The genetic landscape of axonal neuropathies in the middle-aged and elderly

Author:

Senderek Jan,Lassuthova Petra,Kabzińska Dagmara,Abreu Lisa,Baets Jonathan,Beetz Christian,Braathen Geir J.,Brenner David,Dalton Joline,Dankwa LoisORCID,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 IngoORCID,Laing Nigel G.,Lamont Phillipa J.,Wolfgang N. Löscher,Ludolph Albert,Marques 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

Abstract

ObjectiveTo 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.MethodsWe 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.ResultsIn 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.ConclusionsA 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Neurology (clinical)

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