Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. Age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2 was assumed and 51 index case subjects with late-onset CMT2 were screened for mutations by whole-exome (WES) and Sanger sequencing. WES repositories were subsequently queried for further case subjects carrying mutations in the identified candidate gene. Nerve pathology and tissue levels and function of the abnormal protein were studied in order to explore consequences of the mutations. Overall, the authors observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system.
