Repository logo
 

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

Accepted version
Peer-reviewed

Change log

Authors

Senderek, Jan 
Lassuthova, Petra 
Kabzińska, Dagmara 
Abreu, Lisa 
Baets, Jonathan 

Abstract

OBJECTIVE: 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. METHODS: We recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and MME single-gene sequencing (n = 104). We further queried WES repositories for MME variants and measured blood levels of the MME-encoded protein neprilysin. RESULTS: 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%). MME was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of MME for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of MME variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with MME variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of MME variants was often consistent with an incompletely penetrant autosomal-dominant trait and less frequently with autosomal-recessive inheritance. CONCLUSIONS: 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. MME variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.

Description

Keywords

Age of Onset, Aged, Aging, Charcot-Marie-Tooth Disease, Female, Genetic Predisposition to Disease, Hereditary Sensory and Motor Neuropathy, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Neprilysin, Exome Sequencing

Journal Title

Neurology

Conference Name

Journal ISSN

0028-3878
1526-632X

Volume Title

95

Publisher

Ovid Technologies (Wolters Kluwer Health)

Rights

All rights reserved
Sponsorship
Medical Research Council (MR/N025431/2)