The distal hereditary motor neuropathies

J Neurol Neurosurg Psychiatry. 2012 Jan;83(1):6-14. doi: 10.1136/jnnp-2011-300952. Epub 2011 Oct 25.

Abstract

The distal hereditary motor neuropathies (dHMN) comprise a heterogeneous 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Cation Transport Proteins / genetics
  • Copper-Transporting ATPases
  • DNA Helicases
  • DNA-Binding Proteins / genetics
  • Dynactin Complex
  • GTP-Binding Protein gamma Subunits / genetics
  • Glycine-tRNA Ligase / genetics
  • HSP27 Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / genetics
  • Hereditary Sensory and Motor Neuropathy / diagnosis
  • Hereditary Sensory and Motor Neuropathy / genetics*
  • Humans
  • Microtubule-Associated Proteins / genetics
  • Molecular Chaperones
  • Multifunctional Enzymes
  • Protein Serine-Threonine Kinases / genetics
  • RNA Helicases / genetics
  • TRPV Cation Channels / genetics
  • Transcription Factors / genetics

Substances

  • BSCL2 protein, human
  • Cation Transport Proteins
  • DCTN1 protein, human
  • DNA-Binding Proteins
  • Dynactin Complex
  • GTP-Binding Protein gamma Subunits
  • HSP27 Heat-Shock Proteins
  • HSPB1 protein, human
  • HSPB8 protein, human
  • Heat-Shock Proteins
  • IGHMBP2 protein, human
  • Microtubule-Associated Proteins
  • Molecular Chaperones
  • Multifunctional Enzymes
  • TRPV Cation Channels
  • TRPV4 protein, human
  • Transcription Factors
  • Protein Serine-Threonine Kinases
  • Adenosine Triphosphatases
  • SETX protein, human
  • DNA Helicases
  • RNA Helicases
  • Glycine-tRNA Ligase
  • ATP7A protein, human
  • Copper-Transporting ATPases