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, Wolfgang N. Löscher, 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

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15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E3163-E3179
JournalNeurology
Volume95
Issue number24
DOIs
StatePublished - Dec 15 2020
Externally publishedYes

Bibliographical note

Funding Information:
J. Senderek, P. Lassuthova, D. Kabzińska, L. Abreu, and J. Baets report no disclosures relevant to the manuscript. C. Beetz is an employee of Centogene AG, Rostock, Germany. G.J. Braathen, D. Brenner, J. Dalton, L. Dankwa, T. Deconinck, P. De Jonghe, B. Dräger, K. Eggermann, M. Ellis, C. Fischer, and T. Stojkovic report no disclosures relevant to the manuscript. D.N. Herrmann reports consulting activities for GLG, Guidepoint Global, ClearView, SlingShot Insights, Narrow River Management, Alnylam, Regenacy, and Acceleron. R. Horvath, H. Høyer, S. Iglseder, M. Kennerson, K. Kinslechner, J.N. Kohler, I. Kurth, N.G. Laing, P.J. Lamont, W.N. Löscher, A. Ludolph, W. Marques, Jr., G. Nicholson, R. Ong, S. Petri, G. Ravenscroft, A. Rebelo, G. Ricci, S. Rudnik-Schöneborn, A. Schirmacher, B. Schlotter-Weigel, L. Schoels, R. Schüle, M. Synofzik, B. Francou, T.M. Strom, J. Wagner, D. Walk, J. Wanschitz, D. Weinmann, J. Weishaupt, M. Wiessner, R. Windhager, P. Young, S. Züchner, S. Toegel, P. Seeman, and A. Kochański report no disclosures relevant to the manuscript. M. Auer-Grumbach reports having received grant support from Pfizer and consulting activities for Pfizer, Akcea, and Alnylam. Go to Neurology.org/N for full disclosures.

Funding Information:
This work was supported by the Austrian Science Fund (P27634FW to M.A.-G.), the Jubiläumsfonds der Oesterreichischen Nationalbank (No.16880 to M.A.-G.), a research grant from Pfizer (to M.A.-G.), the Fritz-Thyssen-Stiftung (Az.10.15.1.021MN to J.S.), the Bundesministerium für Forschung und Bildung through the German Network for CMT neuropathies (01GM1511B and 01GM1511D to S.R.-S., B.S.-W., and J.S.), the National Science Centre Poland grant (No. 2016/23/B/NZ3/02035 to A.K.), and the Ministry of Health of the Czech Republic (AZV 16-30206 and DRO00064203 to P.L. and P.S.). Further support was obtained from the Newton Fund (MR/N027302/1 to R.H.), the European Research Council (309548 to R.H.), the NIH (U54 NS065712 to D.N.H. and S.Z.; R01NS075764 to S.Z.), the National Health and Medical Research Council (APP1046680 to M.K. and G.N.), the South Eastern Norway Regional Health Authority (HSØ-ID 2016133 to H.H.), the Judy Seltzer Levenson Memorial Fund for CMT Research, the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director (U01HG007708 and U01HG010218), the CMT Association, and The Genesis Project Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Publisher Copyright:
© American Academy of Neurology.

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