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MedWorm: Charcot-Marie-Tooth Disease



MedWorm.com provides a medical RSS filtering service. Over 7000 RSS medical sources are combined and output via different filters. This feed contains the latest news and research in the Charcot-Marie-Tooth Disease category.



Last Build Date: Mon, 21 Mar 2016 17:36:28 +0100

 



Mutations in MME cause an autosomal‐recessive Charcot–Marie–Tooth disease type 2

Thu, 17 Mar 2016 00:00:00 +0100

The objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal‐recessive (AR) CMT. MethodsTo efficiently identify novel causative genes for AR‐CMT, we analyzed 303 unrelated Japanese patients with CMT using whole‐exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation. ResultsWe identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta‐amyloid (Aβ)‐degrading enzy...

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Rehabilitation issues in Charcot-Marie-Tooth disease.

Sun, 13 Mar 2016 09:40:02 +0100

Authors: Kenis-Coskun O, Matthews DJ Abstract Charcot Marie Tooth (CMT) disease is the most common hereditary sensorimotor neuropathy that has a slow onset. It presents usually in childhood, starting distally and from the lower limbs progressing to more proximal muscles. Due to the lack of curative medical treatments and the problematic outcomes of surgical intervention, rehabilitation continues to play a major role in treatment. This paper aims to summarize the rehabilitation approaches like aerobic, stretching and strengthening exercises. Orthotics is another important part of treatment that complete rehabilitative approaches. Orthotic devices that are currently being used and investigated in patients with CMT are also reviewed. The evidence shows that exercise is effective in im...



Charcot-Marie-Tooth type 2 and distal Hereditary Motor Neuropathy: clinical, neurophysiological and genetic findings from a single-centre experience

Wed, 09 Mar 2016 00:00:00 +0100

Charcot-Marie-Tooth (CMT) disease, also known as Hereditary Sensory Motor Neuropathy, is the most common neurologic hereditary disorder with a prevalence of about 1:2500 [29]. (Source: Clinical Neurology and Neurosurgery)



Zebrafish Tg(hb9:MTS-Kaede): a new in vivo tool for studying the axonal movement of mitochondria.

Wed, 09 Mar 2016 00:00:00 +0100

CONCLUSIONS AND GENERAL SIGNIFICANCE: These findings confirm previously published data obtained in cell cultures and strengthen the hypothesis of different mechanism of action of the two MFN2 mutations. Considering the number of neurodegenerative diseases associated to mitochondrial dynamics, the Tg(hb9:MTS-Kaede) zebrafish line is a promising model to study in vivo alterations of mitochondrial transport underlying human diseases. PMID: 26968460 [PubMed - as supplied by publisher] (Source: Biochimica et Biophysica Acta)



A novel p.Val244Leu mutation in MFN2 leads to Charcot-Marie-Tooth disease type 2

Tue, 08 Mar 2016 00:00:00 +0100

Charcot-Marie-Tooth (CMT) disease is one of the most common hereditary peripheral neuropathy. The major clinical features of CMT are progressive muscle weakness of distal extremities and sensory loss. MFN2 encode... (Source: Italian Journal of Pediatrics)



Intermolecular disulfide bond in the dimerization of S-periaxin mediated by Cys88 and Cys139.

Wed, 02 Mar 2016 00:00:00 +0100

Authors: Yang Y, Ren Y, Shi Y Abstract Periaxin is expressed in mammalian Schwann cells and lens fiber cells, and has been identified in a screen for cytoskeleton-associated proteins. Charcot-Marie-Tooth 4F is caused by losses or mutations of the periaxin gene. The periaxin gene encodes two protein isoforms, namely, L-periaxin and S-periaxin. S-periaxin contains 147 amino acid residues and has an N-terminal PDZ domain. In this paper, S-periaxin was reported to be homodimerized through the formation of intermolecular disulfide bonds with its Cys88 and Cys139 residues under mild oxidation conditions. The covalent dimer of S-periaxin was also observed by western blot analysis and bimolecular fluorescence complementation analyses. S-periaxin dimerization formation could be regulated by...



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

Tue, 01 Mar 2016 00:00:00 +0100

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 i...



Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies

Tue, 16 Feb 2016 22:19:01 +0100

Schwann cells produce myelin sheath around peripheral nerve axons. Myelination is critical for rapid propagation of action potentials, as illustrated by the large number of acquired and hereditary peripheral neuropathies, such as diabetic neuropathy or Charcot-Marie-Tooth diseases, that are commonly associated with a process of demyelination. However, the early molecular events that trigger the demyelination program in these diseases remain unknown. Here, we used virally delivered fluorescent probes and in vivo time-lapse imaging in a mouse model of demyelination to investigate the underlying mechanisms of the demyelination process. We demonstrated that mitochondrial calcium released by voltage-dependent anion channel 1 (VDAC1) after sciatic nerve injury triggers Schwann cell demyelination...



ID 270 – Nerve ultrasound findings in cmt neuropathy

Thu, 11 Feb 2016 06:19:55 +0100

We have extensively evaluated nerve ultrasound (US) pattern in different CMT subgroup patients, assessing median, ulnar, fibular, tibial, sural nerves pattern. Sixty-nine patients affected with hereditary neuropathy (including 16 CMT1A, 4 CMT1B, 3 CMT1C, 2 CMT1D, 4 CMT1 not defined, 22 CMT2, 8 CMTX, 10 HNPP) underwent widespread nerve US evaluation. Nerve cross sectional area (CSA) and echotexture were evaluated at four limbs in different sites, both distally and proximally. Data were correlated with age and clinical pictures. (Source: Clinical Neurophysiology)



DGAT2 Mutation in a Family with Autosomal‐Dominant Early‐Onset Axonal Charcot‐Marie‐Tooth Disease

Tue, 09 Feb 2016 00:00:00 +0100

This study will help provide a better understanding of the pathophysiology of axonal CMT and contribute to the molecular diagnostics of peripheral neuropathies. A DGAT2 mutation (p.Y223H) was found in an autosomal dominant axonal CMT family. In the zebrafish larvae, the over‐expressed mutant DGAT2 showed an abrogated formation of the bundle of neuronal axons (fascicles) in the trunk at 3 dpf and significantly decreased number of branched axons per fascicle (BPF) in the peripheral nervous system at 15 dpf. (Source: Human Mutation)

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Epidemiologic Study of Charcot-Marie-Tooth Disease: A Systematic Review

Sat, 06 Feb 2016 00:04:12 +0100

The objectives of this study were to systematically review and assess the quality of studies reporting the incidence and/or prevalence of CMT worldwide. Summary: A total of 802 studies were initially identified, with only 12 meeting the inclusion criteria. CMT prevalence was reported in 10 studies and ranged from 9.7/100,000 in Serbia to 82.3/100,000 in Norway. The frequency of the main subtypes varied from 37.6 to 84% for CMT1 and from 12 to 35.9% for CMT2; the country with the lowest prevalence of CMT1 was Norway, and the country with the highest prevalence of CMT1 was Iceland; on the other hand, CMT2 was least prevalent in the United Kingdom and most prevalent in Norway. Key Messages: This review reveals the gaps that still exist in the epidemiological knowledge of CMT around the world....



FIG4 regulates lysosome membrane homeostasis independent of phosphatase function

Fri, 05 Feb 2016 00:00:00 +0100

FIG4 is a phosphoinositide phosphatase that is mutated in several diseases including Charcot-Marie-Tooth Disease 4J (CMT4J) and Yunis-Varon syndrome (YVS). To investigate the mechanism of disease pathogenesis, we generated Drosophila models of FIG4-related diseases. Fig4 null mutant animals are viable but exhibit marked enlargement of the lysosomal compartment in muscle cells and neurons, accompanied by an age-related decline in flight ability. Transgenic animals expressing Drosophila Fig4 missense mutations corresponding to human pathogenic mutations can partially rescue lysosomal expansion phenotypes, consistent with these mutations causing decreased FIG4 function. Interestingly, Fig4 mutations predicted to inactivate FIG4 phosphatase activity rescue lysosome expansion phenotypes, and mu...



Plant DNA methyltransferase genes: Multiplicity, expression, methylation patterns

Mon, 01 Feb 2016 00:00:00 +0100

Abstract Expression and methylation patterns of genes encoding DNA methyltransferases and their functionally related proteins were studied in organs of Arabidopsis thaliana plants. Genes coding for the major maintenance-type DNA methyltransferases, MET1 and CMT3, and the major de novo-type DNA methyltransferase, DRM2, are actively expressed in all organs. Similar constitutively active expression was observed for genes encoding their functionally related proteins, a histone H3K9 methyltransferase KYP and a catalytically non-active protein DRM3. Expression of the MET1 and CMT3 genes is significantly lower in developing endosperm compared with embryo. Vice versa, expression of the MET2a, MET2b, MET3, and CMT2 genes in endosperm is much more active compared with embryo. A special mai...



A Mutation in PMP2 Causes Dominant Demyelinating Charcot-Marie-Tooth Neuropathy

Mon, 01 Feb 2016 00:00:00 +0100

This report might expand the genetic and clinical features of CMT and a further mechanism study will enhance our understanding of PMP2-associated peripheral neuropathy. (Source: PLoS Genetics)



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

Fri, 29 Jan 2016 00:00:00 +0100

Authors: Brožková DŠ, Haberlová J, Mazanec R, Laštůvková J, Seeman P Abstract Hereditary motor and sensory neuropathy type Russe (HMSNR), also called CMT4G is an autosomal recessive inherited peripheral neuropathy (IPN) caused by a founder mutation in the HK1 gene. HMSNR affects only patients with Roma origin, similar to the better known HMSN type Lom clarified earlier. By testing IPN patients with Roma origin we realized that HMSNR affects surprisingly many patients in the Czech Republic. HMSNR is one of the most frequent types of IPN in this country and seems to be twice more frequent than HMSNL. Pronounced lower limb atrophies and severe deformities often lead to walking inability in even young patients, but hands are usually only mildly affected even after many years of ...

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Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy

Mon, 25 Jan 2016 00:00:00 +0100

Conclusion: We expand the understanding of disease mechanisms, tissue involvement, and phenotypic outcome of HSPB8 mutations. HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex previously only associated with Charcot-Marie-Tooth type 2L (OMIM 60673) and distal hereditary motor neuronopathy type IIa. However, we now demonstrate that patients can develop a myopathy with histologic features of myofibrillar myopathy with aggregates and rimmed vacuoles, similar to the pathology in myopathies due to gene defects in other compounds of the CASA complex such as BAG3 and DNAJB6 after developing the early neurogenic effects. (Source: Neurology)



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

Sat, 23 Jan 2016 08:38:02 +0100

Authors: Kumar CV, Swetha RG, Anbarasu A, Ramaiah S Abstract 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 ...



MFN2‐related genetic and clinical features in a cohort of Chinese CMT2 patients

Sat, 23 Jan 2016 00:00:00 +0100

ConclusionWe report four novel mutations and four rare missense variants. MFN2 mutations account for 18% of CMT2 families in mainland China. The common characteristics of Chinese pedigree are early disease onset and moderate phenotypes. (Source: Journal of the Peripheral Nervous System)



A new next-generation sequencing-based assay for concurrent preimplantation genetic diagnosis of Charcot-Marie-Tooth disease type 1A and aneuploidy screening

Fri, 22 Jan 2016 00:00:00 +0100

Publication date: Available online 21 January 2016 Source:Journal of Genetics and Genomics Author(s): Baoheng Gui, Pu Yang, Zhongyuan Yao, Yanping Li, Donge Liu, Nenghui Liu, Sijia Lu, Desheng Liang, Lingqian Wu (Source: Journal of Genetics and Genomics)



Corrigendum: CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase

Wed, 20 Jan 2016 00:00:00 +0100

Nature advance online publication 20 January 2016. doi:10.1038/nature16499 Authors: Weiwei He, Ge Bai, Huihao Zhou, Na Wei, Nicholas M. White, Janelle Lauer, Huaqing Liu, Yi Shi, Calin Dan Dumitru, Karen Lettieri, Veronica Shubayev, Albena Jordanova, Velina Guergueltcheva, Patrick R. Griffin, Robert W. Burgess, Samuel L. Pfaff & Xiang-Lei Yang (Source: Nature AOP)

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DGAT2 Mutation in a Family with Autosomal Dominant Early‐Onset Axonal Charcot‐Marie‐Tooth Disease

Wed, 20 Jan 2016 00:00:00 +0100

This study will help provide a better understanding of the pathophysiology of axonal CMT and contribute to the molecular diagnostics of peripheral neuropathies. This article is protected by copyright. All rights reserved (Source: Human Mutation)



Charcot-Marie-Tooth 2b associated Rab7 mutations cause axon growth and guidance defects during vertebrate sensory neuron development

Wed, 20 Jan 2016 00:00:00 +0100

Charcot-Marie-Tooth2b (CMT2b) is an axonal form of a human neurodegenerative disease that preferentially affects sensory neurons. CMT2b is dominantly inherited and is characterized by unusually early onset, pr... (Source: Neural Development)



Homozygous p.V116* mutation in C12orf65 results in Leigh syndrome

Thu, 14 Jan 2016 00:00:00 +0100

Conclusions We demonstrate that the identical nonsense mutation in C12orf65 can result in different clinical features, suggesting the involvement of unknown modifiers. (Source: Journal of Neurology, Neurosurgery and Psychiatry)



MORC2 mutations cause axonal Charcot–Marie–Tooth disease with pyramidal signs

Wed, 13 Jan 2016 00:00:00 +0100

ObjectiveTo use linkage analysis and whole exome sequencing to identify the genetic mutation in a multigenerational Australian family with Charcot–Marie–Tooth disease type 2 (CMT2) and pyramidal signs. MethodsGenome‐wide linkage analysis was performed to map the locus. Whole exome sequencing was undertaken on selected individuals (3 affected, 1 normal), and segregation analysis and mutation screening were carried out using high‐resolution melt analysis. The GEM.app database was queried to identify additional families with mutations. ResultsSignificant linkage (2‐point LOD score ≥ +3) and haplotype analysis mapped a new locus for CMT2 and pyramidal signs to a 6.6Mb interval on chromosome 22q12.1–q12.3. Whole exome sequencing identified a novel mutation (p.R252W) in the mic...



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

Tue, 12 Jan 2016 00:00:00 +0100

Publication date: Available online 2 January 2016 Source:The Journal of Molecular Diagnostics Author(s): Vincenzo Lupo, Francisco García-García, Paula Sancho, Cristina Tello, Mar García-Romero, Liliana Villarreal, Antonia Alberti, Rafael Sivera, Joaquín Dopazo, Samuel I. Pascual-Pascual, Celedonio Márquez-Infante, Carlos Casasnovas, Teresa Sevilla, Carmen Espinós 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 ...

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ERRATUM: Novel mutations in genes causing hereditary spastic paraplegia and Charcot-Marie-Tooth neuropathy identified by an optimized protocol for homozygosity mapping based on whole-exome sequencing

Tue, 12 Jan 2016 00:00:00 +0100

Genetics in Medicine 18, 108 (January 2016). doi:10.1038/gim.2015.174 (Source: Genetics in Medicine)



Rescue of neurodegeneration in the Fig4 null mouse by a catalytically inactive FIG4 transgene

Fri, 08 Jan 2016 00:00:00 +0100

The lipid phosphatase FIG4 is a subunit of the protein complex that regulates biosynthesis of the signaling lipid PI(3,5)P2. Mutations of FIG4 result in juvenile lethality and spongiform neurodegeneration in the mouse, and are responsible for the human disorders Charcot–Marie–Tooth disease, Yunis–Varon syndrome and polymicrogyria with seizures. We previously demonstrated that conditional expression of a wild-type FIG4 transgene in neurons is sufficient to rescue most of the abnormalities of Fig4 null mice, including juvenile lethality and extensive neurodegeneration. To evaluate the contribution of the phosphatase activity to the in vivo function of Fig4, we introduced the mutation p.Cys486Ser into the Sac phosphatase active-site motif CX5RT. Transfection of the Fig4Cys48...



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

Fri, 08 Jan 2016 00:00:00 +0100

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 congenit...



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

Fri, 08 Jan 2016 00:00:00 +0100

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 ...



Abstract B199: Novel anti-angiogenic cancer therapeutic strategy by targeting differentiated macrophage lineage cells through N-myc downstream regulated gene 1 (NDRG1)

Thu, 07 Jan 2016 00:00:00 +0100

Conclusion] We discovered the central role of NDRG1 in differentiation of macrophage lineage cells, which affected bone remodeling and tumor angiogenesis. We will discuss which molecules are specifically regulated by NDRG1 during differentiation processes of monocytes/macrophages into angiogenesis-supporting macrophages, and whether these molecules in macrophages could have potentially important target for anti-angiogenesis cancer therapeutics.Citation Format: Kosuke Watari, Tomohiro Shibata, Hiroshi Nabeshima, Ai Shinoda, Yuichi Fukunaga, Akihiko Kawahara, Kazuyuki Karasuyama, Jun-ichi Fukushi, Yuichi Murakami, Michihiko Kuwano, Mayumi Ono. Novel anti-angiogenic cancer therapeutic strategy by targeting differentiated macrophage lineage cells through N-myc downstream regulated gene 1 (NDRG...

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

Sat, 02 Jan 2016 00:00:00 +0100

Abstract 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 an...



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

Sat, 02 Jan 2016 00:00:00 +0100

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. (Source: Journal of Molecular Diagnostics)



Massively Parallel Sequencing Detected a Mutation in the MFN2 Gene Missed by Sanger Sequencing Due to a Primer Mismatch on an SNP Site

Fri, 01 Jan 2016 00:00:00 +0100

We describe a patient with early onset severe axonal Charcot‐Marie‐Tooth disease (CMT2) with dominant inheritance, in whom Sanger sequencing failed to detect a mutation in the mitofusin 2 (MFN2) gene because of a single nucleotide polymorphism (rs2236057) under the PCR primer sequence. The severe early onset phenotype and the family history with severely affected mother (died after delivery) was very suggestive of CMT2A and this suspicion was finally confirmed by a MFN2 mutation. The mutation p.His361Tyr was later detected in the patient by massively parallel sequencing with a gene panel for hereditary neuropathies. According to this information, new primers for amplification and sequencing were designed which bind away from the polymorphic sites of the patient´s DNA. Sanger sequencin...



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

Wed, 23 Dec 2015 19:44:58 +0100

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 wi...



Evaluation of Respiratory Muscle Strength and Pulmonary Function in Patients with Charcot-Marie-Tooth Disease Type 2

Wed, 16 Dec 2015 22:33:15 +0100

The aim of this study was to evaluate the pulmonary condition in a large family with Charcot-Marie-Tooth disease type 2 (CMT2). Eighteen participants diagnosed with CMT2 and 20 healthy individuals were evaluated by spirometry and maximal expiratory and maximal inspiratory pressures (MEP and MIP, respectively). Clinical disability was measured with CMT neuropathy score (CMTNS; range 0-36). One control group (CG) comprising 20 individuals, matched for age, sex and body mass index, were used for comparison. Eight patients were female (44.5%) and 10 patients were male (55.5%); mean age was 31.8 years (range 11-79) and CMTNS range was 6-26. Differences between CMT2 and CG in the spirometry and respiratory muscle strength were statistically significant for all dimensions. There were significant ...

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Evaluation of muscle strength and manual dexterity in patients with Charcot-Marie-Tooth disease

Sun, 13 Dec 2015 00:00:00 +0100

Matched pair study. (Source: Journal of Hand Therapy)



A novel heat shock protein 27 homozygous mutation: widening of the continuum between MND/dHMN/CMT2

Sun, 13 Dec 2015 00:00:00 +0100

(Source: Journal of the Peripheral Nervous System)



Ascorbic acid for the treatment of Charcot-Marie-Tooth disease.

Fri, 11 Dec 2015 00:00:00 +0100

CONCLUSIONS: High-quality evidence indicates that ascorbic acid does not improve the course of CMT1A in adults in terms of the outcome parameters used. According to low-quality evidence, ascorbic acid does not improve the course of CMT1A in children. However, CMT1A is slowly progressive and the outcome parameters show only small change over time. Longer study durations should be considered, and outcome parameters more sensitive to change over time should be designed and validated for future studies. PMID: 26662471 [PubMed - as supplied by publisher] (Source: Cochrane Database of Systematic Reviews)



Clinical and allelic heterogeneity in a pediatric cohort of 11 patients carrying mutation

Thu, 10 Dec 2015 00:00:00 +0100

The Mitofusin 2 gene (MFN2), which encodes a mitochondrial membrane protein, is known to be the first cause of autosomal dominant Charcot–Marie–Tooth disease type 2 (CMT2) with early onset. This gene is involved in typical CMT2A and in more atypical phenotypes as optic atrophy or spastic paraplegia. CMT2 refers to inherited axonal polyneuropathy, which associates progressive peripheral motor and sensory neuropathy, a family history consistent mainly with autosomal dominant inheritance, and normal nerve conduction velocities. (Source: Brain and Development)



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

Thu, 10 Dec 2015 00:00:00 +0100

Authors: Tey S, Ahmad-Annuar A, Drew AP, Shahrizaila N, Nicholson GA, Kennerson ML Abstract 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 eigh...

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Clinical and allelic heterogeneity in a pediatric cohort of 11 patients carrying MFN2 mutation

Thu, 10 Dec 2015 00:00:00 +0100

The Mitofusin 2 gene (MFN2), which encodes a mitochondrial membrane protein, is known to be the first cause of autosomal dominant Charcot–Marie–Tooth disease type 2 (CMT2) with early onset. This gene is involved in typical CMT2A and in more atypical phenotypes as optic atrophy or spastic paraplegia. CMT2 refers to inherited axonal polyneuropathy, which associates progressive peripheral motor and sensory neuropathy, a family history consistent mainly with autosomal dominant inheritance, and normal nerve conduction velocities. (Source: Brain and Development)



MORC2 mutations cause axonal Charcot‐Marie‐Tooth disease with pyramidal signs

Tue, 01 Dec 2015 00:00:00 +0100

This article is protected by copyright. All rights reserved. (Source: Annals of Neurology)



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

Tue, 01 Dec 2015 00:00:00 +0100

Abstract 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...



Case Studies of Transcranial Electrical Motor Evoked Potentials (TCeMEP) on Patients with Charcot-Marie-Tooth Disease during Posterior Spinal Instrumentation and Fusion.

Mon, 30 Nov 2015 21:40:03 +0100

Authors: Schmidt R, Mani P, Weber D Abstract Neuromuscular disease can present many challenges to monitoring technologists in the operating room. This became evident when we received a request to monitor a patient with Charcot-Marie-Tooth disease during posterior spinal instrumentation and fusion for scoliosis. It has been well documented that the nerve conduction velocity is delayed with Charcot-Marie-Tooth disease (Pareyson et al. 2006). The latencies we normally encounter for somatosensory and motor evoked potentials for the upper extremity responses are between 15 and 20 msec, and for the lower extremity responses, are usually between 25 and 35 msec. Recording with a sweep of 100 msec, we assumed we could record a response with a significant delay. We never imagined we would ne...



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

Fri, 27 Nov 2015 14:24:27 +0100

CONCLUSIONS: CMT1A predominated in our series (44%), as previous studies. We emphasize the description of a patient with a mutation in TRPV4 recently described as a cause of CMT2C and three cases, of gypsy consanguineous family, with the same mutation in HINT1 gene, recently described as a cause of axonal neuropathy with neuromyotonia, autosomal recessive (AR-CMT2). The proportion of patients without molecular diagnosis is similar to main European series. PMID: 26602803 [PubMed - in process] (Source: Revista de Neurologia)

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Cavovarus deformity in Charcot-Marie-Tooth disease: is there a hindfoot equinus deformity that needs treatment?

Thu, 26 Nov 2015 00:00:00 +0100

We examined 40 patients (80 feet) with CMT and bilateral cavovarus deformities (19 men and 21 women, mean age 33.6 ± 14.6 years) and the feet of a healthy control population of 13 individuals (7 men and 6 women, mean age 43.9 ± 10.8 years). In all cases 3D instrumented gait analysis results with both conventional Plug-in-Gait analysis and the Heidelberg Foot Measurement Method (HFMM) were used to determine the sagittal plane kinematics, dorsi-plantar flexion (DPF), tibio-talar dorsiflexion (TTDF), and medial arch angle (MAA), and the results of patients and the control group were compared using the 2 methods. Decreased and increased dorsiflexion using TTDF was defined as 1 standard deviation below or above the mean of the control. Comparisons were done using descriptive statistic...



Pathogenic mutations and sequence variants within mitofusin 2 gene in Polish patients with different hereditary motor-sensory neuropathies.

Sun, 22 Nov 2015 13:28:03 +0100

In this study, we searched for MFN2 gene mutations in Polish patients representing the population of nearly 40 million. We decided to include a wide spectrum of clinical phenotypes in the study, proving able to detect, in a group of 67 affected patients: 1) 3 pathogenic mutations; 2) 3 sequence variants of unknown pathogenic status; 3) 9 rare MFN2 gene sequence variants; 4) 6 common polymorphisms. The frequency of MFN2 gene mutations in the whole group of patients is 4.5%. Due to the high frequency of MFN2 gene sequence variants within single patients we could not definitely exclude the cumulative effect of these contributing to the HMSN II phenotype. The MFN2 gene should therefore be considered in Polish HMSN II patients, though it is still not possible to determine its position in HMSN I...



A mutation in the Warburg syndrome gene, RAB3GAP1, causes a similar syndrome with polyneuropathy and neuronal vacuolation in Black Russian Terrier dogs.

Thu, 19 Nov 2015 00:00:00 +0100

Authors: Mhlanga-Mutangadura T, Johnson GS, Schnabel RD, Taylor JF, Johnson GC, Katz ML, Diane Shelton G, Lever TE, Giuliano E, Granger N, Shomper J, O'Brien DP Abstract An autosomal recessive disease of Black Russian Terriers was previously described as a juvenile-onset, laryngeal paralysis and polyneuropathy similar to Charcot Marie Tooth disease in humans. We found that in addition to an axonal neuropathy, affected dogs exhibit microphthalmia, cataracts, and miotic pupils. On histopathology, affected dogs exhibit a spongiform encephalopathy characterized by accumulations of abnormal, membrane-bound vacuoles of various sizes in neuronal cell bodies, axons and adrenal cells. DNA from an individual dog with this polyneuropathy with ocular abnormalities and neuronal vacuolation (POA...



What Are the Clinical Presentation of Charcot-Marie-Tooth Disease?

Mon, 16 Nov 2015 00:10:22 +0100

Discussion Charcot-Marie-Tooth disease (CMT) or hereditary motor and sensory neuropathy, is the most common cause of inherited neuropathies affecting 10-82:100,000 individuals. CMT comprises a heterogeneous group of peripheral, chronic inherited neuropathies that affects both the motor and sensory neurons and which have different genetic causations. Charcot and Marie were both French neurologists and Tooth was a British neurologist who described distal muscle wasting in 1886. Dejerine and Sottas reported the infantile form in 1893 which bears their name for this more severe clinical subtype. CMT classification is advancing as new testing becomes available but currently is classified as: CMT1 Most common variant of CMT (70%) Autosomal dominant Has different subgroups but the most common s...



The modified ultrasound pattern sum score mUPSS as additional diagnostic tool for genetically distinct hereditary neuropathies

Wed, 11 Nov 2015 00:00:00 +0100

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 sig...

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MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study

Sat, 07 Nov 2015 00:00:00 +0100

Publication date: Available online 6 November 2015 Source:The Lancet Neurology Author(s): Jasper M Morrow, Christopher D J Sinclair, Arne Fischmann, Pedro M Machado, Mary M Reilly, Tarek A Yousry, John S Thornton, Michael G Hanna Background A substantial impediment to progress in trials of new therapies in neuromuscular disorders is the absence of responsive outcome measures that correlate with patient functional deficits and are sensitive to early disease processes. Irrespective of the primary molecular defect, neuromuscular disorder pathological processes include disturbance of intramuscular water distribution followed by intramuscular fat accumulation, both quantifiable by MRI. In pathologically distinct neuromuscular disorders, we aimed to determine the comparative responsive...



Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The - Contiguous Gene Duplication Syndrome

Thu, 05 Nov 2015 00:00:00 +0100

The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. (Source: The American Journal of Human Genetics)



Correlates of functional ankle instability in children and adolescents with Charcot-Marie-Tooth disease

Thu, 05 Nov 2015 00:00:00 +0100

Background: Functional ankle instability (FAI) is commonly reported by children and adolescents with Charcot-Marie-Tooth disease (CMT), however,, the specific variables associated with FAI remain unknown. An improved understanding of these variables may suggest interventions to improve ankle stability and possibly prevent the long-term complications associated with ankle instability in this population. The aim of this study was to therefore investigate the relationship between FAI and other functional, structural, anthropometric and demographic characteristics in a cross sectional sample of children and adolescents with CMT. Methods: Thirty children and adolescents with CMT aged 7–18 years were recruited from the Peripheral Neuropathy Clinics of a large tertiary paediatric hospital. Meas...



[Comment] MRI quantifies neuromuscular disease progression

Thu, 05 Nov 2015 00:00:00 +0100

Several studies provide compelling support for the use of MRI as a sensitive non-invasive method to assess skeletal muscle disease progression in various neuromuscular diseases, including Duchenne muscular dystrophy1,2 and limb girdle muscular dystrophy type 2I.3 In The Lancet Neurology, Jasper Morrow and colleagues4 now report the sensitivity of MRI to track disease progression in 20 patients with Charcot-Marie-Tooth disease 1A and 20 patients with inclusion body myositis. (Source: Lancet Neurology)



Adult-onset autosomal dominant spastic paraplegia linked to a GTPase-effector domain mutation of dynamin 2

Fri, 30 Oct 2015 00:00:00 +0100

Conclusion: This is the first report linking a mutation in dynamin 2 to a HSP phenotype. Dynamin 2 mutations have previously been associated with other phenotypes including two forms of Charcot-Marie-Tooth neuropathy and centronuclear myopathy. These strikingly different pathogenic effects may depend on structural relationships the mutations disrupt. Awareness of this distinct association between HSP and c.2155C > T, p.R719W mutation will facilitate ascertainment of additional DNM2 HSP families and will direct future research toward better understanding of cell biological processes involved in these partly overlapping clinical syndromes. (Source: BMC Neurology)

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Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene

Mon, 26 Oct 2015 00:00:00 +0100

We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot–Marie–Tooth disease neuropathy score version 1 or 2 and the Charcot–Marie–Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot–Marie–Tooth disease type 1B. There were 103 patients fro...



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

Mon, 26 Oct 2015 00:00:00 +0100

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 ...



Targeting mutant proteins might be silver bullet for neurodegenerative diseases

Wed, 21 Oct 2015 17:56:26 +0100

A mutant protein has been identified by scientists as culprit in Charcot-Marie-Tooth (CMT) diseases. CMT is a group of hereditary disorders that affects about 1 in every 2,500 people in the United States, making it one of the most common inherited neurological diseases. While different forms of the disease vary in their symptoms and underlying genetic causes, the common thread is that CMT damages the nerves in a person's arms and legs. (Source: ScienceDaily Headlines)



CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase

Wed, 21 Oct 2015 00:00:00 +0100

Nature advance online publication 21 October 2015. doi:10.1038/nature15510 Authors: Weiwei He, Ge Bai, Huihao Zhou, Na Wei, Nicholas M. White, Janelle Lauer, Huaqing Liu, Yi Shi, Calin Dan Dumitru, Karen Lettieri, Veronica Shubayev, Albena Jordanova, Velina Guergueltcheva, Patrick R. Griffin, Robert W. Burgess, Samuel L. Pfaff & Xiang-Lei Yang Selective neuronal loss is a hallmark of neurodegenerative diseases, which, counterintuitively, are often caused by mutations in widely expressed genes. Charcot–Marie–Tooth (CMT) diseases are the most common hereditary peripheral neuropathies, for which there are no effective therapies. A subtype of these diseases—CMT type 2D (CMT2D)—is caused by dominant mutations in GARS, encoding the ubiquitously expressed enzyme glycy...



X-Linked Hereditary Motor Sensory Neuropathy Type 1 (CMTX1) in a Three-Generation Gelao Chinese Family

Mon, 19 Oct 2015 00:00:00 +0100

In this report, we describe a three-generation family (the Gelao nationality, a minority ethnic group from Guizhou Province in the southwest China) with one affected member with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) in each generation. The three affected members carrying the R164W mutation in the Cx32 gene had different clinical symptoms. The proband, a 13-year-old boy presented recurrent episodes of transient central nervous system symptoms and concomitant transient diffuse white matter lesions on magnetic resonance imaging. His grandfather had the peripheral neurological presentations with later onset in the fourth decade, characterized by slowly progressive weakness of the distal muscles, atrophy, and foot deformities. But no sensory loss was observed. The proband's 38-year-ol...



Clinical and genetic spectra in a series of Chinese patients with Charcot–Marie–Tooth disease

Fri, 09 Oct 2015 00:00:00 +0100

Publication date: Available online 8 October 2015 Source:Clinica Chimica Acta Author(s): Rui Wang, Jin He, Jing-Jin Li, Wang Ni, Zhi-Ying Wu, Wan-Jin Chen, Yi Wang 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...



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

Wed, 07 Oct 2015 00:00:00 +0100

Authors: Wang R, He J, Li JJ, Ni W, Wu ZY, Chen WJ, Wang Y Abstract 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 patie...



A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy

Mon, 05 Oct 2015 00:00:00 +0100

Conclusion: We report a novel homozygous mutation in MPV17 from two unrelated patients harboring axonal sensorimotor polyneuropathy without hepatoencephalopathy. This report expands the clinical spectrum of diseases caused by mutations of MPV17, and we recommend MPV17 gene screening for axonal peripheral neuropathies. (Source: BMC Neurology)



Charcot-Marie-Tooth disease: New insights from skin biopsy

Mon, 05 Oct 2015 00:00:00 +0100

Conclusions: This study extends the information gained from skin biopsies on morphologic abnormalities in various forms of CMT and provides insights into potential pathomechanisms of axonal and demyelinating CMT. (Source: Neurology)

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Sporadic hereditary motor and sensory neuropathies: Advances in the diagnosis using next generation sequencing technology

Sat, 03 Oct 2015 00:00:00 +0100

Hereditary motor and sensory neuropathies (HMSN) are genetically heterogeneous disorders affecting peripheral motor and sensory functions. Many different pathogenic variants in several genes involved in the demyelinating, the axonal and the intermediate HMSN forms have been identified, for which all inheritance patterns have been described. The mutation screening currently available is based on Sanger sequencing and is time-consuming and relatively expensive due to the high number of genes involved and to the absence of mutational hot spots. (Source: Journal of the Neurological Sciences)



HDAC1/2-Dependent P0 Expression Maintains Paranodal and Nodal Integrity Independently of Myelin Stability through Interactions with Neurofascins

Fri, 25 Sep 2015 00:00:00 +0100

by Valérie Brügger, Stefanie Engler, Jorge A. Pereira, Sophie Ruff, Michael Horn, Hans Welzl, Emmanuelle Münger, Adrien Vaquié, Páris N. M. Sidiropoulos, Boris Egger, Peter Yotovski, Luis Filgueira, Christian Somandin, Tessa C. Lühmann, Maurizio D’Antonio, Teppei Yamaguchi, Patrick Matthias, Ueli Suter, Claire Jacob 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 mye...



Charcot-Marie-Tooth diseases: an update and some new proposals for the classification

Tue, 22 Sep 2015 00:00:00 +0100

Conclusions We suggest a modification of the current classification and explain why such a change is needed. (Source: Journal of Medical Genetics)



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

Mon, 21 Sep 2015 00:00:00 +0100

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. (Source: Journal of Clinical Anesthesia)



Mitochondrial Dysfunction in a Patient with 8q21.11 Deletion and Charcot-Marie-Tooth Disease Type 2K due to GDAP1 Haploinsufficiency

Fri, 18 Sep 2015 09:03:52 +0100

We describe a female with intellectual disability, failure to thrive, short stature, multiple congenital anomalies, and dysmorphic features and a previously diagnosed de novo 8q21.11 deletion at the age of 7. However, at the age of 11, she experienced neurological and developmental regression. The GDAP1 gene encoding ganglioside-induced differentiation-associated protein 1 was deleted in the patient as a part of the contiguous gene syndrome. We argue that haploinsufficiency of GDAP1 could have contributed to the proband's regression based on its involvement in mitochondrial function and a signal transduction pathway in neuronal development.Mol Syndromol (Source: Molecular Syndromology)

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Complexity of the Hereditary Motor and Sensory Neuropathies: Clinical and Cellular Characterization of the MPZ p.D90E Mutation

Fri, 18 Sep 2015 00:00:00 +0100

This study broadens the clinical phenotype of hereditary motor and sensory neuropathy due to MPZ mutation and emphasises the difficulty of achieving an accurate genetic diagnosis in a sporadic patient to provide an appropriate pharmacologic treatment. (Source: Journal of Child Neurology)



mutations in Italian axonal Charcot-Marie Tooth patients: phenotypic features and clinical course

Thu, 17 Sep 2015 00:00:00 +0100

• Mutations in GDAP1 were found in few family with a late-onset dominant form of CMT.• The AD forms are less severe than AR forms and show a slower disease course.• We analyzed 109 AD-CMT patients for dominant mutations• We identified five pathogenic heterozygous GDAP1 mutations in 8 families.• GDAP1 should be considered among the top genes in axonal CMT patients. (Source: Neuromuscular Disorders)



Interosseous membrane window size for tibialis posterior tendon transfer–geometrical and m.r.i. Analysis

Thu, 17 Sep 2015 00:00:00 +0100

Tibialis posterior transfer was first reported by Ober in 1933.[1] He described the circumtibial technique. This transfer allows the foot to recover (at least partially) its dorsiflexion motion in pathologies such as Charcot-Marie-Tooth, leprosy, mononeuropathy, common peroneal nerve injury, stroke, Duchenne muscular dystrophy, [2–5,7] whenever the deformity is flexible. (Source: Foot and Ankle Surgery)



Mitochondrial and bioenergetic dysfunction in trauma-induced painful peripheral neuropathy

Thu, 17 Sep 2015 00:00:00 +0100

Conclusion: Traumatic peripheral nerve injury induces persistent mitochondrial and bioenergetic dysfunction which implies that pharmacological agents which seek to normalize mitochondrial and bioenergetic dysfunction could be expected to be beneficial for pain treatment. Increases in both glycolytic acidification and non-glycolytic acidification suggest that pH sensitive drugs which preferentially act on acidic tissue will have the ability to preferential act on injured nerves without affecting healthy tissues. (Source: Molecular Pain)



Interosseous membrane window size for tibialis posterior tendon transfer—Geometrical and MRI analysis

Thu, 17 Sep 2015 00:00:00 +0100

Tibialis posterior transfer was first reported by Ober in 1933 [1]. He described the circumtibial technique. This transfer allows the foot to recover (at least partially) its dorsiflexion motion in pathologies such as Charcot-Marie-Tooth, leprosy, mononeuropathy, common peroneal nerve injury, stroke, Duchenne muscular dystrophy [2–5,7], whenever the deformity is flexible. (Source: Foot and Ankle Surgery)

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mutations in Italian axonal Charcot–Marie–Tooth patients: Phenotypic features and clinical course

Thu, 17 Sep 2015 00:00:00 +0100

Charcot–Marie–Tooth disease (CMT) is the most common form of inherited peripheral neuropathy. CMT can be classified in two major subtypes: demyelinating (CMT1, CMT4) and axonal CMT (CMT2); an intermediate subgroup also exists. To date, mutations in over 70 genes have been described [1]. Although time is ripe for a targeted molecular approach to the individual forms of CMT through next-generation sequencing (NGS), careful clinical investigations and gene prioritization might still be treasured. In fact the search for a diagnostic algorithm based on ethnic-specific gene mutation frequencies and the knowledge of gene-related clinical features are still needed for cost-efficient mutation detection and for correct interpretation of large-scale NGS data. (Source: Neuromuscular Disorders)



Dynamin-2 mutations associated with centronuclear myopathy are hypermorphic and lead to T-tubule fragmentation

Thu, 10 Sep 2015 00:00:00 +0100

Skeletal muscle requires adequate membrane trafficking and remodeling to maintain its normal structure and functions. Consequently, many human myopathies are caused by mutations in membrane trafficking machinery. The large GTPase dynamin-2 (Dyn2) is best known for catalyzing membrane fission during clathrin-mediated endocytosis (CME), which is critical for cell signaling and survival. Despite its ubiquitous expression, mutations of Dyn2 are associated with two tissue-specific congenital disorders: centronuclear myopathy (CNM) and Charcot–Marie–Tooth (CMT) neuropathy. Several disease models for CNM-Dyn2 have been established to study its pathogenic mechanism; yet the cellular and biochemical effects of these mutations are still not fully understood. Here we comprehensively compa...



Atypical presentation of charcot-marie-tooth disease 1a: a case report

Mon, 07 Sep 2015 00:00:00 +0100

We report clinical cranial nerve involvement (hypoglossal and glossopharyngeal) in a genetically confirmed CMT1A patient• Predominant and asymmetrical involvement of the upper limbs seen in our patient is seldom found in CMT1A (Source: Neuromuscular Disorders)



Atypical presentation of Charcot–Marie–Tooth disease 1A: A case report

Mon, 07 Sep 2015 00:00:00 +0100

Charcot–Marie–Tooth (CMT) disease, also referred to as hereditary motor and sensory neuropathies (HMSN), is a group of disorders characterized by progressive motor weakness, sensory abnormalities and abnormal nerve conduction velocities or amplitudes [1]. It is the most common inherited neuromuscular disorder affecting at least 1 in 2500 people and was first described in 1886 [2]. The most exciting advance in the understanding of this disorder came with the identification of duplication of peripheral myelin protein 22 (PMP22) gene on chromosome 17 as the cause of CMT1A [3,4]. (Source: Neuromuscular Disorders)



Charcot-Marie-Tooth neuropathy and Mobitz II heart block.

Wed, 02 Sep 2015 00:00:00 +0100

Authors: Ghonim S, Dubrey SW PMID: 26352718 [PubMed - in process] (Source: British Journal of Hospital Medicine)

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Gait patterns of children with Charcot-Marie-Tooth disease

Tue, 01 Sep 2015 00:00:00 +0100

Research question: What are the distinct gait patterns of children with Charcot-Marie-Tooth disease (CMT)? (Source: Gait and Posture)



Hibbs Tenosuspension

Sat, 29 Aug 2015 00:00:00 +0100

This article describes the procedure to transfer the extensor digitorum longus tendons into the peroneus tertius tendon to eliminate a deforming force and create a stabilizing force. (Source: Clinics in Podiatric Medicine and Surgery)



Coexistence of Charcot Marie Tooth disease type 1A and Diabetes in Taiwan: A Clinicopathological Study

Fri, 28 Aug 2015 00:00:00 +0100

Charcot Marie Tooth disease type 1A (CMT1A) is the most commonly inherited demyelinating polyneuropathy with variable phenotypes, affected by several comorbidities, especially diabetes mellitus (DM). Previous studies showed that DM exacerbates the clinical manifestations of CMT1A. (Source: Journal of the Neurological Sciences)



Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy

Wed, 26 Aug 2015 00:00:00 +0100

Multiple symmetric lipomatosis (MSL) is a mitochondrial disorder with impaired brown fat metabolism that has been associated with MERRF mutations in some, but not all, patients. We studied a sibling pair and an unrelated indiviadual who presented with MSL and neuropathy to determine the genetic etiology of this disorder in patients who did not carry the MSL-associated MERRF mutation. Whole-exome sequencing was performed on the siblings, and a rare, shared homozygous mutation in MFN2 (c.2119C>T: p.R707W) was identified. The mutation was not present in their healthy siblings. In silico programs predict it to be pathogenic, and heterozygous carriers of the MFN2 p.R707W substitution are known to have Charcot–Marie–Tooth (CMT) disease. A third, unrelated patient with multiple sym...



COX6A1 mutation causes axonal hereditary motor and sensory neuropathy - the confirmation of the primary report.

Tue, 25 Aug 2015 00:00:00 +0100

Authors: Laššuthová P, Beharka R, Krůtová M, Neupauerová J, Seeman P PMID: 26302975 [PubMed - as supplied by publisher] (Source: Clinical Genetics)

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Crystal structure of the dynamin tetramer

Mon, 24 Aug 2015 00:00:00 +0100

Nature advance online publication 24 August 2015. doi:10.1038/nature14880 Authors: Thomas F. Reubold, Katja Faelber, Nuria Plattner, York Posor, Katharina Ketel, Ute Curth, Jeanette Schlegel, Roopsee Anand, Dietmar J. Manstein, Frank Noé, Volker Haucke, Oliver Daumke & Susanne Eschenburg The mechanochemical protein dynamin is the prototype of the dynamin superfamily of large GTPases, which shape and remodel membranes in diverse cellular processes. Dynamin forms predominantly tetramers in the cytosol, which oligomerize at the neck of clathrin-coated vesicles to mediate constriction and subsequent scission of the membrane. Previous studies have described the architecture of dynamin dimers, but the molecular determinants for dynamin assembly and its regulation have remained unclear....



Hereditary motor and sensory neuropathy lom type in 6-year-old boy: Case report

Sun, 09 Aug 2015 08:37:35 +0100

Six year old boy had slow psychomotor development from an early age. Sitting independently at the age of 11months and walking at the age of 17months. He was always clumsy, often stumbling and falling.Neurological examination on admission to the Institute at the age of 6.6years: wasting of leg muscles, moderate weakness of proximal and distal muscles of legs, absent deep tendon reflexes; eqinovarus. Upper limbs, cranial nerves and sensory exam including hearing were found normal. Magnetic resonance of the brain was normal, and developmental quotient was 78. (Source: Clinical Neurophysiology)



Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

Fri, 07 Aug 2015 00:00:00 +0100

Publication date: Available online 6 August 2015 Source:Cell Reports Author(s): Claudia Gonzaga-Jauregui, Tamar Harel, Tomasz Gambin, Maria Kousi, Laurie B. Griffin, Ludmila Francescatto, Burcak Ozes, Ender Karaca, Shalini N. Jhangiani, Matthew N. Bainbridge, Kim S. Lawson, Davut Pehlivan, Yuji Okamoto, Marjorie Withers, Pedro Mancias, Anne Slavotinek, Pamela J. Reitnauer, Meryem T. Goksungur, Michael Shy, Thomas O. Crawford, Michel Koenig, Jason Willer, Brittany N. Flores, Igor Pediaditrakis, Onder Us, Wojciech Wiszniewski, Yesim Parman, Anthony Antonellis, Donna M. Muzny, Nicholas Katsanis, Esra Battaloglu, Eric Boerwinkle, Richard A. Gibbs, James R. Lupski Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal...



Parasympathetic Dominant Autonomic Dysfunction in Charcot-Marie-Tooth Disease Type 2J with the MPZ Thr124Met Mutation.

Wed, 05 Aug 2015 23:24:45 +0100

Authors: Tokuda N, Noto Y, Kitani-Morii F, Hamano A, Kasai T, Shiga K, Mizuta I, Niwa F, Nakagawa M, Mizuno T Abstract We herein report the case of a 69-year-old woman with Charcot-Marie-Tooth Disease type 2J (CMT2J) who presented with Adie's pupil, deafness, and urinary disturbance in addition to motor symptoms. On autonomic investigation, the coefficient of variation of the R-R intervals was decreased, and a urodynamic analysis showed a hypotonic bladder. A heart rate variability analysis revealed a decreased high frequency component and low frequency/high frequency ratio. Orthostatic hypotension was not present, and the sympathetic skin response and cardiac scintigraphy using (123)I-metaiodobenzylguanidine were normal. A gene analysis showed a known heterozygous mutation associa...

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Intrafamilial clinical variability in individuals carrying the CHCHD10 mutation Gly66Val

Thu, 30 Jul 2015 00:00:00 +0100

ConclusionsOur data demonstrate that even within the same family, the p.Gly66Val variant can cause variable phenotypes ranging from CMT2‐type axonal neuropathy to spinal muscular atrophy, which may also present as an ALS‐like disease. The spectrum of CHCHD10‐related neuromuscular disease has widened rapidly, and we recommend keeping the threshold for genetic testing low particularly when dominant inheritance or mitochondrial pathology is present. (Source: Acta Neurologica Scandinavica)



Spinal and bulbar muscular atrophy and charcot-marie-tooth type 1A: co-existence of two rare neuromuscular genetic diseases in the same patient.

Wed, 29 Jul 2015 00:00:00 +0100

We report the co-occurrence of two rare neuromuscular genetic disorders• The probability of co-existence of SBMA and CMT1A is 1 in 250,000,000• Exceptional co-existence of rare diseases explained atypical features in a simple way (Source: Neuromuscular Disorders)



Recessive hereditary motor and sensory neuropathy caused by IGHMBP2 gene mutation

Mon, 27 Jul 2015 00:00:00 +0100

Hereditary motor and sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth disease (CMT), is a genetically heterogeneous disorder that affects both sensory and motor peripheral nerves. HMSN is characterized by distal and symmetric muscle atrophy in the lower limbs and hands, foot abnormalities, and distal sensory loss. It is associated with more than 50 causative genes or loci; however, the genetic cause remains undetermined in almost 50% of HMSN cases.1,2 (Source: Neurology)



Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E

Mon, 20 Jul 2015 00:00:00 +0100

Conclusions: Decrease in NF abundance may be a pathologic marker of CMT2E. The lack of NF aggregates, consistent with prior studies, suggests that they occur proximally leading to subsequent alterations in the axonal cytoskeleton. The small axonal caliber, along with the normal molecular architecture of nodes and paranodes, explain the reduced velocities detected in patients with CMT2E. Our results also demonstrate that skin biopsy can provide evidence of pathologic and pathogenic abnormalities in patients with CMT2E. (Source: Neurology)



CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis

Tue, 14 Jul 2015 00:00:00 +0100

Conclusions Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. Clinical trial registration ID number NCT01193075. (Source: Journal of Neurology, Neurosurgery and Psychiatry)

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Toe-extension myotonia in myotonic dystrophy type 1

Mon, 13 Jul 2015 00:00:00 +0100

Myotonia is a cardinal symptom of adult-onset myotonic dystrophy type 1 (DM1). Myotonia, delayed relaxation following contraction, is most prominent in the hand and forearm muscles. Two sisters with genetically confirmed DM1 exhibited toe-extension myotonia (video on the Neurology® Web site at Neurology.org) in contrast to toe-flexion myotonia that can occur in DM1. There was a typical warm-up phenomenon. A variant phenotype of Charcot-Marie-Tooth–like polyneuropathy1 was not present. Mutations in the CLCN1 gene encoding the skeletal muscle chloride channel, in addition to abnormal splicing, can enhance myotonia in DM type 2.2 However, in our patients sequencing of the CLCN1 gene did not show mutations. (Source: Neurology)



Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder

Mon, 13 Jul 2015 00:00:00 +0100

Nature Genetics 47, 926 (2015). doi:10.1038/ng.3354 Authors: Alexander J Abrams, Robert B Hufnagel, Adriana Rebelo, Claudia Zanna, Neville Patel, Michael A Gonzalez, Ion J Campeanu, Laurie B Griffin, Saskia Groenewald, Alleene V Strickland, Feifei Tao, Fiorella Speziani, Lisa Abreu, Rebecca Schüle, Leonardo Caporali, Chiara La Morgia, Alessandra Maresca, Rocco Liguori, Raffaele Lodi, Zubair M Ahmed, Kristen L Sund, Xinjian Wang, Laura A Krueger, Yanyan Peng, Carlos E Prada, Cynthia A Prows, Elizabeth K Schorry, Anthony Antonellis, Holly H Zimmerman, Omar A Abdul-Rahman, Yaping Yang, Susan M Downes, Jeffery Prince, Flavia Fontanesi, Antonio Barrientos, Andrea H Németh, Valerio Carelli, Taosheng Huang, Stephan Zuchner & Julia E Dallman Dominant optic atrophy (DOA) and a...






Absence of disrupts Cajal bands in a patient with Charcot-Marie-Tooth disease

Tue, 07 Jul 2015 00:00:00 +0100

• We have identified the first CMT patient with a mutation in DRP2.• The mutation, Q269*, is predicted to result in an absence of the protein product.• Skin biopsy studies confirm this and recapitulate null animal model findings. (Source: Neuromuscular Disorders)



Dominant, toxic gain-of-function mutations in gars lead to non-cell autonomous neuropathology

Mon, 06 Jul 2015 00:00:00 +0100

Charcot–Marie–Tooth (CMT) neuropathies are collectively the most common hereditary neurological condition and a major health burden for society. Dominant mutations in the gene GARS, encoding the ubiquitous enzyme, glycyl-tRNA synthetase (GlyRS), cause peripheral nerve degeneration and lead to CMT disease type 2D. This genetic disorder exemplifies a recurring motif in neurodegeneration, whereby mutations in essential, widely expressed genes have selective deleterious consequences for the nervous system. Here, using novel Drosophila models, we show a potential solution to this phenomenon. Ubiquitous expression of mutant GlyRS leads to motor deficits, progressive neuromuscular junction (NMJ) denervation and pre-synaptic build-up of mutant GlyRS. Intriguingly, neuronal toxicity is,...

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P188. Gender-dependent differences in a cohort of Charcot-Marie-tooth (CMT) patients

Sun, 05 Jul 2015 18:08:28 +0100

Charcot-Marie-Tooth (CMT)-disease is the most common form of hereditary neuropathy and affects approximately 1 in 2500 people. It is inherited in an autosomal-dominant, -recessive or X-linked fashion (Gess et al., 2013). Mutations in >80 genes are known to cause CMT (CeGat). An effective treatment is not available yet.In this project, we aimed to test gender-dependent differences in CMT severity. Data from the German CMT patient registry (Friedrich-Baur-Institut) and our neuromuscular outpatient clinic were evaluated. (Source: Clinical Neurophysiology)



MFN2 deletion of exons 7 and 8: founder mutation in the UK population

Fri, 26 Jun 2015 00:00:00 +0100

Abstract Mitofusin 2 (MFN2) mutations are the most common cause of axonal Charcot‐Marie‐Tooth disease (CMT2). The majority are inherited in an autosomal dominant manner but recessive and semi‐dominant kindreds have also been described. We previously reported a deletion of exon 7 and 8 resulting in nonsense mediated decay, segregating with disease when present in trans with another pathogenic MFN2 mutation. Detailed clinical and electrophysiological data on a series of five affected patients from four kindreds and, when available, their parents and relatives was collected. MFN2 Sanger sequencing, multiplex ligation probe amplification and haplotype analysis was performed. A severe early‐onset CMT phenotype was seen in all cases: progressive distal weakness, wasting and sensory loss ...