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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
The genetic landscape of axonal neuropathies in the middle-aged and elderly: Focus on MME.
Neurology 95, e3163-e3179 (2020)
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, either by variants in 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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
ISSN (print) / ISBN
0028-3878
e-ISSN
1526-632X
Zeitschrift
Neurology
Quellenangaben
Band: 95,
Heft: 24,
Seiten: e3163-e3179
Verlag
Lippincott Williams & Wilkins
Verlagsort
Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Human Genetics (IHG)
Förderungen
Genesis Project Foundation
Ministry of Health of the Czech Republic
National Science Centre Poland
Bundesministerium fur Forschung und Bildung through the German Network for CMT neuropathies
Fritz-Thyssen-Stiftung
Pfizer
Jubilaumsfonds der Oesterreichischen Nationalbank
Newton Fund
European Research Council
CMT Association
NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director
Judy Seltzer Levenson Memorial Fund for CMT Research
South Eastern Norway Regional Health Authority (HSO)
National Health and Medical Research Council
NIH
Austrian Science Fund
Ministry of Health of the Czech Republic
National Science Centre Poland
Bundesministerium fur Forschung und Bildung through the German Network for CMT neuropathies
Fritz-Thyssen-Stiftung
Pfizer
Jubilaumsfonds der Oesterreichischen Nationalbank
Newton Fund
European Research Council
CMT Association
NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director
Judy Seltzer Levenson Memorial Fund for CMT Research
South Eastern Norway Regional Health Authority (HSO)
National Health and Medical Research Council
NIH
Austrian Science Fund