Charcot-Marie-Tooth disease and related genetic neuropathies.
ABSTRACT The inherited peripheral neuropathies are a complex group of disorders caused by mutations in more than 50 genes. Scientifically, these disorders provide extensive information on molecular pathways that cause demyelination, axonal loss, and abnormal interactions between Schwann cells and the axons they ensheathe. Clinically, however, these neuropathies are confusing because it is difficult to determine what gene to test for in a given patient, inheritance patterns may differ among patients, and genetic testing is expensive. This review provides a biological context and guidelines to help neurologists better understand the basis and focus of genetic testing for these disorders.
In the past 5 years, many of the genetic causes of inherited neuropathies have been discovered and the phenotypes of inherited neuropathies have been characterized. Clinical trials of genetic neuropathies are now underway.
It is hoped that this review will lead to a better understanding of these fascinating neuropathies for health care professionals and that this improved understanding will facilitate treatment advances for these presently untreatable diseases.
- SourceAvailable from: Wilson Marques
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- "Interestingly, some of these patients exhibit intellectual deficits (Genari et al., 2011). The typical CMT phenotype includes onset of predominantly motor length-dependent sensory and motor polyneuropathies within the first two decades of life associated with variable sensory manifestations, decreased or absent tendon jerks, and skeletal abnormalities, such as pes cavus, hammer toes, and scoliosis (Thomas et al., 1997; Marques et al., 2005; Patzko and Shy, 2012) However, marked clinical heterogeneity exists, even for the same mutation, in the same family and for identical twins (Marques et al., 1999). Genetic and non-genetic factors must therefore be involved. "
ABSTRACT: This study aimed to conduct a systematic literature review regarding the associations between psychiatric symptoms, functional impairments, and quality of life in patients with CMT. The PUBMED, PsycInfo, SCIELO, and LILACS electronic databases were used, and the following search terms were employed: Charcot-Marie-Tooth, hereditary motor and sensory neuropathy (HMSN), mental disorder, quality of life, psychiatry, psychiatric, and psychological without the use of time-limit filters. According to the adopted inclusion criteria, 20 studies were included and appraised. These studies indicated that patients with CMT exhibited an increased trend toward depressive symptoms compared with the general population. In addition, CMT patients were exposed to a higher risk of reduced quality of life and significant sleep impairment. Considering the comorbidity of CMT with other psychiatric disorders, the heterogeneity of the instruments used to evaluate the psychiatric symptoms compromised the ability to compare the studies examined. Our results indicate a need for a systematic evaluation of these conditions to minimise the impairments and decreased quality of life caused by CMT.ASN Neuro 03/2014; 6(3). DOI:10.1042/AN20130048 · 4.44 Impact Factor
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ABSTRACT: Peripheral nervous system abnormalities, including neuropathy, have been reported in people with cystic fibrosis. These abnormalities have largely been attributed to secondary manifestations of the disease. We tested the hypothesis that disruption of the cystic fibrosis transmembrane conductance regulator (CFTR) gene directly influences nervous system function by studying newborn CFTR(-/-) pigs. We discovered CFTR expression and activity in Schwann cells, and loss of CFTR caused ultrastructural myelin sheath abnormalities similar to those in known neuropathies. Consistent with neuropathic changes, we found increased transcripts for myelin protein zero, a gene that, when mutated, can cause axonal and/or demyelinating neuropathy. In addition, axon density was reduced and conduction velocities of the trigeminal and sciatic nerves were decreased. Moreover, in vivo auditory brainstem evoked potentials revealed delayed conduction of the vestibulocochlear nerve. Our data suggest that loss of CFTR directly alters Schwann cell function and that some nervous system defects in people with cystic fibrosis are likely primary.Proceedings of the National Academy of Sciences 02/2013; DOI:10.1073/pnas.1222729110 · 9.81 Impact Factor
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ABSTRACT: Distal hereditary motor neuropathies (dHMNs) are a heterogenous group of genetic disorders with length-dependent degeneration of motor axons. Obtaining a genetic diagnosis in patients with dHMN remains challenging. We performed exome sequencing in a diagnostic setting in 12 patients with a clinical diagnosis of dHMN. Potential disease-causing variants in genes associated with dHMN and other forms of inherited neuropathies/motor neuron diseases were validated using Sequenom. The coverage in the genes studied was >95% with an average coverage of >50 times. In none of the patients a mutations was found in genes previously reported to be associated with dHMN. However, in 2/12 patients a recessive mutation in histidine triad nucleotide binding protein 1 (HINT1, recently discovered as a cause of axonal neuropathy with neuromyotonia) was identified. Our results demonstrate the diagnostic value of exome sequencing for patients with inherited neuropathies. The phenotypic spectrum of recessive mutations in HINT1 includes dHMN. HINT1 should be added to the list of genes to check for in dHMN.European Journal of Human Genetics advance online publication, 9 October 2013; doi:10.1038/ejhg.2013.231.European journal of human genetics: EJHG 10/2013; DOI:10.1038/ejhg.2013.231 · 4.23 Impact Factor