Mutations in MME cause an autosomal‐recessive Charcot–Marie–Tooth disease type 2

Abstract

ObjectiveThe objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal‐recessive (AR) CMT.MethodsTo efficiently identify novel causative genes for AR‐CMT, we analyzed 303 unrelated Japanese patients with CMT using whole‐exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation.ResultsWe identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta‐amyloid (Aβ)‐degrading enzymes. All patients had a similar phenotype consistent with late‐onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss‐of‐function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aβ in Pittsburgh compound‐B positron emission tomography imaging.InterpretationOur results indicate that loss‐of‐function MME mutations are the most frequent cause of adult‐onset AR‐CMT2 in Japan, and we propose that this new disease should be termed AR‐CMT2T. A loss‐of‐function MME mutation did not cause early‐onset Alzheimer's disease. Identifying the MME mutation responsible for AR‐CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT. Ann Neurol 2016;79:659–672

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

“…Our patients with biallelic mutations in MME have the same clinical characteristics as a cohort of Japanese patients published previously,7 although there appear to be no common genetic variants between these series of patients. Conversely, three out of the 17 mutations detected in this study (p.Trp24*, p.Pro156Leufs*14 and p.Arg448*) were described previously in European and American patients, and linked to late-onset AD polyneuropathies 8.…”

“…In some of our patients, MNCV showed values compatible with an intermediate or even a demyelinating neuropathy, especially in the median nerve. In the patients described by Higuchi et al ,7 MNCV of the median nerve was indicative of an axonal neuropathy in all patients except in one in whom median MNCV was 37.4 m/s. The multifocal pattern of myelinated fibres loss found in the nerve biopsy of patient F4/II:2 has been described in other CMT2 neuropathies like MORC2.…”

“…In the CNS, NEP degrades Aβ amyloid (AB) and most studies have focused on its possible pathogenic role in Alzheimer’s disease17–19; yet, to date MME mutations have not been associated to familiar Alzheimer’s disease. Indeed, none of the Japanese patients with CMT27 were considered to be cognitively impaired after detailed neuropsychological testing. In our cohort, one patient who harboured a MME LoF mutation (p.Pro156Leufs*14) was diagnosed with Alzheimer’s disease, although his cognitive impairment commenced nearly three decades after the neuropathic symptoms appeared.…”

“…In recent years, mutations in the metalloendopeptidase ( MME ) gene were identified as the cause of late-onset autosomal recessive (AR) CMT2 in some Japanese patients 7. Likewise, several cases of autosomal dominant (AD) late-onset neuropathies in European and American families were linked to MME variants 8.…”

Recent advances in the genetic neuropathies

“…Autosomal recessive mutations in the gene MME have been described as the commonest cause of autosomal recessive CMT2 in Japan, having been identified in 10 Japanese families with CMT2 with disease onset in the fifth decade [14*]. …”