Genetic heterogeneity of motor neuropathies

Neurology. 2017 Mar 28;88(13):1226-1234. doi: 10.1212/WNL.0000000000003772. Epub 2017 Mar 1.

Abstract

Objective: To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England.

Methods: Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients).

Results: The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy.

Conclusions: Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Analysis of Variance
  • Charcot-Marie-Tooth Disease / epidemiology*
  • Charcot-Marie-Tooth Disease / genetics
  • Charcot-Marie-Tooth Disease / physiopathology
  • Cohort Studies
  • Connexins / genetics
  • DNA Mutational Analysis
  • Electromyography
  • England / epidemiology
  • Family Health
  • Female
  • GTP Phosphohydrolases / genetics
  • Genetic Heterogeneity*
  • Hereditary Sensory and Motor Neuropathy / epidemiology*
  • Hereditary Sensory and Motor Neuropathy / genetics*
  • Hereditary Sensory and Motor Neuropathy / physiopathology
  • Humans
  • Male
  • Middle Aged
  • Mitochondrial Proteins / genetics
  • Mutation / genetics*
  • Myelin Proteins / genetics
  • Neural Conduction / genetics
  • Young Adult

Substances

  • Connexins
  • Mitochondrial Proteins
  • Myelin Proteins
  • PMP22 protein, human
  • connexin 32
  • GTP Phosphohydrolases
  • MFN2 protein, human