The distal hereditary motor neuropathies (dHMN) comprise a heterogenous group of diseases that share the common feature of a length-dependent predominantly motor neuropathy. Many forms of dHMN have minor sensory abnormalities and/or a significant upper-motor-neuron component, and there is often an overlap with the axonal forms of Charcot–Marie–Tooth disease (CMT2) and with juvenile forms of amyotrophic lateral sclerosis and hereditary spastic paraplegia. Eleven causative genes and four loci have been identified with autosomal dominant, recessive and X-linked patterns of inheritance. Despite advances in the identification of novel gene mutations, 80% of patients with dHMN have a mutation in an as-yet undiscovered gene. The causative genes have implicated proteins with diverse functions such as protein misfolding (HSPB1, HSPB8, BSCL2), RNA metabolism (IGHMBP2, SETX, GARS), axonal transport (HSPB1, DYNC1H1, DCTN1) and cation-channel dysfunction (ATP7A and TRPV4) in motor-nerve disease. This review will summarise the clinical features of the different subtypes of dHMN to help focus genetic testing for the practising clinician. It will also review the neuroscience that underpins our current understanding of how these mutations lead to a motor-specific neuropathy and highlight potential therapeutic strategies. An understanding of the functional consequences of gene mutations will become increasingly important with the advent of next-generation sequencing and the need to determine the pathogenicity of large amounts of individual genetic data.
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Funding AMR is very grateful for his current funding of a fellowship from the National Institutes of Neurological Diseases and Stroke and office of Rare Diseases (U54NS065712). He has also been in receipt of an IPSEN clinical research fellowship. LG is funded by the Brain Research Trust. MMR is grateful to the Medical Research Council (MRC), the Muscular Dystrophy Campaign and the National Institutes of Neurological Diseases and Stroke and office of Rare Diseases (U54NS065712) for their support. This work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centre's funding scheme.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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