Data from: The genetic landscape of axonal neuropathies in the middle aged and elderly: focus on MME (supplementary information)

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.