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

• Published in: Neurology Vol. 95; no. 24; p. e3163
• Main Authors: Senderek, Jan, Lassuthova, Petra, Kabzińska, Dagmara, Abreu, Lisa, Baets, Jonathan, Beetz, Christian, Braathen, Geir J, Brenner, David, Dalton, Joline, Dankwa, Lois, Deconinck, Tine, De Jonghe, Peter, Dräger, Bianca, Eggermann, Katja, Ellis, Melina, Fischer, Carina, Stojkovic, Tanya, Herrmann, David N, Horvath, Rita, Høyer, Helle, Iglseder, Stephan, Kennerson, Marina, Kinslechner, Katharina, Kohler, Jennefer N, Kurth, Ingo, Laing, Nigel G, Lamont, Phillipa J, Wolfgang N, Löscher, Ludolph, Albert, Marques, Jr, Wilson, Nicholson, Garth, Ong, Royston, Petri, Susanne, Ravenscroft, Gianina, Rebelo, Adriana, Ricci, Giulia, Rudnik-Schöneborn, Sabine, Schirmacher, Anja, Schlotter-Weigel, Beate, Schoels, Ludger, Schüle, Rebecca, Synofzik, Matthis, Francou, Bruno, Strom, Tim M, Wagner, Johannes, Walk, David, Wanschitz, Julia, Weinmann, Daniela, Weishaupt, Jochen, Wiessner, Manuela, Windhager, Reinhard, Young, Peter, Züchner, Stephan, Toegel, Stefan, Seeman, Pavel, Kochański, Andrzej, Auer-Grumbach, Michaela
• Format: Journal Article
• Language: English
• Published: United States 15.12.2020
• Subjects: Age of Onset; Aged; Aging - blood; Charcot-Marie-Tooth Disease - blood; Charcot-Marie-Tooth Disease - genetics; Female; Genetic Predisposition to Disease - genetics; Hereditary Sensory and Motor Neuropathy - blood; Hereditary Sensory and Motor Neuropathy - genetics; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Neprilysin - blood; Neprilysin - genetics; Whole Exome Sequencing
• ISSN: 1526-632X
• DOI: 10.1212/WNL.0000000000011132

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 single-gene sequencing (n = 104). We further queried WES repositories for variants and measured blood levels of the -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%). was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of 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. variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.