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Search on : charcot-marie-tooth and disease [Words]
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[PMID]: 29415205
[Au] Autor:Benoy V; Van Helleputte L; Prior R; d'Ydewalle C; Haeck W; Geens N; Scheveneels W; Schevenels B; Cader MZ; Talbot K; Kozikowski AP; Vanden Berghe P; Van Damme P; Robberecht W; Van Den Bosch L
[Ad] Address:KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Research Institute for Neuroscience & Disease (LIND), Leuven, Belgium.
[Ti] Title:HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease.
[So] Source:Brain;, 2018 Feb 05.
[Is] ISSN:1460-2156
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Peripheral nerve axons require a well-organized axonal microtubule network for efficient transport to ensure the constant crosstalk between soma and synapse. Mutations in more than 80 different genes cause Charcot-Marie-Tooth disease, which is the most common inherited disorder affecting peripheral nerves. This genetic heterogeneity has hampered the development of therapeutics for Charcot-Marie-Tooth disease. The aim of this study was to explore whether histone deacetylase 6 (HDAC6) can serve as a therapeutic target focusing on the mutant glycyl-tRNA synthetase (GlyRS/GARS)-induced peripheral neuropathy. Peripheral nerves and dorsal root ganglia from the C201R mutant Gars mouse model showed reduced acetylated α-tubulin levels. In primary dorsal root ganglion neurons, mutant GlyRS affected neurite length and disrupted normal mitochondrial transport. We demonstrated that GlyRS co-immunoprecipitated with HDAC6 and that this interaction was blocked by tubastatin A, a selective inhibitor of the deacetylating function of HDAC6. Moreover, HDAC6 inhibition restored mitochondrial axonal transport in mutant GlyRS-expressing neurons. Systemic delivery of a specific HDAC6 inhibitor increased α-tubulin acetylation in peripheral nerves and partially restored nerve conduction and motor behaviour in mutant Gars mice. Our study demonstrates that α-tubulin deacetylation and disrupted axonal transport may represent a common pathogenic mechanism underlying Charcot-Marie-Tooth disease and it broadens the therapeutic potential of selective HDAC6 inhibition to other genetic forms of axonal Charcot-Marie-Tooth disease.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:Publisher
[do] DOI:10.1093/brain/awx375

  2 / 6057 MEDLINE  
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[PMID]: 29351582
[Au] Autor:Rebelo AP; Saade D; Pereira CV; Farooq A; Huff TC; Abreu L; Moraes CT; Mnatsakanova D; Mathews K; Yang H; Schon EA; Zuchner S; Shy ME
[Ad] Address:Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA.
[Ti] Title:SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency.
[So] Source:Brain;141(3):662-672, 2018 Mar 01.
[Is] ISSN:1460-2156
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Recessive mutations in the mitochondrial copper-binding protein SCO2, cytochrome c oxidase (COX) assembly protein, have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency. Significantly expanding the known phenotypic spectrum, we identified compound heterozygous variants in SCO2 in two unrelated patients with axonal polyneuropathy, also known as Charcot-Marie-Tooth disease type 4. Different from previously described cases, our patients developed predominantly motor neuropathy, they survived infancy, and they have not yet developed the cardiomyopathy that causes death in early infancy in reported patients. Both of our patients harbour missense mutations near the conserved copper-binding motif (CXXXC), including the common pathogenic variant E140K and a novel change D135G. In addition, each patient carries a second mutation located at the same loop region, resulting in compound heterozygote changes E140K/P169T and D135G/R171Q. Patient fibroblasts showed reduced levels of SCO2, decreased copper levels and COX deficiency. Given that another Charcot-Marie-Tooth disease gene, ATP7A, is a known copper transporter, our findings further underline the relevance of copper metabolism in Charcot-Marie-Tooth disease.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:In-Data-Review
[do] DOI:10.1093/brain/awx369

  3 / 6057 MEDLINE  
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[PMID]: 29342275
[Au] Autor:Brenner D; Yilmaz R; Müller K; Grehl T; Petri S; Meyer T; Grosskreutz J; Weydt P; Ruf W; Neuwirth C; Weber M; Pinto S; Claeys KG; Schrank B; Jordan B; Knehr A; Günther K; Hübers A; Zeller D; Kubisch C; Jablonka S; Sendtner M; Klopstock T; de Carvalho M; Sperfeld A; Borck G; Volk AE; Dorst J; Weis J; Otto M; Schuster J; Del Tredici K; Braak H; Danzer KM; Freischmidt A; Meitinger T; Strom TM; Ludolph AC; Andersen PM; Weishaupt JH; German ALS network MND-NET
[Ad] Address:Neurology Department, Ulm University, Ulm, Germany.
[Ti] Title:Hot-spot KIF5A mutations cause familial ALS.
[So] Source:Brain;, 2018 Jan 12.
[Is] ISSN:1460-2156
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 × 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p.Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 × 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:Publisher
[do] DOI:10.1093/brain/awx370

  4 / 6057 MEDLINE  
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[PMID]: 29246495
[Au] Autor:Lee S; Bazick H; Chittoor-Vinod V; Al Salihi MO; Xia G; Notterpek L
[Ad] Address:Department of Neuroscience, College of Medicine, University of Florida, Gainesville, Florida.
[Ti] Title:Elevated Peripheral Myelin Protein 22, Reduced Mitotic Potential, and Proteasome Impairment in Dermal Fibroblasts from Charcot-Marie-Tooth Disease Type 1A Patients.
[So] Source:Am J Pathol;188(3):728-738, 2018 Mar.
[Is] ISSN:1525-2191
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:A common form of hereditary autosomal dominant demyelinating neuropathy known as Charcot-Marie-Tooth disease type 1A (CMT1A) is linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Although studies from animal models have led to better understanding of the pathobiology of these neuropathies, there continues to be a gap in the translation of findings from rodents to humans. Because PMP22 was originally identified in fibroblasts as growth arrest specific gene 3 (gas3) and is expressed broadly in the body, it was tested whether skin cells from neuropathic patients would display the cellular pathology observed in Schwann cells from rodent models. Dermal fibroblasts from two CMT1A pedigrees with confirmed PMP22 gene duplication were studied. Samples from age-matched non-neuropathic individuals were used as controls. CMT1A patient-derived cultures contain approximately 1.5-fold elevated levels of PMP22 mRNA, exhibit reduced mitotic potential, and display intracellular protein aggregates as compared to cells from unaffected individuals. The presence of cytosolic PMP22 coincides with a decrease in proteasome activity and an increase in autophagy-lysosomal proteins, including LC3-II and LAMP1. These results indicate that the abnormalities in the subcellular processing of excess PMP22 elicit a detectable response in human CMT1A fibroblasts, a phenotype that resembles Schwann cells from neuropathic mice. These findings support the use of human CMT1A fibroblasts as a platform for therapy testing.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1712
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:In-Data-Review

  5 / 6057 MEDLINE  
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[PMID]: 29521025
[Au] Autor:Mandarakas MR; Rose KJ; Sanmaneechai O; Menezes MP; Refshauge KM; Burns J
[Ad] Address:The University of Sydney, Sydney, New South Wales, Australia.
[Ti] Title:Functional outcome measures for infantile Charcot-Marie-Tooth disease: A systematic review.
[So] Source:J Peripher Nerv Syst;, 2018 Mar 09.
[Is] ISSN:1529-8027
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:A functional outcome measure for infants (aged 0-3 years) with Charcot-Marie-Tooth disease (CMT) is needed for upcoming disease-modifying trials. A systematic review of outcome measures for infants with neuromuscular disorders was completed to determine if validated measures were available for the CMT infant population. We assessed 20,375 papers and identified seven functional outcome measures for infants with neuromuscular disorders. Six were developed and validated for Spinal Muscular Atrophy (SMA). There were no CMT-specific outcome measures identified, however one (Motor Function Measure) assessed a range of neuromuscular disorders including 13 infants and children with CMT. The included studies exhibited 'good' face, discriminant, convergent and concurrent validity and reported excellent intra- and inter-rater reliability. No outcome measure was subjected to Item Response Theory. Studies reported outcome measures comprising of 51 different items assessing six domains of function: reflexive movement, axial movement, limb movement, positioning, gross motor and fine-motor skills. Scoring of items ranged from 2-7 - point rating scales; none were scaled to normative reference values to account for changes in growth and development. The SMA-focus of most items is likely to produce ceiling effects and lack sensitivity and responsiveness for within and between types of CMT in infants. Nevertheless, several items across scales assessing distal strength, gross- and fine-motor function, could be included in the development of a composite functional outcome measure for infants with CMT to assess disease-modifying interventions.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:Publisher
[do] DOI:10.1111/jns.12258

  6 / 6057 MEDLINE  
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[PMID]: 29520015
[Au] Autor:Mo Z; Zhao X; Liu H; Hu Q; Chen XQ; Pham J; Wei N; Liu Z; Zhou J; Burgess RW; Pfaff SL; Caskey CT; Wu C; Bai G; Yang XL
[Ad] Address:Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA.
[Ti] Title:Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy.
[So] Source:Nat Commun;9(1):1007, 2018 Mar 08.
[Is] ISSN:2041-1723
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease's specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset. An HDAC6 inhibitor used to restore α-tubulin acetylation rescues axonal transport deficits and improves motor functions of CMT2D mice. These results link the aberrant GlyRS-HDAC6 interaction to CMT2D pathology and suggest HDAC6 as an effective therapeutic target. Moreover, the HDAC6 interaction differs from Nrp1 interaction among GlyRS mutants and correlates with divergent clinical presentations, indicating the existence of multiple and different mechanisms in CMT2D.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:In-Data-Review
[do] DOI:10.1038/s41467-018-03461-z

  7 / 6057 MEDLINE  
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[PMID]: 29518270
[Au] Autor:Hu B; Mccollum M; Ravi V; Arpag S; Moiseev D; Castoro R; Mobley BC; Burnette BW; Siskind C; Day JW; Yawn R; Feely S; Li Y; Yan Q; Shy ME; Li J
[Ad] Address:Department of Neurology, Center for Human Genetic Research, and Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, Tennessee.
[Ti] Title:Myelin Abnormality in CMT4J Recapitulates Features of Acquired Demyelination.
[So] Source:Ann Neurol;, 2018 Mar 08.
[Is] ISSN:1531-8249
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:OBJECTIVE: Charcot-Marie-Tooth type 4J (CMT4J) is a rare autosomal recessive neuropathy caused by mutations in FIG4 that result in loss of FIG4 protein. This study investigates the natural history and mechanisms of segmental demyelination in CMT4J. METHODS: Over the past 9 years, we have enrolled and studied a cohort of 12 CMT4J patients, including 6 novel FIG4 mutations. We evaluated these patients and related mouse models using morphological, electrophysiological and biochemical approaches. RESULTS: We found sensory motor demyelinating polyneuropathy consistently in all patients. This underlying myelin pathology was associated with non-uniform slowing of conduction velocities, conduction block, and temporal dispersion on nerve conduction studies (NCS), which resemble those features in acquired demyelinating peripheral nerve diseases. Segmental demyelination was also confirmed in mice without Fig4 (Fig4 ). The demyelination was associated with an increase of Schwann cell dedifferentiation and macrophages in spinal roots where nerve blood barriers are weak. Schwann cell dedifferentiation was induced by the increasing intracellular Ca . Suppression of Ca level by a chelator reduced dedifferentiation and demyelination of Schwann cells in vitro and in vivo. Interestingly, cell-specific knockout of Fig4 in mouse Schwann cells or neurons failed to cause segmental demyelination. INTERPRETATION: Myelin change in CMT4J recapitulates the features of acquired demyelinating neuropathies. This pathology is not Schwann cell autonomous. Instead, it relates to systemic processes involving interactions of multiple cell types and abnormally elevated intracellular Ca . Injection of a Ca chelator in Fig4 mice improved segmental demyelination, thereby providing a therapeutic strategy against demyelination. This article is protected by copyright. All rights reserved.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:Publisher
[do] DOI:10.1002/ana.25198

  8 / 6057 MEDLINE  
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[PMID]: 29246265
[Au] Autor:Polat P; Pham H; Li J; Bagai K
[Ad] Address:Pediatric Neurology, Vanderbilt University Medical Center, Nashville, Tennessee.
[Ti] Title:Improvement of Neuropathy Symptoms With Treatment of Obstructive Sleep Apnea in a Patient With Charcot-Marie-Tooth Disease.
[So] Source:J Clin Sleep Med;14(2):289-291, 2018 Feb 15.
[Is] ISSN:1550-9397
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:ABSTRACT: This is a case report describing a 53-year-old woman with Charcot-Marie-Tooth disease, obstructive sleep apnea, and a 6-year history of numbness in bilateral upper extremities, feet, and in the trunk that resolved with initiation of continuous positive airway pressure for her obstructive sleep apnea.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1712
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:In-Data-Review
[do] DOI:10.5664/jcsm.6956

  9 / 6057 MEDLINE  
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[PMID]: 29372391
[Au] Autor:Pakhrin PS; Xie Y; Hu Z; Li X; Liu L; Huang S; Wang B; Yang Z; Zhang J; Liu X; Xia K; Tang B; Zhang R
[Ad] Address:Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
[Ti] Title:Genotype-phenotype correlation and frequency of distribution in a cohort of Chinese Charcot-Marie-Tooth patients associated with GDAP1 mutations.
[So] Source:J Neurol;265(3):637-646, 2018 Mar.
[Is] ISSN:1432-1459
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:Mutations in ganglioside-induced differentiation-associated-protein 1 (GDAP1) have been associated with both subtypes of Charcot-Marie-Tooth (CMT) disease, autosomal recessive (CMT4A and AR-CMT2K) and autosomal dominant (AD-CMT2K). Over 80 different mutations have been identified so far. With the use of Sanger sequencing and Next Generation Sequencing (NGS) technologies, we screened a cohort of 306 unrelated Chinese CMT patients and identified 8 variants in the GDAP1 gene in 4 families, 5 of which were novel (R41H, N201Kfs*5, Q38X, V215I and Q38R). Application of Bioinformatics tool and classification according to the American College of Medical Genetics (ACMG) predicted them of being likely pathogenic with the exception of one variant of uncertain significance (VUS). In addition, we detected the presence of a single heterozygous variant of uncertain significance H256R in one additional family from the CMT cohorts. We found a GDAP1 prevalence rate of 1.63% (5/306). Three families (families 1, 2 and 3) were found to have an autosomal recessive (AR) pattern of inheritance while family 4 displayed an autosomal dominant (AD) mode of inheritance. Electro-physiologic studies revealed an axonal type of neuropathy (AR-CMT2K and AD-CMT2K) in all affected individuals. Clinical characteristics and findings in our study demonstrated that the recessive form presented earlier in life and exhibited severe symptoms and rapid evolution compared to the dominant form. We observed a marked intra-familial variability within the AD family in terms of age at disease onset, symptom severity and clinical progression. Our study expands the mutational spectrum of GDAP1-related CMT disease with the identification of new and unreported GDAP1 variants and demonstrates the predominance of the axonal form of neuropathy in CMT disease associated with GDAP1. We highlight the clinical characteristics associated with these genotypes and describe the relative frequency of GDAP1 variants amongst the Chinese population.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180307
[Lr] Last revision date:180307
[St] Status:In-Process
[do] DOI:10.1007/s00415-018-8743-9

  10 / 6057 MEDLINE  
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[PMID]: 29429969
[Au] Autor:Magy L; Mathis S; Le Masson G; Goizet C; Tazir M; Vallat JM
[Ad] Address:From the Department of Neurology (L.M., J.-M.V.), Centre de Référence Neuropathies Rares, CHU Limoges; Department of Neurology, Nerve-Muscle Unit (S.M., G.L.M.), and Department of Neurogenetics (C.G.), CHU Bordeaux (Pellegrin Hospital), France; and Department of Neurology (M.T.), CHU Mustapha Bacha,
[Ti] Title:Updating the classification of inherited neuropathies: Results of an international survey.
[So] Source:Neurology;90(10):e870-e876, 2018 Mar 06.
[Is] ISSN:1526-632X
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:OBJECTIVE: The continual discovery of disease-causing gene mutations has led to difficulties in the complex classification of Charcot-Marie-Tooth diseases (CMT) that needs to be revised. METHODS: We recently published a proposal to update the classification of inherited neuropathies. The reactions from colleagues prompted us to diffuse the proposal and ask people if they would be ready for such a change. We therefore performed an internet survey (from October 1, 2016, to December 1, 2016) that included more than 300 CMT worldwide specialists (practitioners and scientists) from various countries. A questionnaire (with proposals to update and simplify the way in which CMT is classified) was sent by e-mail to all participants in the last International Charcot-Marie-Tooth and Related Neuropathy Consortium meeting held in Venice, September 8-10, 2016 (as identified through an e-mail list). RESULTS: Of the 107 CMT specialists who answered the survey, 65% considered that changes are needed and that our proposals constituted an improvement over the historical classification of CMT. CONCLUSIONS: Based on recent proposals in the medical literature, these results highlight that most specialists think that changes are needed to the classification of CMT.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180306
[Lr] Last revision date:180306
[St] Status:In-Data-Review
[do] DOI:10.1212/WNL.0000000000005074


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