dSMA

• dHMN I:  +/- UMN

  • HSPB1 - AD

  • HSPB8 - Junveile onset

  • GARS - Distal LE

  • DYNC1H1

  • 7q34

• dHMN IIB:  +/- UMN

  • HSPB1 - AD

• dHMN IIA: +/- UMN

  • HSPB8: Distal LE

• dHMN II:  BSCL1

• dHMN IIC: HSBP3: AR

• dHMN III: 11q13: AR, childhood onset, distal predominant

• dHMN IV: PLEKHG5: AR, childhood onset, distal predominant, diaphgragmatic paralysis, scapular winging.

• dHMN VA:  GARS:  AD, onset in hands, +/- UMN

• dHMN VB: BSCL2:  AD onset in hands,  ventilatory distress

• dHMN VI: IGHMBP2: infantile, vocal cord paralysis

• dHMN VIIB: 

  • DCTN1: AD distal LE

  • TRPV4

• dHMN VII A: 2q14: UMN

• fALS4: SETX:  AD distal LE

• ATP7A: X-linked distal LE

• 9p21.1: AR distal LE: Abnormal cervical spine imaging. 

Benign focal amyotrophy

Scapuloperoneal

• PMP22

• TRPV4

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.