Reduced SOCE in cells with CMT recessive missense mutations in the α-loop of GDAP1, but not dominant mutations, was associated with smaller SOCE-stimulated respiration. These cases of GDAP1 deficiency also resulted in a decreased ER-Ca2+ levels which may have pathological implications. The results suggest that CMT neurons may be under energetic constraints upon stimulation by Ca2+ mobilization agonists and point to a potential role of perturbed mitochondria-ER interaction related to energy metabolism in forms of CMT caused by some of the recessive or null mutations of GDAP1. PMID:28220846

  19. Defining the impact on yeast ATP synthase of two pathogenic human mitochondrial DNA mutations, T9185C and T9191C.

    Science.gov (United States)

    Kabala, Anna Magdalena; Lasserre, Jean-Paul; Ackerman, Sharon H; di Rago, Jean-Paul; Kucharczyk, Roza

    2014-05-01

    Mutations in the human mitochondrial ATP6 gene encoding ATP synthase subunit a/6 (referred to as Atp6p in yeast) are at the base of neurodegenerative disorders like Neurogenic Ataxia and Retinitis Pigmentosa (NARP), Leigh syndrome (LS), Charcot-Marie-Tooth (CMT), and ataxia telangiectasia. In previous studies, using the yeast Saccharomyces cerevisiae as a model we were able to better define how several of these mutations impact the ATP synthase. Here we report the construction of yeast models of two other ATP6 pathogenic mutations, T9185C and T9191C. The first one was reported as conferring a mild, sometimes reversible, CMT clinical phenotype; the second one has been described in a patient presenting with severe LS. We found that an equivalent of the T9185C mutation partially impaired the functioning of yeast ATP synthase, with only a 30% deficit in mitochondrial ATP production. An equivalent of the mutation T9191C had much more severe effects, with a nearly complete block in yeast Atp6p assembly and an >95% drop in the rate of ATP synthesis. These findings provide a molecular basis for the relative severities of the diseases induced by T9185C and T9191C.

  20. Effect of Electroacupuncture on the Expression of Glycyl-tRNA Synthetase and Ultrastructure Changes in Atrophied Rat Peroneus Longus Muscle Induced by Sciatic Nerve Injection Injury

    Directory of Open Access Journals (Sweden)

    Meng Wang

    2016-01-01

    Full Text Available Glycyl-tRNA synthetase (GlyRS is one of the key enzymes involved in protein synthesis. Its mutations have been reported to cause Charcot-Marie-Tooth disease which demonstrates muscular atrophy in distal extremities, particularly manifested in peroneus muscles. In this situation, the dysfunctions of mitochondria and sarcoplasmic reticulum (SR affect energy supply and excitation-contraction coupling of muscle fibers, therefore resulting in muscular atrophy. Although the treatment of muscular atrophy is a global urgent problem, it can be improved by electroacupuncture (EA treatment. To investigate the mechanism underlying EA treatment improving muscular atrophy, we focused on the perspective of protein synthesis by establishing a penicillin injection-induced sciatic nerve injury model. In our model, injured rats without treatment showed decreased sciatic functional index (SFI, decreased peroneus longus muscle weight and muscle fiber cross-sectional area, aggregated mitochondria with vacuoles appearing, swollen SR, and downregulated mRNA and protein expression levels of GlyRS and myosin heavy chain IIb (MHC-IIb. The injured rats with EA treatment showed significant recovery. These results indicated that EA stimulation can alleviate peroneus longus muscular atrophy induced by iatrogenic sciatic nerve injury through promoting the recovery of GlyRS and muscle ultrastructure and increasing muscle protein synthesis.

  1. Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

    Science.gov (United States)

    Volpi, Vera G.; Touvier, Thierry; D'Antonio, Maurizio

    2017-01-01

    Reaching the correct three-dimensional structure is crucial for the proper function of a protein. The endoplasmic reticulum (ER) is the organelle where secreted and transmembrane proteins are synthesized and folded. To guarantee high fidelity of protein synthesis and maturation in the ER, cells have evolved ER-protein quality control (ERQC) systems, which assist protein folding and promptly degrade aberrant gene products. Only correctly folded proteins that pass ERQC checkpoints are allowed to exit the ER and reach their final destination. Misfolded glycoproteins are detected and targeted for degradation by the proteasome in a process known as endoplasmic reticulum-associated degradation (ERAD). The excess of unstructured proteins in the ER triggers an adaptive signal transduction pathway, called unfolded protein response (UPR), which in turn potentiates ERQC activities in order to reduce the levels of aberrant molecules. When the situation cannot be restored, the UPR drives cells to apoptosis. Myelin-forming cells of the central and peripheral nervous system (oligodendrocytes and Schwann cells) synthesize a large amount of myelin proteins and lipids and therefore are particularly susceptible to ERQC failure. Indeed, deficits in ERQC and activation of ER stress/UPR have been implicated in several myelin disorders, such as Pelizaeus-Merzbacher and Krabbe leucodystrophies, vanishing white matter disease and Charcot-Marie-Tooth neuropathies. Here we discuss recent evidence underlying the importance of proper ERQC functions in genetic disorders of myelinating glia. PMID:28101003

  2. 腓骨肌萎缩症的基因学研究进展

    Institute of Scientific and Technical Information of China (English)

    吴志国; 肖波; 肖剑锋

    2003-01-01

    @@ 腓骨肌萎缩症(Charcot marie tooth disease,CMT)是一类高发病率的周围神经系统单基因遗传病,发病率为1/2500,其遗传方式有常染色体显性遗传(AD)、常染色体隐性遗传(AR)及X连锁显性或隐性遗传(XD或XR).其主要临床表现为胫前腓骨肌及手部肌萎缩伴无力,足下垂,跨越步态,弓形足,膝踝反射减弱或消失,儿童、青少年、成年期均可发病,慢性进行性病程,致残率高.临床上根据CMT的病理和电生理特点分为两型,即脱髓鞘型(CMT1型)和轴突型(CMT2型),其中CMT1型约占CMT总数的70%.

  3. Glutamate signals through mGluR2 to control Schwann cell differentiation and proliferation

    Science.gov (United States)

    Saitoh, Fuminori; Wakatsuki, Shuji; Tokunaga, Shinji; Fujieda, Hiroki; Araki, Toshiyuki

    2016-01-01

    Rapid saltatory nerve conduction is facilitated by myelin structure, which is produced by Schwann cells (SC) in the peripheral nervous system (PNS). Proper development and degeneration/regeneration after injury requires regulated phenotypic changes of SC. We have previously shown that glutamate can induce SC proliferation in culture. Here we show that glutamate signals through metabotropic glutamate receptor 2 (mGluR2) to induce Erk phosphorylation in SC. mGluR2-elicited Erk phosphorylation requires ErbB2/3 receptor tyrosine kinase phosphorylation to limit the signaling cascade that promotes phosphorylation of Erk, but not Akt. We found that Gβγ and Src are involved in subcellular signaling downstream of mGluR2. We also found that glutamate can transform myelinating SC to proliferating SC, while inhibition of mGluR2 signaling can inhibit demyelination of injured nerves in vivo. These data suggest pathophysiological significance of mGluR2 signaling in PNS and its possible therapeutic importance to combat demyelinating disorders including Charcot-Marie-Tooth disease. PMID:27432639

  4. 遗传性运动感觉性周围神经病I型肌电图的特点

    Institute of Scientific and Technical Information of China (English)

    梁银杏; 葛辉; 卢锡林; 吕建敏

    2010-01-01

    目的:探讨遗传性运动感觉性周围神经病(Charcot-Marie-Tooth disease,简称CMT) I型肌电图的特点.方法:回顾性总结和分析36例CMTI型患者的双侧上肢远端及下肢常规肌电图及周围神经传导速度及波幅改变情况.结果:36例CMTI型患者肌电图检查示所有患者均表现为神经源性损害,胫神经、腓神经、正中神经和尺神经均有不同程度的传导速度下降甚至不能引出,波幅降低.结论:CMTI是最常见的CMT类型,肌电图和周围神经传导速度是诊断腓骨肌萎缩症的可靠方法,并能预测疾病的进展程度.

  5. 腓骨肌萎缩症1例报告

    Institute of Scientific and Technical Information of China (English)

    杨萍; 孙美珍; 牛小媛

    2010-01-01

    @@ 腓骨肌萎缩症又称遗传性运动感觉性神经病,即夏科一马里-图思病(Charcot-Marie-Tooth disease,CMT).该病是遗传性周围神经病之一,具有明显的临床异质性和遗传异质性,发病率为1/2 500~1/10 000[1],其临床特点为慢性、进行性以双下肢为主的四肢远端肌肉无力和肌萎缩,没有或仅有轻微的感觉障碍.多在20岁以前发病,病情进展缓慢,多数是常染色体显性遗传,也有隐性遗传和X连锁遗传,部分散发[2-3].

  6. HDAC1/2-Dependent P0 Expression Maintains Paranodal and Nodal Integrity Independently of Myelin Stability through Interactions with Neurofascins.

    Directory of Open Access Journals (Sweden)

    Valérie Brügger

    Full Text Available The pathogenesis of peripheral neuropathies in adults is linked to maintenance mechanisms that are not well understood. Here, we elucidate a novel critical maintenance mechanism for Schwann cell (SC-axon interaction. Using mouse genetics, ablation of the transcriptional regulators histone deacetylases 1 and 2 (HDAC1/2 in adult SCs severely affected paranodal and nodal integrity and led to demyelination/remyelination. Expression levels of the HDAC1/2 target gene myelin protein zero (P0 were reduced by half, accompanied by altered localization and stability of neurofascin (NFasc155, NFasc186, and loss of Caspr and septate-like junctions. We identify P0 as a novel binding partner of NFasc155 and NFasc186, both in vivo and by in vitro adhesion assay. Furthermore, we demonstrate that HDAC1/2-dependent P0 expression is crucial for the maintenance of paranodal/nodal integrity and axonal function through interaction of P0 with neurofascins. In addition, we show that the latter mechanism is impaired by some P0 mutations that lead to late onset Charcot-Marie-Tooth disease.

  7. Describing the hexapeptide identity platform between the influenza A H5N1 and Homo sapiens proteomes

    Directory of Open Access Journals (Sweden)

    Darja Kanduc

    2010-09-01

    Full Text Available Darja KanducDepartment of Biochemistry and Molecular Biology, University of Bari, ItalyAbstract: We searched the primary sequence of influenza A H5N1 polyprotein for hexamer amino acid sequences shared with human proteins using the Protein International Resource database and the exact peptide matching analysis program. We find that the viral polyprotein shares numerous hexapeptides with the human proteome. The human proteins involved in the viral overlap are represented by antigens associated with basic cell functions such as proliferation, development, and differentiation. Of special importance, many human proteins that share peptide sequences with influenza A polyprotein are antigens such as reelin, neurexin I-a, myosin-IXa, Bardet–Biedl syndrome 10 protein, Williams syndrome transcription factor, disrupted in schizophrenia 1 protein, amyotrophic lateral sclerosis 2 chromosomal region candidate gene 17 protein, fragile X mental retardation 2 protein, and jouberin. That is, the viral-vs-human overlap involves human proteins that, when altered, have been reported to be potentially associated with multiple neurological disorders that can include autism, epilepsy, obesity, dystonia, ataxia–telangiectasia, amyotrophic lateral sclerosis, sensorineural deafness, sudden infant death syndrome, Charcot-Marie-Tooth disease, and myelination. The present data are discussed as a possible molecular basis for understanding influenza A viral escape from immunosurveillance and for defining anti-influenza immune-therapeutic approaches devoid of collateral adverse events.Keywords: peptide sharing, neurological disorders, host-pathogen relationships, viral escape from immunosurveillance

  8. Unusual presentation of hereditary neuropathy with liability to pressure palsies

    Directory of Open Access Journals (Sweden)

    Andary Michael T

    2008-01-01

    Full Text Available Abstract Background Hereditary neuropathy with liability to pressure palsies (HNPP is an autosomal-dominant painless peripheral neuropathy characterized by episodes of repeated focal pressure neuropathies at sites of entrapment/compression, with a considerable variability in the clinical course. Electrodiagnostic and genetic testing are important in the diagnostic evaluation of these patients. Case presentation We report an unusual HNPP phenotype, five compression neuropathies in four nerves in a patient with bilateral hand numbness. A 42-year-old female, presented with acute bilateral paresthesias and weakness in her hands after starting yoga exercises requiring hyperextension of her hands at the wrists. Her presentation was complicated by: a a remote history of acute onset foot drop and subsequent improvement, b previous diagnoses of demyelinating peripheral neuropathy, possibly Charcot-Marie-Tooth disease, and c exposure to leprosy. Electrodiagnostic testing showed 5 separate compression neuropathies in 4 nerves including: severe left and right ulnar neuropathies at the wrist, left and right median neuropathies at the wrist and left ulnar neuropathy at the elbow. There was a mild generalized, primarily demyelinating, peripheral polyneuropathy. Based on the clinical suspicion and electrodiagnostic findings, consistent with profound demyelination in areas of compression, genetic analysis was done which identified a deletion of the PMP-22 gene consistent with HNPP. Conclusion HNPP can present with unusual phenotypes, such as 5 separate mononeuropathies, bilateral ulnar and median neuropathies at the wrists and ulnar neuropathy at the elbow with mild peripheral demyelinating polyneuropathy associated with the PMP-22 gene deletion.

  9. Effect of Electroacupuncture on the Expression of Glycyl-tRNA Synthetase and Ultrastructure Changes in Atrophied Rat Peroneus Longus Muscle Induced by Sciatic Nerve Injection Injury.

    Science.gov (United States)

    Wang, Meng; Zhang, Xiao Ming; Yang, Sheng Bo

    2016-01-01

    Glycyl-tRNA synthetase (GlyRS) is one of the key enzymes involved in protein synthesis. Its mutations have been reported to cause Charcot-Marie-Tooth disease which demonstrates muscular atrophy in distal extremities, particularly manifested in peroneus muscles. In this situation, the dysfunctions of mitochondria and sarcoplasmic reticulum (SR) affect energy supply and excitation-contraction coupling of muscle fibers, therefore resulting in muscular atrophy. Although the treatment of muscular atrophy is a global urgent problem, it can be improved by electroacupuncture (EA) treatment. To investigate the mechanism underlying EA treatment improving muscular atrophy, we focused on the perspective of protein synthesis by establishing a penicillin injection-induced sciatic nerve injury model. In our model, injured rats without treatment showed decreased sciatic functional index (SFI), decreased peroneus longus muscle weight and muscle fiber cross-sectional area, aggregated mitochondria with vacuoles appearing, swollen SR, and downregulated mRNA and protein expression levels of GlyRS and myosin heavy chain IIb (MHC-IIb). The injured rats with EA treatment showed significant recovery. These results indicated that EA stimulation can alleviate peroneus longus muscular atrophy induced by iatrogenic sciatic nerve injury through promoting the recovery of GlyRS and muscle ultrastructure and increasing muscle protein synthesis.

  10. 腓骨肌萎缩症1型和2型的临床与基因学研究现状

    Institute of Scientific and Technical Information of China (English)

    段晓慧; 顾卫红; 王国相

    2009-01-01

    腓骨肌萎缩症(charcot marie tooth disease,CMT)是一组最常见的周围神经单基因遗传病,具有高度的临床变异性和遗传异质性。CMT患病率约为1/2500,遗传方式可为常染色体显性,常染色体隐眭和X连锁遗传。由于运动和感觉神经元均受累,多年前被归属于遗传性运动感觉神经病(hereditary motor and sensory neuropathy,HMSN)。自1991年发现由17号染色体短臂11.2区(17p11.2)1.5Mb的正向串联重复突变导致CMT1A.

  11. [Current issues in hereditary neuropathies].

    Science.gov (United States)

    Lacour, A

    2013-12-01

    This short review highlights five studies published in 2012 in the field of Charcot-Marie-Tooth disease (CMT) and transthyretin familial amyloid neuropathies (TTR-FAN). Regarding CMT, an Australian pediatric study shows the high prevalence of impaired speech perception and hearing disability in children with CMT1 or CMT2 with normal or near normal audiometry (Rance et al., 2012). In a second study, the clinical and electrophysiological characteristics of 14 patients with CMT4C due to mutations in SH3TC2 gene are described (Yger et al., 2012). The 3 clinical hallmarks of CMT4C patients in this French cohort are the high prevalence of scoliosis, the proximal motor weakness and the cranial nerves involvement. Concerning TTR-FAN, the first data from French and international registries are reported (Adams et al., 2012; Coelho et al., 2013) and a phase II trial describes the results of taurourodeoxycholic acid and doxycycline treatment (Obici et al., 2012).

  12. Dispersion of compound muscle action potential in hereditary neuropathies and chronic inflammatory demyelinating polyneuropathy.

    Science.gov (United States)

    Stanton, Michael; Pannoni, Valerie; Lewis, Richard A; Logigian, Eric L; Naguib, Demian; Shy, Michael E; Cleland, James; Herrmann, David N

    2006-10-01

    Distal compound muscle action potential (DCMAP) dispersion, defined as a DCMAP duration > or = 9 ms, and proximal-distal (P-D) CMAP dispersion are considered useful in the electrodiagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Distal and P-D CMAP dispersion have not been fully studied in hereditary neuropathies, and it is not known whether these measures distinguish hereditary from acquired demyelination. We compared DCMAP duration and P-D CMAP dispersion in 91 genetically characterized hereditary neuropathies and 33 subjects with CIDP. DCMAP dispersion was more frequent in nerves affected by CIDP (41.5%) than in Charcot-Marie-Tooth disease (CMT)1A (24.4%), CMT1B (7.4%), hereditary neuropathy with liability to pressure palsies (HNPP) (10.5%), or CMTX (9.8%). P-D CMAP dispersion was more frequent in CIDP (27.7% of nerves) than in hereditary neuropathies (16.3%) when applying American Academy of Neurology (AAN) criteria; however, its frequency was similar in CIDP and the hereditary neuropathies using the more restrictive criteria of the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). Although dispersion is more common in CIDP than in the hereditary neuropathies, DCMAP and P-D dispersion occur in at least one motor nerve in a significant proportion of hereditary neuropathies, and cannot be used in isolation to distinguish acquired from hereditary demyelination.

  13. Molecular genetics of hereditary sensory neuropathies.

    Science.gov (United States)

    Auer-Grumbach, Michaela; Mauko, Barbara; Auer-Grumbach, Piet; Pieber, Thomas R

    2006-01-01

    Hereditary sensory neuropathies (HSN), also known as hereditary sensory and autonomic neuropathies (HSAN), are a clinically and genetically heterogeneous group of disorders. They are caused by neuronal atrophy and degeneration, predominantly affecting peripheral sensory and autonomic neurons. Both congenital and juvenile to adulthood onset is possible. Currently, the classification of the HSN depends on the mode of inheritance, age at onset, and clinical presentation. Hallmark features are progressive sensory loss, chronic skin ulcers, and other skin abnormalities. Spontaneous fractures and neuropathic arthropathy are frequent complications and often necessitate amputations. Autonomic features vary between different subgroups. Distal muscle weakness and wasting may be present and is sometimes so prominent that it becomes difficult to distinguish HSN from Charcot-Marie-Tooth syndrome. Recent major advances in molecular genetics have led to the identification of seven gene loci and six-disease causing genes for autosomal-dominant and autosomal-recessive HSN. These genes have been shown to play roles in lipid metabolism and the regulation of intracellular vesicular transport, but also a presumptive transcriptional regulator, a nerve growth factor receptor, and a nerve growth factor have been described among the causative genes in HSN. Nevertheless, it remains unclear how mutations in the known genes lead to the phenotype of HSN. In this review, we summarize the recent progress of the molecular genetics of the HSN and the implicated genes.

  14. Evaluation of a patient with suspected chronic demyelinating polyneuropathy.

    Science.gov (United States)

    Jani-Acsadi, Agnes; Lewis, Richard A

    2013-01-01

    Demyelinating neuropathies are typically characterized by physiological slowing of conduction velocity and pathologically by segmental loss of myelin and in some instances, evidence of remyelination. Clinically, patients with demyelinating neuropathy can be seen with inherited disorders (Charcot-Marie-Tooth disease) or acquired disorders, typically immune-mediated or inflammatory. The acquired disorders can be either acute or subacute as seen in the acute inflammatory demyelinating polyneuropathy (AIDP) form of Guillain-Barré syndrome or chronic progressive or relapsing disorders such as chronic inflammatory demyelinating polyneuropathy. It is important to develop a logical approach to diagnosing these disorders. This requires an understanding of the clinical, genetic, physiological, and pathological features of these neuropathies. Clinically, important features to consider are the temporal progression, degree of symmetry, and involvement of proximal as well as distal muscles. Genetically, recognizing the different inheritance patterns and age of onset allow for a coordinated approach to determining a specific genotype. Physiologically, besides nerve conduction slowing, other physiological hallmarks of demyelination include temporal dispersion of compound motor action potentials (CMAP) on proximal stimulation, conduction block, and distal CMAP duration prolongation with certain patterns of involvement pointing to specific disorders. This chapter focuses on these various aspects of the evaluation of patients with chronic acquired demyelinating neuropathies to develop a comprehensive and thoughtful diagnostic concept.

  15. Prevalence of type 2 diabetes is higher in peripheral artery disease than in coronary artery disease patients.

    Science.gov (United States)

    Silbernagel, Guenther; Rein, Philipp; Saely, Christoph H; Engelberger, Rolf P; Willenberg, Torsten; Do, Dai-Do; Kucher, Nils; Baumgartner, Iris; Drexel, Heinz

    2015-03-01

    Type 2 diabetes mellitus and pre-diabetes are risk factors for atherosclerosis and are highly prevalent in patients with coronary artery disease. However, the prevalence of impaired glucose metabolism in patients with peripheral artery disease is not as well elucidated. We aimed at comparing prevalence rates of type 2 diabetes mellitus and pre-diabetes, which were diagnosed according to the current American Diabetes Association criteria, among 364 patients with peripheral artery disease, 529 patients with coronary artery disease and 383 controls. The prevalence of type 2 diabetes mellitus in peripheral artery disease patients was 49.7%. It was significantly higher in these patients than in coronary artery disease patients (34.4%; p disease group with the coronary artery disease group (p disease group with controls (p prevalence of pre-diabetes among non-diabetic subjects was high in all three study groups (64.5% in peripheral artery disease patients, 63.4% in coronary artery disease patients and 61.8% in controls), without significant between-group differences. In conclusion, the prevalence of type 2 diabetes mellitus is even higher in peripheral artery disease patients than in coronary artery disease patients. This observation underlines the need to consider impaired glucose regulation in the management of peripheral artery disease.

  16. MR imaging in adults with Gaucher disease type I: evulation of marrow involvement and disease activity

    Energy Technology Data Exchange (ETDEWEB)

    Hermann, G. (Dept. of Radiology, Mount Sinai Medical Center, City Univ. of New York, NY (United States)); Shaprio, R.S. (Dept. of Radiology, Mount Sinai Medical Center, City Univ. of New York, NY (United States)); Abdelwahab, I.F. (Dept. of Radiology, Mount Sinai Medical Center, City Univ. of New York, NY (United States)); Grabowski, G. (Dept. of Pediatrics, Mount Sinai Medical Center, City Univ. of New York, NY (United States))

    1993-05-01

    An investigation was conducted to determine the usefulness of magnetic resonance imaging (MRI) in the evaluation of bone marrow involvement in patients with Gaucher disease type I. T1- and T2-weighted images were obtained of the lower extremities of 29 adult patients. Patients were classified into one of three groups based on marrow signal patterns on T1- and T2-weighted images as well as change in signal intensity from T1- to T2-weighted images. An increase in signal intensity from T1- to T2-weighted images was the criterion for an 'active process' within the bone marrow. Classification of the 29 patients produced the following results: Group A: Normal, 4 patients; group B: Marrow infiltration, 16 patients; group C: Marrow infiltration plus active marrow process, 9 patients. Correlation with clinical findings revealed that all nine patients with evidence of an active marrow process on MRI (group C) had acute bone pain. Conversely, only one of the remaining 20 patients (groups A and B) had bone pain. There was no correlation between disease activity and findings on conventional radiographs. We conclude the MRI provides an excellent noninvasive assessment of the extent and activity of marrow involvement in type I Gaucher disease. (orig.)

  17. Supramaximal Stimulus Intensity as a Diagnostic Tool in Chronic Demyelinating Neuropathy

    Science.gov (United States)

    Parker, Vivien; Warman Chardon, Jodi; Mills, Julie; Goldsmith, Claire; Bourque, Pierre R.

    2016-01-01

    Objective. The ability to correctly identify chronic demyelinating neuropathy can have important therapeutic and prognostic significance. The stimulus intensity value required to obtain a supramaximal compound muscle action potential amplitude is a commonly acquired data point that has not been formally assessed as a diagnostic tool in routine nerve conduction studies to identify chronic neuropathies. We postulated that this value was significantly elevated in chronic demyelinating neuropathy. Methods. We retrospectively reviewed electrophysiology laboratory records to compare the stimulus intensity values recorded during median and ulnar motor nerve conduction studies. The groups studied included normal controls (n = 42) and the following diagnostic categories: chronic inflammatory demyelinating neuropathy (CIDP) (n = 20), acquired inflammatory demyelinating neuropathy (AIDP) (n = 13), Charcot Marie Tooth (CMT) type 1 or 4C (n = 15), carpal tunnel syndrome (CTS) (n = 11), and amyotrophic lateral sclerosis (ALS) (n = 18). Results. Supramaximal intensities were significantly higher in patients with CMT (median nerve: 43.4 mA) and CIDP (median nerve: 38.9 mA), whereas values similar to normal controls (median nerve: 25.3 mA) were obtained in ALS, CTS, and AIDP. Conclusions. Supramaximal stimulus intensity may be used as an additional criterion to identify the pathophysiology of neuropathy. We postulate that endoneurial hypertrophic changes may increase electrical impedance and thus the threshold of excitation at nodes of Ranvier. PMID:27413732

  18. Functional characterization of the human mariner transposon Hsmar2.

    Directory of Open Access Journals (Sweden)

    Estel Gil

    Full Text Available DNA transposons are mobile elements with the ability to mobilize and transport genetic information between different chromosomal loci. Unfortunately, most transposons copies are currently inactivated, little is known about mariner elements in humans despite their role in the evolution of the human genome, even though the Hsmar2 transposon is associated to hotspots for homologous recombination involved in human genetic disorders as Charcot-Marie-Tooth, Prader-Willi/Angelman, and Williams syndromes. This manuscript describes the functional characterization of the human HSMAR2 transposase generated from fossil sequences and shows that the native HSMAR2 is active in human cells, but also in bacteria, with an efficiency similar to other mariner elements. We observe that the sub-cellular localization of HSMAR2 is dependent on the host cell type, and is cytotoxic when overexpressed in HeLa cells. Finally, we also demonstrate that the binding of HSMAR2 to its own ITRs is specific, and that the excision reaction leaves non-canonical footprints both in bacteria and eukaryotic cells.

  19. Supramaximal Stimulus Intensity as a Diagnostic Tool in Chronic Demyelinating Neuropathy

    Directory of Open Access Journals (Sweden)

    Vivien Parker

    2016-01-01

    Full Text Available Objective. The ability to correctly identify chronic demyelinating neuropathy can have important therapeutic and prognostic significance. The stimulus intensity value required to obtain a supramaximal compound muscle action potential amplitude is a commonly acquired data point that has not been formally assessed as a diagnostic tool in routine nerve conduction studies to identify chronic neuropathies. We postulated that this value was significantly elevated in chronic demyelinating neuropathy. Methods. We retrospectively reviewed electrophysiology laboratory records to compare the stimulus intensity values recorded during median and ulnar motor nerve conduction studies. The groups studied included normal controls (n=42 and the following diagnostic categories: chronic inflammatory demyelinating neuropathy (CIDP (n=20, acquired inflammatory demyelinating neuropathy (AIDP (n=13, Charcot Marie Tooth (CMT type 1 or 4C (n=15, carpal tunnel syndrome (CTS (n=11, and amyotrophic lateral sclerosis (ALS (n=18. Results. Supramaximal intensities were significantly higher in patients with CMT (median nerve: 43.4 mA and CIDP (median nerve: 38.9 mA, whereas values similar to normal controls (median nerve: 25.3 mA were obtained in ALS, CTS, and AIDP. Conclusions. Supramaximal stimulus intensity may be used as an additional criterion to identify the pathophysiology of neuropathy. We postulate that endoneurial hypertrophic changes may increase electrical impedance and thus the threshold of excitation at nodes of Ranvier.

  20. Glycogen Storage Disease Type Ia in Canines: A Model for Human Metabolic and Genetic Liver Disease

    Directory of Open Access Journals (Sweden)

    Andrew Specht

    2011-01-01

    Full Text Available A canine model of Glycogen storage disease type Ia (GSDIa is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases.

  1. Type V Collagen in Health, Disease, and Fibrosis.

    Science.gov (United States)

    Mak, Ki M; Png, Chien Yi M; Lee, Danielle J

    2016-05-01

    Type V collagen (COLV) is a regulatory fibril-forming collagen. It has at least three different molecular isoforms-α1(V)2 α2(V), α1(V)3, and α1(V)α2(V)α3(V)-formed by combinations of three different polypeptide α chains-α1(V), α2(V), and α3(V). COL V is a relatively minor collagen of the extracellular matrix (ECM). Morphologically, COLV occurs as heterotypic fibrils with type I collagen (COLI), microfilaments, or 12-nm-thick fibrils. COLV is synthesized in various mesenchymal cells and its gene expression is modulated by TGF-β and growth factors. While resistant to digestion by interstitial collagenases, native and denatured COLV are degraded by metalloproteinases and gelatinases, thereby promoting ECM remodeling. COLV interacts with matrix collagens and structural proteins, conferring structural integrity to tissue scaffolds. It binds matrix macromolecules, modulating cellular behavior, and functions. COLV co-assembles with COLI into heterotypic fibrils in the cornea and skin dermis, acting as a dominant regulator of collagen fibrillogenesis. COLV deficiency is associated with loss of corneal transparency and classic Ehlers-Danlos syndrome, while COLV overexpression is found in cancer, granulation tissue, inflammation, atherosclerosis, and fibrosis of lungs, skin, kidneys, adipose tissue, and liver. COLV isoform containing the α3(V) chain is involved in mediating pancreatic islet cell functions. In the liver, COLV is a minor but regular component of the ECM. Increases in COLV are associated with both early and advanced hepatic fibrosis. The neoepitopes of COLV have been shown to be a useful noninvasive serum biomarker for assessing fibrotic progression and resolution in experimental hepatic fibrosis. COLV is multifunctional in health, disease, and fibrosis.

  2. Neurofibromatosis type 2 appears to be a genetically homogeneous disease

    Energy Technology Data Exchange (ETDEWEB)

    Narod, S.A.; Parry, D.M.; Parboosingh, J.; Lenoir, G.M.; Ruttledge, M.; Fischer, G.; Eldridge, R.; Martuza, R.L.; Frontali, M.; Haines, J.; Gusella, J.F.; Rouleau, G.A.

    1992-09-01

    Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome characterized by the development of vestibular schwannomas and other tumors of the nervous system, including cranial and spinal meningiomos, schwannomas, and ependymomas. The presence of bilateral vestibular schwannomas is sufficient for the diagnosis. Skin manifestations are less common than in neurofibromatosis type 1 (NF1; von Recklinghausen disease). The apparent clinical distinction between NF1 and NF2 has been confirmed at the level of the gene locus by linkage studies; the gene for NF1 maps to chromosome 17, where as the gene for NF2 has been assigned (in a single family) to chromosome 22. To increase the precision of the genetic mapping of NF2 and to determine whether additional susceptibility loci exist, the authors have performed linkage analysis on 12 families with NF2 by using four polymorphic markers from chromosome 22 and a marker at the NF1 locus on chromosome 17. The results confirm the assignment of the gene for NF2 to chromosome 22 and do not support the hypothesis of genetic heterogeneity. The authors believe that chromosome 22 markers can now be used for presymptomatic diagnosis in selected families. The NF2 gene is tightly linked to the D22S32 locus (maximum lod score 4.12; recombination fraction 0). A CA-repeat polymorphism at the CRYB2 locus was the most informative marker in the families (lod score 5.99), but because the observed recombination fraction between NF2 and CRYB2 was 10 cM, predictions using this marker will need to be interpreted with caution. 42 refs., 4 figs., 3 tabs.

  3. Heterogeneous pattern of bone disease in adult type 1 Gaucher disease: clinical and pathological correlates.

    Science.gov (United States)

    van Dussen, L; Lips, P; van Essen, H W; Hollak, C E M; Bravenboer, N

    2014-09-01

    Gaucher disease (GD) is a lysosomal storage disorder characterized by accumulation of glucosylceramide in macrophages, so-called Gaucher cells, as a result of a deficiency of the lysosomal enzyme glucocerebrosidase. Bone complications are an important cause of morbidity of GD and are thought to result from imbalance in bone remodeling. Bone manifestations among GD patients demonstrate a large variation including increased osteoclastic bone resorption, low bone formation and osteonecrosis. The purpose of the current case series is to describe the histological features observed in undecalcified bone samples, obtained from three GD patients, and evaluate the relationship with clinical features in these patients. Bone fragments were obtained from three adult type 1 GD patients with variable degrees of bone disease during orthopedic surgery. Specimens were embedded without prior decalcification in methylmethacrylate and prepared for histology according to standardized laboratory procedures. Histology revealed a heterogeneous pattern of bone involvement. High cellularity of bone marrow, abundant presence of Gaucher cells (GCs) and high turnover were observed in a patient with a history of multiple bone complications, while minimal bone turnover and few GCs were detected in the mildest affected patient in this series. An intermediate picture with relatively low bone turnover and a substantial amount of Gaucher cells was demonstrated in the third, moderately affected patient. No gross abnormalities in three biochemical markers of bone turnover (osteocalcin, N-terminal propeptide of type 1 procollagen and type 1 collagen C-terminal telopeptide) were noted. Plastic embedding and subsequent Goldner and TRAP staining offered a unique possibility to study bone histological findings in GD. Our data show that bone manifestations in GD may vary both clinically as well as histologically and bone disease in GD will likely require a personalized approach.

  4. Validating the Type D personality construct in Chinese patients with coronary heart disease

    DEFF Research Database (Denmark)

    Yu, Doris S F; Thompson, David R; Yu, Cheuk Man

    2010-01-01

    Type D personality predicts poor prognosis in coronary heart disease (CHD) but little is known about Type D in non-Western cultures. We examined the (a) validity of the Type D construct and its assessment with the DS14 scale in the Chinese culture, (b) prevalence of Type D, and (c) gender vs. Type...

  5. Detection of type 1 prion protein in variant Creutzfeldt-Jakob disease

    NARCIS (Netherlands)

    Yull, H.M.; Ritchie, D.L.; Langeveld, J.P.M.; Zijderveld, van F.G.; Bruce, M.E.; Ironside, J.W.; Head, M.W.

    2006-01-01

    Molecular typing of the abnormal form of the prion protein (PrPSc) has come to be regarded as a powerful tool in the investigation of the prion diseases. All evidence thus far presented indicates a single PrPSc molecular type in variant Creutzfeldt-Jakob disease (termed type 2B), presumably resultin

  6. Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease

    Science.gov (United States)

    Mistry, Pramod K.; Liu, Jun; Sun, Li; Chuang, Wei-Lien; Yuen, Tony; Yang, Ruhua; Lu, Ping; Zhang, Kate; Li, Jianhua; Keutzer, Joan; Stachnik, Agnes; Mennone, Albert; Boyer, James L.; Jain, Dhanpat; Brady, Roscoe O.; New, Maria I.; Zaidi, Mone

    2014-01-01

    The inherited deficiency of the lysosomal glucocerebrosidase (GBA) due to mutations in the GBA gene results in Gaucher disease (GD). A vast majority of patients present with nonneuronopathic, type 1 GD (GD1). GBA deficiency causes the accumulation of two key sphingolipids, glucosylceramide (GL-1) and glucosylsphingosine (LysoGL-1), classically noted within the lysosomes of mononuclear phagocytes. How metabolites of GL-1 or LysoGL-1 produced by extralysosomal glucocerebrosidase GBA2 contribute to the GD1 pathophysiology is not known. We recently recapitulated hepatosplenomegaly, cytopenia, hypercytokinemia, and the bone-formation defect of human GD1 through conditional deletion of Gba in Mx1–Cre+:GD1 mice. Here we show that the deletion of Gba2 significantly rescues the GD1 clinical phenotype, despite enhanced elevations in GL-1 and LysoGL-1. Most notably, the reduced bone volume and bone formation rate are normalized. These results suggest that metabolism of GL-1 or LysoGL-1 into downstream bioactive lipids is a major contributor to the bone-formation defect. Direct testing revealed a strong inhibition of osteoblast viability by nanomolar concentrations of sphingosine, but not of ceramide. These findings are consistent with toxicity of high circulating sphingosine levels in GD1 patients, which decline upon enzyme-replacement therapy; serum ceramide levels remain unchanged. Together, complementary results from mice and humans affected with GD1 not only pinpoint sphingosine as being an osteoblast toxin, but also set forth Gba2 as a viable therapeutic target for the development of inhibitors to ameliorate certain disabling consequences of GD1. PMID:24639522

  7. Dynamin 2 mutations in Charcot–Marie–Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination

    DEFF Research Database (Denmark)

    Sidiropoulos, Páris; Miehe, Michaela; Bock, Thomas

    2016-01-01

    and neurons from the peripheral nervous system expressing dominant intermediate Charcot-Marie-Tooth neuropathy mutants showed defects in clathrin-mediated endocytosis. We demonstrate that, as a consequence, protein surface levels are altered in Schwann cells. Furthermore, we discovered that myelination...

  8. Thyroid disease in insulin-treated patients with type 2 diabetes: a retrospective study

    OpenAIRE

    Witting, Valerie; Bergis, Dominik; Sadet, Dilek; Badenhoop, Klaus

    2014-01-01

    Background: Diabetes mellitus and thyroid diseases frequently coexist. In order to evaluate how thyroid disorders interfere with glycemic control, we analysed insulin-treated type 2 diabetes patients with thyroid disease. Methods: Diabetes patients (n = 1.957) were retrospectively investigated. We focused on type 2 diabetes patients who had been admitted for insulin-treatment and diagnosed thyroid diseases (n = 328). Patients were divided into three groups according to thyroid disease mani...

  9. Prevalence of Celiac Disease in Omani Children with Type 1 Diabetes Mellitus: A Cross Sectional Study

    OpenAIRE

    Siham Al-Sinani; Sharef Waadallah Sharef; Saif Al-Yaarubi; Ibrahim Al-Zakwani; Khalid Al-Naamani; Aisha Al-Hajri; Said Al-Hasani

    2013-01-01

    Objective: Published studies on the prevalence of celiac disease in type 1 diabetes mellitus from the Arab World are scant. We aim to report the prevalence of celiac disease in Omani children with type 1 diabetes mellitus.Methods: Children with type 1 diabetes mellitus were prospectively screened for celiac disease, at Sultan Qaboos University Hospital, Muscat, Oman over a period of one year (June 2011 - May 2012). Serum anti tissue transglutaminase IgA, endomysial IgA antibodies and total Ig...

  10. Clinical features of adult patients with Eisenmenger syndrome associated with different types of congenital heart disease

    Institute of Scientific and Technical Information of China (English)

    陈果

    2013-01-01

    Objective To explore the clinical features and hemodynamics of adult patients with Eisenmenger syndrome in different types of congenital heart diseases (CHD) .Methods Patients with Eisenmenger syndrome with different types of CHD diagnosed by right heart

  11. Literature review on laminopathy and case report of a novel laminopathy%核纤层蛋白病一例并文献复习

    Institute of Scientific and Technical Information of China (English)

    蔡梦茵; 梁华; 李明; 毕艳; 朱延华; 陈香; 孙卫平; 严晋华; 翁建平

    2009-01-01

    Objective To identify the clinical spectrum and the clinical diagnostic criteria of laminopathy. Methods We here reported a novel laminopathy case. Based on the clinical features of the case and overall review on the related literatures, we aimed to identify the clinical characteristics including involved tissue origination, clinical diagnosis, differentiation diagnosis, treatment and prognosis of laminopathy. Multiple systems including skin, skeleton, skeletal muscle, cardiac muscle, nerve and adipose tissue were estimated by laboratory investigations. Results The case manifested as the prominent progeroid disorders, multiple system (skin, skeleton, skeletal muscle, fat and nerve) degeneration and early-onset cystadenoma of the ovary. The case's presentation could be classified as a novel laminopathy which manifested as an overlapping phenotype among Charcot-Marie-Tooth disease, limb-girdle muscle dystrophy,Dunnigan-type familial partial lipodystrophy, mandibuloaral dysplasia, and atypical Werner syndrome.Conclusions Laminopathy is a rare disease which manifested as a wide clinical spectrum. Based on the clinical diagnosis, further study on candidate gene screening will help to elucidate the molecular mechanism.%目的 探讨核纤层蛋白病的诊断及治疗方法,提高对核纤层蛋白病的认识.方法 结合1例核纤层蛋白病患者的临床资料和文献复习,详细分析该病的组织起源、临床病理特点、分型、诊断、罄别诊断、治疗及预后等,完善患者各系统筛查以评估皮肤、骨骼、骨骼肌、心肌、神经和脂肪组织的受累情况.结果 各系统筛查结果提示患者多组织(皮肤、骨骼、骨骼肌、脂肪、神经)发育不良/加速退行性变伴左卵巢良性浆液性囊腺瘤.其临床表现复杂,重叠了Charcot-Marie-Tooth病、Emery-Dreffuss肌营养不良、Dunnigan型家族性部分性脂肪萎缩、脂肪萎缩性糖尿病并下颌骨肢端发育不良症、非典型Werner综合

  12. Increased vital exhaustion among type-D patients with ischemic heart disease

    NARCIS (Netherlands)

    Pedersen, SS; Middel, B

    2001-01-01

    Objective: To investigate the prevalence of the "distressed personality" (type-D) in cardiac patients and to explore the relationships between type-D, gender, vital exhaustion and angina pectoris. Methods: A questionnaire was completed by 171 patients scheduled for coronary angiography (CAG) at base

  13. Application of KDIGO classifcation of chronic kidney disease for analyzing the prevalence of kidney disease and other vascular diseases in 1645 type 2 diabetic patients

    Institute of Scientific and Technical Information of China (English)

    李明

    2014-01-01

    Objective To analyze the prevalence,risk factors of kidney disease in type 2 diabetic patients with KDIGO classification of chronic kidney disease,and to study cardiovascular and cerebrovascular diseases and death in these patients,so as to investigate the significance of the KDIGO classification system.Methods One thousand six hundred and forty-five type 2 diabetic patients who were in

  14. Is type D personality here to stay? Emerging evidence across cardiovascular disease patient groups

    NARCIS (Netherlands)

    S.S. Pedersen (Susanne); J. Denollet (Johan)

    2006-01-01

    textabstractThe distressed personality (Type D) is an emerging risk factor in cardiovascular disease (CVD) that incurs a risk on par with left ventricular dysfunction in patients with ischemic heart disease. Type D is defined as the co-occurring tendencies to experience increased negative emotions a

  15. An Acoustic Study of the Relationships among Neurologic Disease, Dysarthria Type, and Severity of Dysarthria

    Science.gov (United States)

    Kim, Yunjung; Kent, Raymond D.; Weismer, Gary

    2011-01-01

    Purpose: This study examined acoustic predictors of speech intelligibility in speakers with several types of dysarthria secondary to different diseases and conducted classification analysis solely by acoustic measures according to 3 variables (disease, speech severity, and dysarthria type). Method: Speech recordings from 107 speakers with…

  16. The association of type D personality with quality of life in patients with Parkinson's disease

    NARCIS (Netherlands)

    Dubayova, Tatiana; Nagyova, Iveta; Havlikova, Eva; Rosenberger, Jaroslav; Gdovinova, Zuzana; Middel, Berrie; van Dijk, Jitse P.; Groothoff, Johan W.

    2009-01-01

    Objectives: Personality traits appear as determinants of quality of life (QoL) in most chronic diseases. Type D personality is characterized by ineffective coping strategies that reduce QoL in patients with coronary heart disease. The aim of this study was to evaluate whether Type D personality also

  17. Novel Risk Factors for Type II Diabetes Mellitus and Coronary Heart Disease

    NARCIS (Netherlands)

    A. Dehghan (Abbas)

    2010-01-01

    textabstractDespite the huge advances made in the understanding of type II diabetes and coronary heart disease (CHD), these diseases still constitute a major health problem. Since the 1950s, epidemiologists focused on chronic disorders, including type II diabetes and CHD. Major aims of their researc

  18. Crystal structure of the extracellular domain of human myelin protein zero

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Zhigang; Wang, Yong; Yedidi, Ravikiran S.; Brunzelle, Joseph S.; Kovari, Iulia A.; Sohi, Jasloveleen; Kamholz, John; Kovari, Ladislau C. (WSU-MED); (NWU)

    2012-03-27

    Charcot-Marie-Tooth disease (CMT), a hereditary motor and sensory neuropathy, is the most common genetic neuropathy with an incidence of 1 in 2600. Several forms of CMT have been identified arising from different genomic abnormalities such as CMT1 including CMT1A, CMT1B, and CMTX. CMT1 with associated peripheral nervous system (PNS) demyelination, the most frequent diagnosis, demonstrates slowed nerve conduction velocities and segmental demyelination upon nerve biopsy. One of its subtypes, CMT1A, presents a 1.5-Mb duplication in the p11-p12 region of the human chromosome 17 which encodes peripheral myelin protein 22 (PMP22). CMT1B, a less common form, arises from the mutations in the myelin protein zero (MPZ) gene on chromosome 1, region q22-q23, which encodes the major structural component of the peripheral myelin. A rare type of CMT1 has been found recently and is caused by point mutations in early growth response gene 2 (EGR2), encoding a zinc finger transcription factor in Schwann cells. In addition, CMTX, an X-linked form of CMT, arises from a mutation in the connexin-32 gene. Myelin protein zero, associated with CMT1B, is a transmembrane protein of 219 amino acid residues. Human MPZ consists of three domains: 125 residues constitute the glycosylated immunoglobulin-like extracellular domain; 27 residues span the membrane; and 67 residues comprise the highly basic intracellular domain. MPZ makes up approximately 50% of the protein content of myelin, and is expressed predominantly in Schwann cells, the myelinating cell of the PNS. Myelin protein zero, a homophilic adhesion molecule, is a member of the immunoglobulin super-family and is essential for normal myelin structure and function. In addition, MPZ knockout mice displayed abnormal myelin that severely affects the myelination pathway, and overexpression of MPZ causes congenital hypomyelination of peripheral nerves. Myelin protein zero mutations account for {approx}5% of patients with CMT. To date, over 125

  19. Type D personality and health status in cardiovascular disease populations

    DEFF Research Database (Denmark)

    Versteeg, Henneke; Spek, Viola; Pedersen, Susanne S.

    2012-01-01

    in patient-reported physical and mental health status among cardiovascular patients. Methods: A computerized search of the literature through PUBMED and PsychINFO (from 1995 to May 2011) was performed and prospective studies were selected that analysed the association between Type D personality and health...... status in cardiovascular patients. Two separate meta-analyses were performed for the association of Type D personality with physical and mental health status, respectively. Results: Of all identified studies, ten studies met the selection criteria. The meta-analyses showed that Type D was associated......: Type D personality was shown to be an independent correlate of impaired patient-reported physical and mental health status in various cardiovascular patient groups. Clinicians should be aware of the association between chronic psychological distress and poor patient-reported outcomes....

  20. L-alanine supplementation in late infantile glycogen storage disease type II.

    Science.gov (United States)

    Bodamer, Olaf A; Haas, Dorothea; Hermans, Monique M; Reuser, Arnold J; Hoffmann, Georg F

    2002-08-01

    We report a male with late infantile glycogen storage disease type II (Pompe's disease) who presented at 12 months of age with muscular hypotonia and developmental delay. Oral supplementation with L-alanine has been administered for 5 years. Progression of skeletal myopathy was slow, and cardiomyopathy resolved almost completely. L-alanine may be a valuable supplement for infants with glycogen storage disease type II.

  1. Bone- and bone marrow scintigraphy in Gaucher disease type 1

    Energy Technology Data Exchange (ETDEWEB)

    Mikosch, P. [Dept. of Nuclear Medicine and Endocrinology, State Hospital Klagenfurt (Austria); Dept. of Internal Medicine II, State Hospital Klagenfurt (Austria); Zitter, F. [Dept. of Internal Medicine II, State Hospital Klagenfurt (Austria); Gallowitsch, H.J.; Lind, P. [Dept. of Nuclear Medicine and Endocrinology, State Hospital Klagenfurt (Austria); Wuertz, F. [Dept. of Pathology, State Hospital Klagenfurt (Austria); Mehta, A.B.; Hughes, D.A. [Lysosomal Storage Disorder Unit, Dept. of Academic Haematology, Royal Free and Univ. Coll. Medical School, London (United Kingdom)

    2008-07-01

    Scintigraphy is a method for imaging metabolism and should be viewed as complimentary to morphological imaging. Bone and bone marrow scintigraphy can particularly contribute to the detection of focal disease in Gaucher disease. In bone crises it can discriminate within three days after pain onset between local infection and aseptic necrosis. A further advantage of bone- and bone marrow scintigraphy is the visualization of the whole skeleton within one setting. Whole body imaging for focal lesions might thus be an objective in GD, in particular in patients complaining of several painful sites. Direct imaging of bone marrow deposits in GD by MIBI scintigraphy might be of special interest in children in whom bone marrow undergoes a developmental conversion from red to yellow marrow in the ap-pendicular skeleton. MRI interpretation in young GD patients is thus difficult in order to estimate the exact amount and extent of bone marrow infiltration by Gaucher cells. 99mTc-MIBI scintigraphy with its direct visualization of lipid storage could thus add interesting additional information not shown with other methods including MRI. Although MRI is the most accepted imaging modality in assessing the skeletal status in GD, a selective use of scintigraphy for imaging bone and bone marrow may add information in the evaluation of patients with Gaucher disease.

  2. Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Edvinsson, Lars; Chen, Qingwen

    2009-01-01

    expression in subcutaneous arteries from patients with different degrees of ischemic heart disease. METHODS: Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina...... pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ETA) and type B (ETB), and angiotensin type 1 (AT1) and type 2 (AT2) receptors expression and function were examined using immunohistochemistry, Western blot and in vitro...... in the healthy controls (100% +/- 28%). The data was confirmed by Western blotting. Arteries from CABG patients showed increased vasoconstriction upon administration of the selective ETB receptor agonist sarafotoxin S6c, compared to healthy controls (P difference was found for the ETA receptors...

  3. C-type natriuretic-derived peptides as biomarkers in human disease

    DEFF Research Database (Denmark)

    Lippert, Solvej Kølvraa; Goetze, Jens Peter

    2010-01-01

    and extracellular fluid volume. Atrial natriuretic peptide and B-type natriuretic peptide have gained considerable diagnostic interest as biomarkers in cardiovascular disease. By contrast, C-type natriuretic peptide has not yet been ascribed a role in human diagnostics. This perspective aims at recapitulating...... the present biochemical and clinical issues concerning C-type natriuretic peptide measurement in plasma as a potential biomarker....

  4. Type 1 diabetes mellitus, coeliac disease, and lymphoma: a report of four cases.

    LENUS (Irish Health Repository)

    O'Connor, T M

    2012-02-03

    INTRODUCTION: Patients with Type 1 diabetes mellitus have a high prevalence of coeliac disease, symptoms of which are often mild, atypical, or absent. Untreated coeliac disease is associated with an increased risk of malignancy, particularly of lymphoma. We describe four patients with Type 1 diabetes mellitus and coeliac disease who developed lymphoma. CASE REPORTS: Two patients were male and two female. In three patients, coeliac disease and lymphoma were diagnosed simultaneously. Enteropathy-associated T cell lymphoma occurred in two patients, Hodgkin\\'s disease in one, and B cell lymphoma in one. Response to treatment was in general poor, and three patients died soon after the diagnosis of lymphoma was made. CONCLUSION: As the relative risk of lymphoma is reduced by a gluten-free diet, a high index of suspicion for coeliac disease should exist in all Type 1 diabetic patients with unexplained constitutional or gastrointestinal symptoms.

  5. Both type 1 and type 2a muscle fibers can respond to enzyme therapy in Pompe disease.

    Science.gov (United States)

    Drost, Maarten R; Schaart, Gert; van Dijk, Paul; van Capelle, Carine I; van der Vusse, Ger J; Delhaas, Tammo; van der Ploeg, Ans T; Reuser, Arnold J J

    2008-02-01

    Muscle weakness is the main symptom of Pompe disease, a lysosomal storage disorder for which major clinical benefits of enzyme replacement therapy (ERT) have been documented recently. Restoration of skeletal muscle function is a challenging goal. Type 2 muscle fibers of mice with Pompe disease have proven resistant to therapy. To investigate the response in humans, we studied muscle biopsies of a severely affected infant before and after 17 months of therapy. Type 1 and 2a fibers were marked with antibodies, and lysosome-associated membrane protein-1 (Lamp1) was used as the lysosomal membrane marker. Quantitative measurements showed a 2.5-3-fold increase of fiber cross-sectional area of both fiber types during therapy and normalization of the Lamp1 signal in approximately 95% of type 1 and approximately 75% of type 2a fibers. The response of both type 1 and 2a muscle fibers in the patient studied herein corroborates the beneficial effects of enzyme therapy seen in patients with Pompe disease.

  6. Phenotype/genotype correlations in Gaucher disease type 1: Clinical and therapeutic implications

    Energy Technology Data Exchange (ETDEWEB)

    Sibille, A.; Eng, C.M.; Kim, S.J.; Pastores, G. (Mount Sinai School of Medicine, New York, NY (United States)); Grabowski, G.A. (Mount Sinai School of Medicine, New York, NY (United States) Univ. of Cincinnati, OH (United States))

    1993-06-01

    Gaucher disease is the most frequent lysosomal storage disease and the most prevalent genetic disease among Ashkenazi Jews. Gaucher disease type 1 is characterized by marked variability of the phenotype and by the absence of neuronopathic involvement. To test the hypothesis that this phenotypic variability was due to genetic compounds of several different mutant alleles, 161 symptomatic patients with Gaucher disease type 1 (> 90% Ashkenazi Jewish) were analyzed for clinical involvement, and their genotypes were determined. Qualitative and quantitative measures of disease involvement included age at onset of the disease manifestations, hepatic and splenic volumes, age at splenectomy, and severity of bony disease. High statistically significant differences (P < .005) were found in each clinical parameter in patients with the N370S/N370S genotype compared with those patients with the N370S/84GG, N370S/L444P, and N370/ genotypes. The symptomatic N370S homozygotes had onset of their disease two to three decades later than patients with the other genotypes. In addition, patients with the latter genotypes have much more severely involved livers, spleens, and bones and had a higher incidence of splenectomy at an earlier age. These predictive genotype analyses provide the basis for genetic care delivery and therapeutic recommendations in patients affected with Gaucher disease type 1. 38 refs., 1 fig., 4 tabs.

  7. MIXED HYALINE VASCULAR AND PLASMA CELL TYPE CASTLEMAN’S DISEASE: REPORT OF A CASE

    Directory of Open Access Journals (Sweden)

    F. Asgarani

    2006-05-01

    Full Text Available Castleman’s disease (angiofollicular lymphoid hyperplasia includes a heterogeneous group of lymphoproliferative disorders. The cause of this disease remains uncertain. There are two types of localized Castleman’s disease: the more common hyaline vascular and the plasma cell types. Mixed variant is an uncommon localized lesion in general population. The lesions can occur in any part of the body that contains lymphoid tissue, although seventy percent are found in the anterior mediastinum. We report a thirty years old boy with Castleman’s disease who presented with fever, anorexia, weight loss,sweating, anemia and abdominal mass. The histologic examination of the biopsy specimens revealed a mixed hyaline vascular and plasma cell type of Castleman’s disease.

  8. Evaluation of Cladribine treatment in refractory celiac disease type

    Institute of Scientific and Technical Information of China (English)

    Greetje J Tack; Wieke HM Verbeek; Abdul Al-Toma; Dirk J Kuik; Marco WJ Schreurs; Otto Visser; Chris JJ Mulder

    2011-01-01

    AIM: To evaluate cladribine [2-chlorodeoxyadenosine (2-CdA)] therapy in refractory celiac disease (RCD) Ⅱ. METHODS: An open-label cohort-study of RCD Ⅱ patients treated with 2-CdA was performed between 2000 and 2010. Survival rate, enteropathy associated T-cell lymphoma (EATL) occurrence, clinical course, and histological and immunological response rates were evaluated. RESULTS: Overall, 32 patients were included with a median follow-up of 31 mo. Eighteen patients responded well to 2-CdA. Patients responsive to 2-CdA had a statistically significant increased survival compared to those who were unresponsive. The overall 3- and 5-year survival was 83% in the responder and 63% and 22% in the non-responder group, respectively. The overall 2-year clinical, histological and immunological response rates were 81%, 47% and 41%, respectively. Progression into EATL was reported in 16%, all of these patients died. CONCLUSION: Treatment of RCD Ⅱ with 2-CdA holds promise, showing excellent clinical and histological response rates, and probably less frequent transition into EATL.

  9. Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review.

    NARCIS (Netherlands)

    Cup, E.H.C.; Pieterse, A.J.; Broek-Pastoor, J.M. Ten; Munneke, M.; Engelen, B.G.M. van; Hendricks, H.T.; Wilt, G.J. van der; Oostendorp, R.A.B.

    2007-01-01

    OBJECTIVE: To summarize and critically appraise the available evidence on exercise therapy and other types of physical therapies for patients with neuromuscular diseases (NMD). DATA SOURCES: Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews, Medline, CINAHL,

  10. Prevalence of Celiac Disease in Omani Children with Type 1 Diabetes Mellitus: A Cross Sectional Study

    Directory of Open Access Journals (Sweden)

    Siham Al-Sinani

    2013-07-01

    Full Text Available Objective: Published studies on the prevalence of celiac disease in type 1 diabetes mellitus from the Arab World are scant. We aim to report the prevalence of celiac disease in Omani children with type 1 diabetes mellitus.Methods: Children with type 1 diabetes mellitus were prospectively screened for celiac disease, at Sultan Qaboos University Hospital, Muscat, Oman over a period of one year (June 2011 - May 2012. Serum anti tissue transglutaminase IgA, endomysial IgA antibodies and total IgA were measured for screening of celiac disease. Children with positive anti-tissue transglutaminase and/or endomysial IgA antibodies underwent endoscopy.Results: A total of 103 children with type 1 diabetes mellitus were initially included. Ten patients were lost to follow up. Ninety-three patients aged 2-17 years underwent screening for celiac disease. Sixteen patients had positive anti-tissue transglutaminase (17%. Fourteen patients underwent endoscopy with duodenal biopsies, while two were lost to follow-up. Five patients with positive anti-tissue transglutaminase had intestinal biopsy proven celiac disease. The prevalence of celiac disease is 5.5% in our cohort of children and adolescents with type 1 diabetes mellitus.Conclusions: The prevalence of celiac disease in Omani children and adolescents with type 1 diabetes mellitus is similar to the World’s reported prevalence, but is less than that reported for Middle Eastern Arab children. To our knowledge, this is the first reported study on the prevalence of celiac disease in Omani children with type 1 diabetes mellitus.

  11. The Association Between Insulin Resistance And Advanced Renal Disease In Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    Duţă Irina

    2015-06-01

    Full Text Available Background and Aims. Insulin resistance is documented in type 1 diabetes and it has been associated with chronic complications. Diabetic nephropathy is a major cause of morbidity and mortality. The purpose of this article is to quantify insulin resistance in type 1 diabetes subjects according to the presence or absence of advanced renal disease. A secondary objective was to study the possible association between insulin resistance and advanced renal disease.

  12. Effect of disease duration on personality type in multiple sclerosis patients and healthy individual

    Directory of Open Access Journals (Sweden)

    Sahar Vesal

    2016-01-01

    Full Text Available Background: Multiple sclerosis may have profound emotional consequences. The relation between psychological and physical factors could lead patients toward unforeseen disease. This study focuses on multiple sclerosis (MS disease duration on personality type A and B in relation to individuals' behaviors. Materials and Methods: This descriptive-analytical study was conducted in Isfahan Alzahra hospital in 2013. Three hundred MS patients and 100 healthy individuals were determined. The distributed questionnaires related to MS patients and considering the descriptive statistics such as demographic variables. Data were analyzed by SPSS software (version 18 based on Chi-square test and independent T-test. Results: Disease duration varied between 1 to 38 years: 30% (1-4 years, 38% (5-10 years, 20% (10-20 years, and 12% (more than 20 years. Significant relationship was observed between disease duration and tendency to type A (higher stress. This relation was positive and significant in Relapsing Remitting MS patients; but negative correlation was seen in Secondary Progressive MS patients. These patients tended to type B (lower stress when disease duration increased. Conclusions: Individuals with disease duration of one year and less than one year tend to type A personality, while patients with increment of disease duration have tendency to type B.

  13. Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

    Directory of Open Access Journals (Sweden)

    Malmsjö Malin

    2009-08-01

    Full Text Available Abstract Background Endothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor expression in subcutaneous arteries from patients with different degrees of ischemic heart disease. Methods Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG surgery because of ischemic heart disease (n = 15, patients with angina pectoris without established myocardial infarction (n = 15 and matched cardiovascular healthy controls (n = 15. Endothelin type A (ETA and type B (ETB, and angiotensin type 1 (AT1 and type 2 (AT2 receptors expression and function were examined using immunohistochemistry, Western blot and in vitro pharmacology. Results ETA and, to a lesser extent, ETB receptor staining was observed in the healthy vascular smooth muscle cells. The level of ETB receptor expression was higher in patients undergoing CABG surgery (250% ± 23%; P B receptor agonist sarafotoxin S6c, compared to healthy controls (P A receptors. AT1 and, to a lesser extent, AT2 receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT1 receptor expression was higher in both the angina pectoris (128% ± 25%; P 1 receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s. Conclusion The results demonstrate, for the first time, upregulation of ETB and AT1 receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.

  14. Compromised quality of life in patients with both Type 1 diabetes mellitus and coeliac disease

    DEFF Research Database (Denmark)

    Bakker, S F; Pouwer, F; Tushuizen, M E

    2013-01-01

    AIMS: Type 1 diabetes mellitus and coeliac disease are two chronic illnesses associated with each other. Both diseases and their treatments can seriously impair quality of life. The objective of the present study was to investigate health-related quality of life in adult patients diagnosed with b...

  15. Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease

    NARCIS (Netherlands)

    Smyth, Deborah J.; Plagnol, Vincent; Walker, Neil M.; Cooper, Jason D.; Downes, Kate; Yang, Jennie H. M.; Howson, Joanna M. M.; Stevens, Helen; McManus, Ross; Wijmenga, Cisca; Heap, Graham A.; Dubois, Patrick C.; Clayton, David G.; Hunt, Karen A.; van Heel, David A.; Todd, John A.

    2008-01-01

    Background: Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on chromosome 6p21, we tested whether non-HLA loci are shared. Methods: We evaluated the associat

  16. Risk factors and treatment of pediatric chronic diseases : Type 1 diabetes, asthma and allergy

    NARCIS (Netherlands)

    Ahmadizar, F.

    2016-01-01

    Chronic diseases such as type 1 diabetes (T1DM) and asthma are leading causes of morbidity and mortality worldwide. The increase in the number of children with chronic diseases is a major concern. Early detection through improved screening and diagnostic tests, better diagnosis based on updated guid

  17. Differentiation of prions from L-type BSE versus sporadic Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Nicot, Simon; Bencsik, Anna; Morignat, Eric; Mestre-Francés, Nadine; Perret-Liaudet, Armand; Baron, Thierry

    2012-12-01

    We compared transmission characteristics for prions from L-type bovine spongiform encephalopathy and MM2-cortical sporadic Creutzfeldt-Jakob disease in the Syrian golden hamster and an ovine prion protein-transgenic mouse line and isolated distinct prion strains. Our findings suggest the absence of a causal relationship between these diseases, but further investigation is warranted.

  18. Liver transplantation for glycogen storage disease types I, III, and IV

    NARCIS (Netherlands)

    Matern, D; Starzl, TE; Arnaout, W; Barnard, J; Bynon, JS; Dhawan, A; Emond, J; Haagsma, EB; Hug, G; Lachaux, A; Smit, GPA; Chen, YT

    1999-01-01

    Glycogen storage disease (GSD) types I, III, and IV can be associated with severe liver disease. The possible development of hepatocellular carcinoma and/or hepatic failure make these GSDs potential candidates for liver transplantation. Early diagnosis and initiation of effective dietary therapy hav

  19. [Efficacy of metformin as initial therapy in patients with coronary artery disease and diabetes type 2].

    Science.gov (United States)

    Lavrenko, A V; Kutsenko, L A; Solokhina, I L; Rasin, M S; Kaĭdashev, I P

    2011-01-01

    The use of metformin during the first month of treatment of patients with coronary artery disease and diabetes type 2 led to the decrease of insulin resistance and reduced activity of systemic inflammation (significant decrease in the concentrations of IL-1, IL-6, IL-8 and TNF-alpha). Reduced activity of systemic inflammation had a beneficial effect on the course of coronary artery disease (significant decrease in the functional class of stable angina). Type 2 diabetes appears to be quite successfully modifiable risk factor for coronary artery disease by the adequate controls.

  20. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Gaede, Peter; Vedel, Pernille; Larsen, Nicolai

    2003-01-01

    Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2...