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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F20%3A10417215" target="_blank" >RIV/00216208:11130/20:10417215 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00064203:_____/20:10417215

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=LTrq16lky9" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=LTrq16lky9</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1212/WNL.0000000000011132" target="_blank" >10.1212/WNL.0000000000011132</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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 &gt;=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&apos; 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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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 &gt;=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&apos; 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Neurology

ISSN

0028-3878

e-ISSN

—

Svazek periodika

95

Číslo periodika v rámci svazku

24

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

17

Strana od-do

"e3163"-"e3179"

Kód UT WoS článku

000607315800013

EID výsledku v databázi Scopus

2-s2.0-85096452508