Charcot-Marie-Tooth disease. Eur J Hum Genet

Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
European journal of human genetics: EJHG (Impact Factor: 4.35). 04/2009; 17(6):703-10. DOI: 10.1038/ejhg.2009.31
Source: PubMed


Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves. During the last decade over two dozen genes have been identified in which mutations cause CMT. The disease illustrates a multitude of genetic principles, including diverse mutational mechanisms from point mutations to copy number variation (CNV), allelic heterogeneity, age-dependent penetrance and variable expressivity. Population based studies have determined the contributions of the various genes to disease burden enabling evidence-based approaches to genetic testing.

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Available from: Kinga Szigeti, Mar 11, 2014
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    • "Charcot-Marie-Tooth disease (CMT) is one of the most frequent hereditary neuromuscular diseases (NMD), with a prevalence in France of 1 out of 2500 persons [1]. In fact, CMT is a group of diseases characterized by damage to the nerves of the arms and the legs (peripheral nerves) and presenting considerable genetic heterogeneity, with more than 30 potentially responsible genes [2] [3] [4] [5]. Patients suffering from CMT are categorized in sub-groups according to nerve damage and mode of transmission (CMT1: demyelinating form, autosomal dominant; CMT2: axonal form, autosomal dominant or recessive; CMT4: demyelinating form; autosomal recessive; CMTX: form related to chromosome X and IAD: intermediate autosomal dominant) [4] and present highly variable clinical pictures (peroneal muscle atrophy, damaged intrinsic hand muscles, areflexia, deformation of the feet. . "
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    ABSTRACT: Objectif Étudier l’applicabilité et la sensibilité au changement du score total et des trois sous-scores, D1, D2 et D3 de la mesure de fonction motrice chez des patients atteints de maladie de Charcot Marie Tooth. Patients et méthodes Étude descriptive sur 233 patients âgés de 4 à 86 ans. Les scores ont été analysés en fonction de l’âge et du type de la maladie. Les sensibilités au changement ont été étudiées chez les patients ayant eu au moins deux évaluations espacées d’au moins six mois. Résultats Les scores de la Mesure de Fonction Motrice diminuent avec l’âge, surtout les sous-scores D1 et D3. Il n’existe pas de différence significative en fonction du type de la maladie. Les scores des patients non ambulants sont significativement plus faibles que ceux des patients ambulants. La sensibilité au changement est significative chez les Charcot-Marie-Tooth type 2. Conclusion La mesure de fonction motrice est une échelle applicable, surtout D1 et D3, au suivi des patients atteints de la maladie de Charcot-Marie-Tooth de façon longitudinale. Sa sensibilité au changement nécessite d’être confirmée en utilisant des durées d’étude plus longues compte tenu de l’évolutivité de la maladie.
    Full-text · Article · Sep 2014 · Annals of Physical and Rehabilitation Medicine
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    • "In humans a characteristic feature of CMT1A is the progressive nature of the disease which typically surfaces in the second decade of life (Jani-Acsadi et al., 2008; Szigeti and Lupski, 2009). While disease progression is a critical aspect of the neuropathies, there have been a limited number of studies examining affected nerves at different stages of lifespan . "
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    ABSTRACT: Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary demyelinating neuropathy linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Transgenic C22 mice, a model of CMT1A, display many features of the human disease, including slowed nerve conduction velocity and demyelination of peripheral nerves. How overproduction of PMP22 leads to compromised myelin and axon pathology is not fully understood, but likely involves subcellular alterations in protein homeostatic mechanisms within affected Schwann cells. The subcellular response to abnormally localized PMP22 includes the recruitment of the ubiquitin-proteasome system (UPS), autophagosomes and heat shock proteins. Here we assessed biochemical markers of these protein homeostatic pathways in nerves from PMP22-overexpressing neuropathic mice between the ages of 2-12 months to ascertain their potential contribution to disease progression. In nerves of 3 week old mice, using endoglycosidases and western blotting, we found altered processing of the exogenous human PMP22, an abnormality that becomes more prevalent with age. Along with the ongoing accrual of misfolded PMP22, the activity of the proteasome becomes compromised and proteins required for autophagy induction and lysosome biogenesis are upregulated. Moreover, cytosolic chaperones are consistently elevated in nerves from neuropathic mice, with the most prominent change in HSP70. The gradual alterations in protein homeostatic response are accompanied by Schwann cell de-differentiation and macrophage infiltration. Together, these results show that while subcellular protein quality control mechanisms respond appropriately to the presence of the overproduced PMP22, with aging they are unable to prevent the accrual of misfolded proteins.
    Full-text · Article · Oct 2013 · ASN Neuro
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    • "CMT is classified into autosomal-dominant CMT1 (demyelinating) and CMT2 (axonal), CMT1X (X-linked), and autosomalrecessive neuropathies. CMT is caused by mutations in genes that encode proteins with different locations, including compact and non-compact myelin, Schwann cells, and axons, and that are involved in very different functions, ranging from compaction and maintenance of myelin to cytoskeleton formation, axonal transport, and mitochondrial metabolism [149] [150] [151] Although there is a variability of genes involved in the pathogenesis of CMT, the final common pathway is represented by a axonal degenerative process [151] [152] [153]. CMT type 1A (CMT1A) is caused by a duplication on chromosome 17p11.2 "
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    ABSTRACT: More than 30 different Transient Receptor Potential channels (TRP) have been identified in mammals and are grouped in 6 families. Members of these subunit families, specifically of the vanilloid TRP (TRPV), melastatin TRP (TRPM), ankyrin TRP (TRPA), polycystin TRP (TRPP) and canonical or classical TRP (TRPC) family, are considered relevant in central nervous system neurodegenerative diseases. In fact, TRP channels have received increased attention in recent years, since they are involved in a broad array of pathways and respond to different environmental stimuli. Preclinical research has identified TRPs involved in hereditary neuropathies as well as in a heterogeneous group of neuronal disorders. Moreover, changes in TRP channel expression and functionality have been associated to diabetic thermal hyperalgesia, painful neuropathies and headache. At the molecular level, TRPs are involved in a wide range of mechanisms regulating osmosis, thermal, stretch, chemical and sensory signaling, highlighting TRPs as potential targets for pharmacological intervention. The area of small molecule TRP agonists/antagonists drug development is moving rapidly. This review will evaluate current evidence that supports particular TRP channels as targets for novel drugs, summarizing the current perspectives for the therapeutic potential of TRP agonists and antagonists in the treatment of a wide range of neuropathies, along with potential adverse effects that may limit drug development.
    Full-text · Article · Feb 2013 · CNS & neurological disorders drug targets
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