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.
"However, Tyr119Cys allows myelination to develop and causes an adult onset neuropathy. Moreover, while Arg98Cys causes infantile disease it appears to do so by activating an intracellular process called the unfolded protein response rather than by disrupting myelin wrapping (Patzko et al., 2012; Saporta et al., 2012). Therefore, how a novel cysteine would cause neuropathy in CMT1B is more complicated than initially perceived. "
"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. "
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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; 110(8). DOI:10.1073/pnas.1222729110 · 9.67 Impact Factor
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