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

Jan Senderek, Petra Lassuthova, Dagmara Kabzińska, Lisa Abreu, Jonathan Baets, Christian Beetz, Geir J. Braathen, David Brenner, Joline Dalton, Lois Dankwa, Tine Deconinck, Peter De Jonghe, Bianca Dräger, Katja Eggermann, Melina Ellis, Carina Fischer, Tanya Stojkovic, David N. Herrmann, Rita Horvath, Helle HøyerStephan Iglseder, Marina Kennerson, Katharina Kinslechner, Jennefer N. Kohler, Ingo Kurth, Nigel G. Laing, Phillipa J. Lamont, Löscher Wolfgang N, Albert Ludolph, Wilson Marques, Garth Nicholson, Royston Ong, Susanne Petri, Gianina Ravenscroft, Adriana Rebelo, Giulia Ricci, Sabine Rudnik-Schöneborn, Anja Schirmacher, Beate Schlotter-Weigel, Ludger Schoels, Rebecca Schüle, Matthis Synofzik, Bruno Francou, Tim M. Strom, Johannes Wagner, David Walk, Julia Wanschitz, Daniela Weinmann, Jochen Weishaupt, Manuela Wiessner, Reinhard Windhager, Peter Young, Stephan Züchner, Stefan Toegel, Pavel Seeman, Andrzej Kochański, Michaela Auer-Grumbach

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)E3163-E3179
Issue number24
StatePublished - Dec 15 2020

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© 2020 American Academy of Neurology.


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