Abstract
Abstract Inherited peripheral neuropathy is the most common hereditary neuromuscular disease with a prevalence of about 1:2,500. The most frequent form is Charcot-Marie-Tooth disease (CMT, or hereditary motor and sensory neuropathy [HMSN]). Other clinical entities are hereditary neuropathy with liability to pressure palsies (HNPP), distal hereditary motor neuropathies (dHMN), and hereditary sensory and autonomic neuropathies (HSAN). With the exception of HNPP, which is almost always caused by defects of the PMP22 gene, all other forms show genetic heterogeneity with altogether more than 100 genes involved. Mutation detection rates vary considerably, reaching up to 80 % in demyelinating CMT (CMT1) but are still as low as 10–30 % in axonal CMT (CMT2), dHMN, and HSAN. Based on current information, analysis of only four genes (PMP22, GJB1, MPZ, MFN2) identifies 80–90 % of CMT-causing mutations that can be detected in all known disease genes. For the remaining patients, parallel analysis of multiple neuropathy genes using next-generation sequencing is now replacing phenotype-oriented multistep gene-by-gene sequencing. Such approaches tend to generate a wealth of genetic information that requires comprehensive evaluation of the pathogenic relevance of identified variants. In this review, we present current classification systems, specific phenotypic clues, and diagnostic yields in the different subgroups of hereditary CMT and motor neuropathies.
Highlights
Inherited peripheral neuropathy is the most common hereditary neuromuscular disease with a prevalence of about 1:2,500
We present current classification systems, specific phenotypic clues, and diagnostic yields in the different subgroups of hereditary CMT and motor neuropathies
We propose rational diagnostic algorithms based on genotype-phenotype correlations, mutation detection rates, and results of massive parallel sequencing technologies
Summary
Abstract: Inherited peripheral neuropathy is the most common hereditary neuromuscular disease with a prevalence of about 1:2,500. The most frequent form is CharcotMarie-Tooth disease (CMT, or hereditary motor and sensory neuropathy [HMSN]). Parallel analysis of multiple neuropathy genes using next-generation sequencing is replacing phenotype-oriented multistep gene-by-gene sequencing. Such approaches tend to generate a wealth of genetic information that requires comprehensive evaluation of the pathogenic relevance of identified variants. Charcot-Marie-Tooth (CMT) disease, denoted as hereditary motor and sensory neuropathy (HMSN), is clinically and genetically closely related to hereditary neuropathy with liability to pressure palsies (HNPP) and distal hereditary motor neuropathies (dHMN), known as distal spinal muscular atrophy (DSMA). CMT, dHMN, and HSAN are genetically highly heterogeneous with close to 100 different genes involved while there is one single major gene for HNPP. While the clinical picture in classical CMT normally gives no clue as regards the underlying genetic cause, there may be specific features pointing towards a distinct genetic subtype (Table 1)
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