{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:46:47Z","timestamp":1791298007724,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2016,3,17]],"date-time":"2016-03-17T00:00:00Z","timestamp":1458172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Nervous and Mental Disorders and Research Committee for Charcot-Marie-Tooth Disease, Neuropathy, Ataxic Disease and Applying Health and Technology of Ministry of Health, Welfare and Labour, Japan"},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2016,4]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The objective of this study was to identify new causes of Charcot\u2013Marie\u2013Tooth (CMT) disease in patients with autosomal\u2010recessive (AR) CMT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To efficiently identify novel causative genes for AR\u2010CMT, we analyzed 303 unrelated Japanese patients with CMT using whole\u2010exome sequencing and extracted recessive variants\/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (<jats:italic>MME<\/jats:italic>) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the<jats:italic>MME<\/jats:italic>mutation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified recessive mutations in<jats:italic>MME<\/jats:italic>in 10 patients. The<jats:italic>MME<\/jats:italic>gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta\u2010amyloid (A\u03b2)\u2010degrading enzymes. All patients had a similar phenotype consistent with late\u2010onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the<jats:italic>MME<\/jats:italic>mutations could be loss\u2010of\u2010function 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 A\u03b2 in Pittsburgh compound\u2010B positron emission tomography imaging.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our results indicate that loss\u2010of\u2010function<jats:italic>MME<\/jats:italic>mutations are the most frequent cause of adult\u2010onset AR\u2010CMT2 in Japan, and we propose that this new disease should be termed AR\u2010CMT2T. A loss\u2010of\u2010function<jats:italic>MME<\/jats:italic>mutation did not cause early\u2010onset Alzheimer's disease. Identifying the<jats:italic>MME<\/jats:italic>mutation responsible for AR\u2010CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT. 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