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Charcot marie tooth disease

Mario A Saporta, Renata de Moraes Maciel
The human skin is richly innervated by nerve fibers of different calibers and functions, including thickly myelinated large fibers that act as afferents for mechanoreceptors in the dermal papillae. Skin biopsies offer minimally invasive access to these myelinated fibers, in which each internode represents an individual myelinating Schwann cell. Using this approach, human myelinated nerve fibers can be analyzed by several methods, including immunostaining, morphometric and ultrastructural analysis, and molecular biology techniques...
2018: Methods in Molecular Biology
Melissa R Mandarakas, Kristy J Rose, Oranee Sanmaneechai, Manoj P Menezes, Kathryn M Refshauge, Joshua Burns
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...
March 9, 2018: Journal of the Peripheral Nervous System: JPNS
Pedro J Tomaselli, Mahima Kapoor, Andrea Cortese, James M Polke, Alexander M Rossor, Mary M Reilly
Mutations in mitofusin 2 (MFN2) are the most common cause of axonal Charcot Marie Tooth disease (CMT2) (Polke; 2011). Additional features known to occasionally occur with MFN2-related disorders are optic atrophy, pyramidal signs, scoliosis and deafness (Zuchner, 2006; Feely, 2011; Bombelli, 2014). Cognitive impairment has been reported in a small number of patients with MFN2 mutations (Del Bo, 2008; Genari, 2011; Tufano, 2015).
March 9, 2018: Journal of the Peripheral Nervous System: JPNS
Stuart J Grice, James N Sleigh, M Zameel Cader
Dominant mutations in GARS , encoding the ubiquitous enzyme glycyl-tRNA synthetase (GlyRS), cause peripheral nerve degeneration and Charcot-Marie-Tooth disease type 2D (CMT2D). This genetic disorder exemplifies a recurring paradigm in neurodegeneration, in which mutations in essential genes cause selective degeneration of the nervous system. Recent evidence suggests that the mechanism underlying CMT2D involves extracellular neomorphic binding of mutant GlyRS to neuronally-expressed proteins. Consistent with this, our previous studies indicate a non-cell autonomous mechanism, whereby mutant GlyRS is secreted and interacts with the neuromuscular junction (NMJ)...
2018: Frontiers in Molecular Neuroscience
Zhongying Mo, Xiaobei Zhao, Huaqing Liu, Qinghua Hu, Xu-Qiao Chen, Jessica Pham, Na Wei, Ze Liu, Jiadong Zhou, Robert W Burgess, Samuel L Pfaff, C Thomas Caskey, Chengbiao Wu, Ge Bai, Xiang-Lei Yang
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...
March 8, 2018: Nature Communications
Bo Hu, Megan Mccollum, Vignesh Ravi, Sezgi Arpag, Daniel Moiseev, Ryan Castoro, Bret C Mobley, Bryan W Burnette, Carly Siskind, John W Day, Robin Yawn, Shawna Feely, Yuebing Li, Qing Yan, Michael E Shy, Jun Li
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...
March 8, 2018: Annals of Neurology
Raji P Grewal, Kinsi Oberoi, Leema Reddy Peddareddygari
Charcot-Marie-Tooth disease type 4C, an autosomal recessive genetic neuropathy, is caused by mutations in the SH3TC2 (SH3 domain and tetratricopeptide repeats 2) gene. Interestingly, although mutations in this gene have been observed in European gypsies, a population that originated in India, there are few publications describing Indian patients. We report our analysis of a 50-year-old woman of Asian Indian descent with onset of progressive distal weakness and sensory loss in childhood. A clinical examination revealed the presence of a neuropathy with pes cavus without spinal abnormalities...
January 2018: Case Reports in Neurology
Roopam Jariwal, Basel Shoua, Katayoun Sabetian, Piruthiviraj Natarajan, Everardo Cobos
Charcot-Marie-Tooth (CMT) disease is a hereditary demyelinating disease of the peripheral nervous system that results in sensory and motor dysfunction. CMT includes a spectrum of diseases with different types of mutations in the genes encoding myelin protein, resulting in a variety of dysfunctions in its life cycle. In CMT subtype 1A there is duplication mutation of peripheral myelin protein 22 gene on chromosome 17. Incomplete penetrance, gene-dosage effect, and variable expressivity can attribute to the asymptomatic nature of the disease in some subset of patients...
January 2018: Journal of Investigative Medicine High Impact Case Reports
Petra Lassuthova, Adriana P Rebelo, Gianina Ravenscroft, Phillipa J Lamont, Mark R Davis, Fiore Manganelli, Shawna M Feely, Chelsea Bacon, Dana Šafka Brožková, Jana Haberlova, Radim Mazanec, Feifei Tao, Cima Saghira, Lisa Abreu, Steve Courel, Eric Powell, Elena Buglo, Dana M Bis, Megan F Baxter, Royston W Ong, Lorna Marns, Yi-Chung Lee, Yunhong Bai, Daniel G Isom, René Barro-Soria, Ki W Chung, Steven S Scherer, H Peter Larsson, Nigel G Laing, Byung-Ok Choi, Pavel Seeman, Michael E Shy, Lucio Santoro, Stephan Zuchner
Although mutations in more than 90 genes are known to cause CMT, the underlying genetic cause of CMT remains unknown in more than 50% of affected individuals. The discovery of additional genes that harbor CMT2-causing mutations increasingly depends on sharing sequence data on a global level. In this way-by combining data from seven countries on four continents-we were able to define mutations in ATP1A1, which encodes the alpha1 subunit of the Na+ ,K+ -ATPase, as a cause of autosomal-dominant CMT2. Seven missense changes were identified that segregated within individual pedigrees: c...
March 1, 2018: American Journal of Human Genetics
Klaus Rüther
Hereditary optic nerve disorders are rare. For ophthalmologists, Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) are of particular relevance. LHON and ADOA are diseases of the retinal ganglion cells and are caused by mitchochondrial dysfunction. LHON is based on mutations of the mitochondrial, ADOA of the nuclear DNA. LHON is a disease that usually leads to severe visual impairment (visual acuity < 0.1). Since there is an approved therapy for LHON (Idebenone [Raxone]), the diagnosis has to be confirmed immediately by means of molecular genetic diagnostics...
February 28, 2018: Klinische Monatsblätter Für Augenheilkunde
Chiara Pisciotta, Michael E Shy
The genetic neuropathies are a clinically and genetically heterogeneous group of diseases that can broadly be classified into two groups: those in which the neuropathy is the sole or primary part of the disorder (Charcot-Marie-Tooth disease, CMT) and those in which the neuropathy is part of a more generalized neurologic or multisystem disorder (e.g., familial amyloid polyneuropathy, neuropathies associated with mitochondrial diseases, with hereditary ataxias, porphyrias). The former is the most common group, with a prevalence of 1 in 2500 people, and this chapter will concentrate on CMT...
2018: Handbook of Clinical Neurology
Katja Eggermann, Burkhard Gess, Martin Häusler, Joachim Weis, Andreas Hahn, Ingo Kurth
BACKGROUND: Hereditary peripheral neuropathies constitute a large group of genetic diseases, with an overall prevalence of 1:2500. In recent years, the use of so-called next-generation sequencing (NGS) has led to the identification of many previously unknown involved genes and genetic defects that cause neuropathy. In this article, we review the procedures and utility of genetic evaluation for hereditary neurop - athies, while also considering the implications of the fact that causally directed treatment of these disorders is generally unavailable...
February 9, 2018: Deutsches Ärzteblatt International
Cima Saghira, Dana M Bis, David Stanek, Alleene Strickland, David N Herrmann, Mary M Reilly, Steven S Scherer, Michael E Shy, Stephan Züchner
Charcot-Marie-Tooth disease (CMT) is an umbrella term for inherited neuropathies affecting an estimated one in 2,500 people. Over 120 CMT and related genes have been identified and clinical gene panels often contain more than 100 genes. Such a large genomic space will invariantly yield variants of uncertain clinical significance (VUS) in nearly any person tested. This rise in number of VUS creates major challenges for genetic counseling. Additionally, fewer individual variants in known genes are being published as the academic merit is decreasing, and most testing now happens in clinical laboratories, which typically do not correlate their variants with clinical phenotypes...
February 22, 2018: Human Mutation
James P Orengo, Pravin Khemani, John W Day, Jun Li, Carly E Siskind
We describe a family with Charcot Marie Tooth disease type 4J presenting with features of Charcot Marie Tooth disease plus parkinsonism and aphemia. Genetic testing found two variants in the FIG4 gene: c.122T>C (p.I41T) - the most common Charcot Marie Tooth disease type 4J variant - and c.1949-10T>G (intronic). Proband fibroblasts showed absent FIG4 protein on western blot, and skipping of exon 18 by RT-PCR. As most patients with Charcot Marie Tooth disease type 4J do not have central nervous system deficits, we postulate the intronic variant and I41T mutation together are causing loss of FIG4 protein and subsequently the central nervous system findings in our family...
February 2018: Annals of Clinical and Translational Neurology
David K Lorance, Kelly A Mandigo, Michael K Hehir
OBJECTIVES: We report the clinical phenotype in 3 consecutive generations with demyelinating Charcot-Marie-Tooth disease that possess a novel sequence variant of myelin protein zero (MPZ). METHODS: Family members from 3 consecutive generations were interviewed, examined, and studied with electrodiagnostic testing. Commercially available next-generation sequencing was performed for the proband. Single-gene analysis was performed for the remaining family members. RESULTS: All patients demonstrated symmetric distal weakness; symmetric distal sensory loss; and diminished deep tendon reflexes...
March 2018: Journal of Clinical Neuromuscular Disease
A Kagiava, C Karaiskos, J Richter, C Tryfonos, G Lapathitis, I Sargiannidou, C Christodoulou, K A Kleopa
GJB1 gene mutations affecting the gap junction protein connexin32 (Cx32) cause the X-linked Charcot-Marie-Tooth disease (CMT1X), a common inherited neuropathy. Targeted expression of virally delivered Cx32 in Schwann cells following intrathecal injection of lentiviral vectors in the Cx32 knockout (KO) mouse model of the disease has led to morphological and functional improvement. To examine whether this approach could be effective in CMT1X patients expressing different Cx32 mutants, we treated transgenic Cx32 KO mice expressing the T55I, R75W or N175D CMT1X mutations...
February 14, 2018: Human Molecular Genetics
Manisha Juneja, Abdelkrim Azmi, Jonathan Baets, Andreas Roos, Matthew J Jennings, Paola Saveri, Chiara Pisciotta, Nathalie Bernard-Marissal, Bernard L Schneider, Catherine Verfaillie, Roman Chrast, Pavel Seeman, Angelika F Hahn, Peter de Jonghe, Stuart Maudsley, Rita Horvath, Davide Pareyson, Vincent Timmerman
BACKGROUND: Charcot-Marie-Tooth type 2 (CMT2) neuropathy is characterised by a vast clinical and genetic heterogeneity complicating its diagnosis and therapeutic intervention. Identification of molecular signatures that are common to multiple CMT2 subtypes can aid in developing therapeutic strategies and measuring disease outcomes. METHODS: A proteomics-based approach was performed on lymphoblasts from CMT2 patients genetically diagnosed with different gene mutations to identify differentially regulated proteins...
February 15, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
Christopher H Douse, Stuart Bloor, Yangci Liu, Maria Shamin, Iva A Tchasovnikarova, Richard T Timms, Paul J Lehner, Yorgo Modis
Missense mutations in MORC2 cause neuropathies including spinal muscular atrophy and Charcot-Marie-Tooth disease. We recently identified MORC2 as an effector of epigenetic silencing by the human silencing hub (HUSH). Here we report the biochemical and cellular activities of MORC2 variants, alongside crystal structures of wild-type and neuropathic forms of a human MORC2 fragment comprising the GHKL-type ATPase module and CW-type zinc finger. This fragment dimerizes upon binding ATP and contains a hinged, functionally critical coiled-coil insertion absent in other GHKL ATPases...
February 13, 2018: Nature Communications
Shizuka Takaku, Hideji Yako, Naoko Niimi, Tomoyo Akamine, Daiji Kawanami, Kazunori Utsunomiya, Kazunori Sango
Co-culture models of neurons and Schwann cells have been utilized for the study of myelination and demyelination in the peripheral nervous system; in most of the previous studies, however, these cells were obtained by primary culture with embryonic or neonatal animals. A spontaneously immortalized Schwann cell line IFRS1 from long-term cultures of adult Fischer rat peripheral nerves has been shown to retain fundamental ability to myelinate neurites in co-cultures with adult rat dorsal root ganglion neurons and nerve growth factor-primed PC12 cells...
February 12, 2018: Histochemistry and Cell Biology
Laurent Magy, Stéphane Mathis, Gwendal Le Masson, Cyril Goizet, Meriem Tazir, Jean-Michel Vallat
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...
February 2, 2018: Neurology
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