The genetic landscape of axonal neuropathies in the middle-aged and elderly: Focus on <i>MME</i>.

Abstract

To test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years. We recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and <i>MME</i> single-gene sequencing (n = 104). We further queried WES repositories for <i>MME</i> variants and measured blood levels of the <i>MME</i>-encoded protein neprilysin. In the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). <i>MME</i> was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of <i>MME</i> for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of <i>MME</i> variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with <i>MME</i> variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of <i>MME</i> variants was often consistent with an incompletely penetrant autosomal-dominant trait and less frequently with autosomal-recessive inheritance. A detectable fraction of unexplained late-onset axonal neuropathies is genetically determined, by variants in either CMT genes or genes involved in other conditions that affect the peripheral nerves and can mimic a CMT phenotype. <i>MME</i> variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.