Hidden Genetic Neuropathies Revealed in Older Adults by Decade of DNA Testing

Charcot–Marie–Tooth disease has long been imagined as an ailment of youth, a condition that announces itself in childhood with clumsy steps, high arches, and wasted calf muscles. A decade of genetic testing at one of France’s leading neuromuscular centers is now overturning that assumption. In a retrospective study spanning 2015 to 2025, researchers at La Timone University Hospital in Marseille found that nearly one in ten patients who underwent next-generation sequencing for suspected hereditary neuropathy after the age of fifty carried a confirmed genetic diagnosis of Charcot–Marie–Tooth disease, despite never having noticed symptoms until well into middle or late life. The findings, published in the Journal of Neurology, suggest that a substantial reservoir of inherited neuropathy has been hiding in plain sight among older adults, frequently mislabeled as inflammatory, toxic, or simply unexplained nerve damage.

The Marseille team, led by Etienne Fortanier and Shahram Attarian, combed through the records of 642 patients tested after their fiftieth birthday at their referral center. Fifty-seven of them, or 8.9 percent, met the study’s strict definition of late-onset CMT: symptoms beginning after age fifty combined with a class 5 pathogenic variant, the highest confidence category in the American College of Medical Genetics and Genomics framework for interpreting sequence variants. That threshold matters. By demanding both a late clinical onset and an unambiguously disease-causing mutation, the investigators filtered out the incidental genetic noise that often complicates interpretation of sequencing results in older populations, where variants of uncertain significance are common.

The clinical picture that emerged was strikingly mild compared with classic early-onset CMT. High arches, known as pes cavus, were present in 80.7 percent of the confirmed cases, and a family history of neuropathy appeared in 63.2 percent. Yet disability remained modest across the group, measured with validated instruments such as the Charcot–Marie–Tooth Neuropathy Score. This mildness is precisely what makes late-onset CMT so easy to miss. A patient who develops slowly progressive numbness and balance trouble at fifty-eight, without dramatic muscle wasting, is far more likely to be worked up for an acquired neuropathy than to be sent for hereditary testing, particularly when the family history is small or incomplete.

The genetic landscape revealed by the sequencing was remarkably diverse. Pathogenic variants were distributed across twenty different genes, a breadth that would have been practically impossible to capture under the old candidate-gene testing paradigm, in which laboratories screened one gene at a time based on the presumed inheritance pattern and nerve conduction profile. The single most common finding was the PMP22 duplication, the canonical cause of the demyelinating CMT1A subtype, present in 32 percent of cases. But a notable share of diagnoses involved genes only recently linked to late-onset phenotypes, including MME, which encodes the membrane metallo-endopeptidase neprilysin, LRSAM1, an E3 ubiquitin ligase involved in autophagy, MPZ, which encodes myelin protein zero, and MFN2, the mitofusin gene that governs mitochondrial fusion.

The prominence of MME and LRSAM1 in this cohort reinforces a growing international consensus that axonal neuropathies beginning in middle and old age carry a distinct genetic signature. Earlier studies from Japan, Italy, France, and the United Kingdom have pointed in the same direction, and whole-genome sequencing efforts have shown that broadening the genetic net raises diagnostic yields substantially. What the Marseille study adds is a decade of single-center consistency: the same referral service, the same testing pipeline, and the same clinical assessment framework applied uniformly across ten years, minimizing the referral and methodological heterogeneity that can distort multi-center surveys.

To understand what distinguishes genuine late-onset CMT from the many other neuropathies that afflict older adults, the researchers assembled a control group twice the size of the case series: 114 age- and sex-matched patients who had negative CMT-targeted sequencing and a confirmed alternative diagnosis. The main alternative diagnoses in this control group were inflammatory neuropathies, including chronic inflammatory demyelinating polyradiculoneuropathy, idiopathic axonal neuropathies, and toxic neuropathies. These are precisely the entities that dominate the differential diagnosis of progressive distal weakness and sensory loss after fifty, and misattributing hereditary disease to one of them carries real consequences, from unnecessary immunoglobulin therapy to missed genetic counseling for adult children who may carry the same variant.

Multivariate analysis distilled the distinction to three independent predictors. A family history of neuropathy, the presence of pes cavus, and a median motor nerve conduction velocity below 38 meters per second were each independently associated with late-onset CMT rather than an acquired alternative. The conduction threshold is technically meaningful: velocities below 38 meters per second in the median nerve conventionally demarcate demyelinating from axonal physiology, and their association with genetically confirmed CMT in this late-onset cohort indicates that even patients whose disease surfaces late often retain the electrophysiological fingerprint of their underlying molecular lesion. In practical terms, a neurologist evaluating an older patient with an unexplained neuropathy now has a compact, bedside-derivable triad that should trigger referral for comprehensive genetic testing.

The implications extend beyond diagnosis into the design of clinical trials. As gene-specific therapies for CMT edge closer to the clinic, natural history data on late-onset populations become essential, because the pace of progression, the burden of disability, and the range of causative genes all differ from the pediatric and young-adult cohorts in which most historical natural history studies were conducted. A trial designed around early-onset CMT1A assumptions may be poorly suited to a sixty-year-old with an MME-related axonal neuropathy that has progressed imperceptibly for a decade. Recognizing that nearly a tenth of tested patients over fifty harbor a genetic diagnosis means trial recruiters, outcome measure developers, and regulatory strategists must account for this older, genetically heterogeneous population.

There are also counseling dimensions that the study only begins to address. Each of the twenty implicated genes carries its own inheritance pattern, penetrance profile, and recurrence risk for offspring. An autosomal dominant MFN2 variant identified in a fifty-four-year-old has immediate implications for siblings and children, some of whom may already be experiencing subtle symptoms they have not connected. Conversely, identifying a recessive MME variant can reassure relatives and reshape reproductive planning. The Marseille findings argue for embedding genetic counselors within neuromuscular clinics that serve older adults, rather than treating hereditary neuropathy as a pediatric subspecialty concern.

The study’s limitations are those inherent to its design. It is retrospective, drawn from a single highly specialized referral center, which likely inflates the proportion of genetically confirmed cases relative to community practice, where testing rates remain low and referral thresholds high. The 8.9 percent figure should therefore be read as a prevalence among tested patients, not among all older adults with neuropathy. Still, the message travels well beyond Marseille: in the next-generation sequencing era, the age cutoffs that once guided who deserved hereditary testing have lost their justification. A family history, high arches, and slowed median nerve conduction in a patient of any age should now be enough to open the door to a comprehensive gene panel, because the genetic causes of neuropathy clearly do not respect a fiftieth birthday.

Subject of Research: Genetically confirmed late-onset Charcot–Marie–Tooth neuropathy diagnosed by next-generation sequencing in patients over 50

Article Title: Late-onset CMT neuropathy in the NGS era: a 10-year retrospective study

Article References: Fortanier, E., Bonello-Palot, N., Verschueren, A., Kouton, L., Grapperon, A.-M., Salort-Campana, E., Corazza, G., de Bovis, V. M., du Closel, L. B., Delmont, E., & Attarian, S. (2026). Late-onset CMT neuropathy in the NGS era: a 10-year retrospective study. Journal of Neurology, 273(10), Article 624. https://doi.org/10.1007/s00415-026-14154-9

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14154-9

Keywords: Charcot-Marie-Tooth disease, hereditary neuropathy, next-generation sequencing, late-onset disease, PMP22 duplication, MME, LRSAM1, MPZ, MFN2, pes cavus, nerve conduction velocity, genetic diagnosis