Late-onset Charcot-Marie-Tooth accounts for nearly 9% of neuropathies after age 50
The study reports a 10-year retrospective analysis of next-generation sequencing results for suspected hereditary neuropathy at a single referral center, identifying late-onset Charcot-Marie-Tooth (CMT) disease in 8.9% of 642 patients with symptom onset after age 50. Pathogenic variants spanned 20 genes, with PMP22 duplication accounting for 32%, while multivariate analysis linked family history, pes cavus, and median nerve conduction velocities below 38 m/s to the diagnosis. These findings provide practical phenotypic markers that laboratory directors and neurologists can use to optimize genetic testing strategies for older adults presenting with acquired-appearing neuropathies.
The original study
Late-onset CMT neuropathy in the NGS era: a 10-year retrospective study.
- Authors
- Fortanier E, Bonello-Palot N, Verschueren A, Kouton L, Grapperon AM, Salort-Campana E, et al.
- Journal
- Journal of neurology
- Type
- Journal Article
- PMID
- 42799779
Original abstract
BACKGROUND AND AIM: Late-onset Charcot-Marie-Tooth (CMT) disease remains under-recognized and may mimic acquired neuropathies in older adults. We aimed to determine the prevalence and clinical, electrophysiological, and genetic characteristics of genetically confirmed late-onset CMT and to identify features distinguishing it from late-onset non-CMT neuropathies. METHODS: We retrospectively reviewed all patients who underwent next-generation sequencing (NGS) for suspected hereditary neuropathy between 2015 and 2025 at a single neuromuscular referral center. Late-onset CMT was defined by symptom onset after 50 years and a class 5 pathogenic variant. Clinical, electrophysiological, genetic, and functional data were collected. Patients were compared with a 2:1 age- and sex-matched control group with late-onset neuropathies, negative CMT-targeted NGS, and a confirmed alternative diagnosis. RESULTS: Among 642 patients tested after age 50, 57 had genetically confirmed late-onset CMT (8.9%). Pes cavus (80.7%) and a family history of neuropathy (63.2%) were the most frequent clinical features, while disability remained mild. Pathogenic variants involved 20 genes, with a 32% prevalence of PMP22 duplication and frequent involvement of MME, LRSAM1, MPZ, and MFN2. The main alternative diagnoses were inflammatory, idiopathic axonal, and toxic neuropathies. Compared with controls (n = 114), family history, pes cavus, and median nerve conduction velocity < 38 m/s were independently associated with late-onset CMT in multivariate analyses. DISCUSSION: Late-onset CMT accounts for a substantial proportion of neuropathies after age 50. Family history, pes cavus, and slowed median nerve conduction should prompt comprehensive genetic testing, particularly including genes associated with late-onset phenotypes.