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Charcot-Marie-Tooth review

Paloma González-Sánchez, Jorgina Satrústegui, Francesc Palau, Araceli Del Arco
The pathology of Charcot-Marie-Tooth (CMT), a disease arising from mutations in different genes, has been associated with an impairment of mitochondrial dynamics and axonal biology of mitochondria. Mutations in ganglioside-induced differentiation-associated protein 1 ( GDAP1 ) cause several forms of CMT neuropathy, but the pathogenic mechanisms involved remain unclear. GDAP1 is an outer mitochondrial membrane protein highly expressed in neurons. It has been proposed to play a role in different aspects of mitochondrial physiology, including mitochondrial dynamics, oxidative stress processes, and mitochondrial transport along the axons...
January 18, 2019: International Journal of Molecular Sciences
Andrzej Kochański, Dagmara Kabzińska, Weronika Rzepnikowska, Katarzyna Binięda, Artur Kiepura
Hereditary motor and sensory neuropathies (HMSN) also called as Charcot-Marie-Tooth disorders (CMT) are extremely heterogeneous group of disorders of peripheral nervous system. Over 80 genes have been reported in different types of CMT. In all CMT affected patients the main symptoms are slowly progressive wasting of the distal muscles of the lower and upper limbs. To date no efficient therapeutic approach basing upon molecular pathology of CMT has been proposed. This review presents the current state of knowledge concerning clinical, molecular pathogenesis and experimental therapy aspects in CMT disorders...
December 29, 2018: Postepy Biochemii
Melissa R Mandarakas, Manoj P Menezes, Kristy J Rose, Rosemary Shy, Kate Eichinger, Maria Foscan, Timothy Estilow, Rachel Kennedy, Karen Herbert, Paula Bray, Kathryn Refshauge, Monique M Ryan, Eppie M Yiu, Michelle Farrar, Hugo Sampaio, Isabella Moroni, Emanuela Pagliano, Davide Pareyson, Sabrina W Yum, David N Herrmann, Gyula Acsadi, Michael E Shy, Joshua Burns, Oranee Sanmaneechai
Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS)...
December 1, 2018: Brain: a Journal of Neurology
Mo Zhao, Nika Maani, James J Dowling
Dynamin 2 (DNM2) belongs to a family of large GTPases that are well known for mediating membrane fission by oligomerizing at the neck of membrane invaginations. Autosomal dominant mutations in the ubiquitously expressed DNM2 cause 2 discrete neuromuscular diseases: autosomal dominant centronuclear myopathy (ADCNM) and dominant intermediate Charcot-Marie-Tooth neuropathy (CMT). CNM and CMT mutations may affect DNM2 in distinct manners: CNM mutations may cause protein hyperactivity with elevated GTPase and fission activities, while CMT mutations could impair DNM2 lipid binding and activity...
November 13, 2018: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Artur Jan Kiepura, Andrzej Kochański
Charcot‑Marie‑Tooth type 1A (CMT1A) is a dysmyelinating disease of the peripheral nervous system that results in a slow progressive weakening and wasting of the distal muscles of the upper and lower limbs. Despite extensive research and clinical trials there is still no treatment for CMT1A that results in complete neurological improvement. Recent studies investigating various pharmacological modulators of adenylyl cyclase activity, including ascorbic acid and ligands of G protein‑coupled receptors (GPCRs), provide hope for future treatments of this type of hereditary motor and sensory neuropathy...
2018: Acta Neurobiologiae Experimentalis
Vincenzo Salpietro, Andreea Manole, Stephanie Efthymiou, Henry Houlden
The rapid development in the last 10-15 years of microarray technologies, such as oligonucleotide array Comparative Genomic Hybridization (CGH) and Single Nucleotide Polymorphisms (SNP) genotyping array, has improved the identification of fine chromosomal structural variants, ranging in length from kilobases (kb) to megabases (Mb), as an important cause of genetic differences among healthy individuals and also as disease-susceptibility and/or disease-causing factors. Structural genomic variations due to unbalanced chromosomal rearrangements are known as Copy-Number Variants (CNVs) and these include variably sized deletions, duplications, triplications and translocations...
September 2018: Current Genomics
Shantá D Hinton
Pseudophosphatases are atypical members of the protein tyrosine phosphatase superfamily. Mutations within their catalytic signature motif render them catalytically inactive. Despite this lack of catalytic function, pseudophosphatases have been implicated in various diseases such as Charcot Marie-Tooth disorder, cancer, metabolic disorder, and obesity. Moreover, they have roles in various signaling networks such as spermatogenesis, apoptosis, stress response, tumorigenesis, and neurite differentiation. This review highlights the roles of pseudophosphatases as essential regulators in signaling cascades, providing insight into the function of these catalytically inactive enzymes...
August 2, 2018: Biochimica et biophysica acta. Molecular cell research
Rossella Cannarella, Giovanni Burgio, Enzo S Vicari, Sandro La Vignera, Rosita A Condorelli, Aldo E Calogero
INTRODUCTION: Charcot-Marie-Tooth (CMT) is the most common inherited polyneuropathy. Polyneuropathies are likely to affect the urogenital system. Urogenital dysfunction is rarely investigated and may be underestimated in CMT patients. AIM: The aim of the present study was to perform a systematic review of the literature to collect all the available evidence on the presence of urogenital dysfunction and in patients with CMT. METHODS: Data sources were MEDLINE, Pubmed, Scopus, and Google Scholar...
July 31, 2018: Aging Male: the Official Journal of the International Society for the Study of the Aging Male
Mario Bortolozzi
Connexin 32 (Cx32) is a fundamental protein in the peripheral nervous system (PNS) as its mutations cause the X-linked form of Charcot-Marie-Tooth disease (CMT1X), the second most common form of hereditary motor and sensory neuropathy and a demyelinating disease for which there is no effective therapy. Since mutations of the GJB1 gene encoding Cx32 were first reported in 1993, over 450 different mutations associated with CMT1X including missense, frameshift, deletion and non-sense ones have been identified...
2018: Frontiers in Molecular Neuroscience
Manisha Juneja, Joshua Burns, Mario A Saporta, Vincent Timmerman
Much has been achieved in terms of understanding the complex clinical and genetic heterogeneity of Charcot-Marie-Tooth neuropathy (CMT). Since the identification of mutations in the first CMT associated gene, PMP22 , the technological advancement in molecular genetics and gene technology has allowed scientists to generate diverse animal models expressing monogenetic mutations that closely resemble the CMT phenotype. Additionally, one can now culture patient-derived neurons in a dish using cellular reprogramming and differentiation techniques...
July 17, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
Qingxian Wen, Longqiao Cao, Cun Yang, Yanchen Xie
Background: Electrophysiological examination plays an important role in the diagnosis of X-linked Charcot-Marie-Tooth disease (CMTX1) with transient central nervous system deficits. However, the electrophysiological features are seldom reported. Methods: We reviewed and analyzed published reports to determine the electrophysiological features of CMTX1 patients with transient central nervous system deficits. Results: A total of 21 CMTX1 patients with transient central nervous system deficits were found in 17 published case reports/series...
2018: Frontiers in Neurology
Andrew Sy, Jerry Cheng, Robert Cooper, Lisa Mueller
Vincristine (VCR) is a common chemotherapeutic agent used in the treatment of multiple types of pediatric tumors. VCR's adverse effects are well documented and commonly involve peripheral neuropathy via axonal degeneration. Neuropathic severity is dose-dependent, with sensory deficits occurring with as little as 4 mg cumulative dose. Severe peripheral neuropathy is generally rare, but its effects become additive when given to patients with undiagnosed hereditary peripheral neuropathy such as Charcot-Marie-Tooth...
June 5, 2018: Journal of Pediatric Hematology/oncology
C Lane Anzalone, Sarah Nuhanovic, Amy P Olund, Matthew L Carlson
Introduction: Charcot-Marie-Tooth (CMT) disease is a peripheral hereditary neuropathy associated with motor and sensory impairment and can result in profound sensorineural hearing loss (SNHL). Currently, the role of cochlear implantation in the setting of CMT and other progressive peripheral neurodegenerative disorders is not well established. Methods: Case report and review of the English literature. Results: A 70-year-old male with CMT was referred for evaluation of progressive asymmetric SNHL and reported a 15-year duration of deafness involving the left ear...
2018: Case Reports in Medicine
Helen Azevedo, Camila Pupe, Rouse Pereira, Osvaldo J M Nascimento
Charcot-Marie-Tooth (CMT) disease, the most common inherited peripheral neuropathy, has pain as one of its clinical features, yet it remains underdiagnosed and undertreated. This literature review assessed data related to pain from CMT to determine its prevalence, type and importance as a symptom, which, unlike other symptoms, is likely to be treated. The research encompassed 2007 to 2017 and included five articles that addressed pain from CMT. All of the papers concurred that pain is frequently present in CMT patients, yet its classification remains undefined as there has been no consensus in the literature about the mechanisms that cause it...
April 2018: Arquivos de Neuro-psiquiatria
Weronika Rzepnikowska, Andrzej Kochański
In 2002 a series of mutations in the GDAP1 gene were reported in patients suffering from Charcot‑Marie‑Tooth disease manifesting as early-onset, progressive distal‑muscle wasting and weakness. The molecular etiology of Charcot‑Marie‑Tooth ‑GDAP1 disease has been elucidated but its pathogenesis remains unclear, especially given the seemingly contradictory function of the GDAP1 protein. Expression of GDAP1 is observed almost exclusively in neuronal cells, however, the GDAP1 protein is present in mitochondria, where it plays a role in fission, a ubiquitous process occurring in all cells...
2018: Acta Neurobiologiae Experimentalis
Manoj Kanhangad, Kayla Cornett, Megan H Brewer, Garth A Nicholson, Monique M Ryan, Robert L Smith, Gopinath M Subramanian, Helen K Young, Stephan Züchner, Marina L Kennerson, Joshua Burns, Manoj P Menezes
OBJECTIVE: To describe in detail the clinical profile of Charcot-Marie-Tooth disease subtype 3 (CMTX3) to aid appropriate genetic testing and rehabilitative therapy. METHODS: We reviewed the clinical and neurophysiologic profile and CMT Pediatric Scale (CMTPedS) assessments of 11 children with CMTX3. RESULTS: Compared with the more common forms of CMT, CMT1A and CMTX, CMTX3 was characterized by early onset with early and progressive hand weakness...
May 8, 2018: Neurology
Anthony N Cutrupi, Megan H Brewer, Garth A Nicholson, Marina L Kennerson
Inherited peripheral neuropathies (IPNs) are a clinically and genetically heterogeneous group of diseases affecting the motor and sensory peripheral nerves. IPNs have benefited from gene discovery and genetic diagnosis using next-generation sequencing with over 80 causative genes available for testing. Despite this success, up to 50% of cases remain genetically unsolved. In the absence of protein coding mutations, noncoding DNA or structural variation (SV) mutations are a possible explanation. The most common IPN, Charcot-Marie-Tooth neuropathy type 1A (CMT1A), is caused by a 1...
May 2018: Molecular Genetics & Genomic Medicine
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 (CMT) disease 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...
June 2018: Journal of the Peripheral Nervous System: JPNS
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
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