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Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations.
- Source :
-
Journal of medical genetics [J Med Genet] 2018 Dec; Vol. 55 (12), pp. 814-823. Date of Electronic Publication: 2018 Nov 10. - Publication Year :
- 2018
-
Abstract
- 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 .<br />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.<br />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.<br />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.<br />Competing Interests: Competing interests: None declared.<br /> (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)
- Subjects :
- Adult
Aged
Alleles
Amino Acid Substitution
Electromyography
Electrophysiological Phenomena
Female
Gene Frequency
Genes, Recessive
Genotype
Humans
Magnetic Resonance Imaging
Male
Metalloendopeptidases metabolism
Middle Aged
Pedigree
Genetic Association Studies
Inheritance Patterns
Metalloendopeptidases genetics
Mutation
Peripheral Nervous System Diseases diagnosis
Peripheral Nervous System Diseases genetics
Phenotype
Subjects
Details
- Language :
- English
- ISSN :
- 1468-6244
- Volume :
- 55
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of medical genetics
- Publication Type :
- Academic Journal
- Accession number :
- 30415211
- Full Text :
- https://doi.org/10.1136/jmedgenet-2018-105650