Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations

J Med Genet. 2018 Dec;55(12):814-823. doi: 10.1136/jmedgenet-2018-105650. Epub 2018 Nov 10.


Background: Mutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME.

Methods: We screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members.

Results: We found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease.

Conclusion: MME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.

Keywords: clinical genetics; diagnostics; genetic screening/counselling; neuromuscular disease; peripheral nerve disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Amino Acid Substitution
  • Electromyography
  • Electrophysiological Phenomena
  • Female
  • Gene Frequency
  • Genes, Recessive
  • Genetic Association Studies*
  • Genotype
  • Humans
  • Inheritance Patterns*
  • Magnetic Resonance Imaging
  • Male
  • Metalloendopeptidases / genetics*
  • Metalloendopeptidases / metabolism
  • Middle Aged
  • Mutation*
  • Pedigree
  • Peripheral Nervous System Diseases / diagnosis*
  • Peripheral Nervous System Diseases / genetics*
  • Phenotype*


  • Metalloendopeptidases

Supplementary concepts

  • Inherited Peripheral Neuropathy