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

The research, led by Biswajit Dey and Santosh Kumar Guru at the National Institute of Pharmaceutical Education and Research in Hyderabad, India, together with colleagues at Sambalpur University and other Indian institutions, focused on an enzyme called glutamate dehydrogenase 1, or GDH1. This enzyme sits at a critical junction of cellular metabolism, where it converts glutamate, the breakdown product of the amino acid glutamine, into alpha-ketoglutarate, a molecule that feeds directly into the Krebs cycle inside mitochondria. In doing so, GDH1 performs what biologists call an anaplerotic function: it replenishes the intermediates that the Krebs cycle constantly consumes, keeping the mitochondrial engine running. The new work shows that persister cells in triple-negative breast cancer lean heavily on this engine, and that without it, they simply cannot survive.

Triple-negative breast cancer is defined by the absence of the three molecular targets that modern therapy exploits most effectively: the estrogen receptor, the progesterone receptor, and the HER2 protein. Because none of these handles exist for drugs to grab, patients with this subtype rely almost entirely on chemotherapy, which makes the emergence of drug-tolerant persister cells a particularly dangerous problem. The Indian team began by mining publicly available clinical datasets and found that breast cancer patients with elevated GDH1 expression had significantly worse prognoses. That epidemiological clue set the stage for a detailed mechanistic investigation into what GDH1 actually does inside cells that have just survived a chemotherapeutic hit.

Using laboratory models of triple-negative breast cancer, the researchers generated persister cells by exposing them to chemotherapy and isolating the survivors. Multiple independent techniques then converged on the same conclusion. Western blotting and quantitative reverse-transcription polymerase chain reaction showed that GDH1 protein and messenger RNA were both upregulated in the persister population. Immunofluorescence microscopy visualized the increased enzyme directly inside the surviving cells, and mass spectrometry provided an unbiased proteomic confirmation. Extracellular flux assays, which measure the real-time oxygen consumption and acidification of living cells, revealed that this GDH1 surge came with a shift in mitochondrial metabolism, indicating that the persisters were not merely idle survivors but metabolically reprogrammed cells actively burning glutamine-derived fuel.

The functional consequences of this reprogramming were striking. When the team measured cell viability and migratory capacity, GDH1-high persister cells proved both hardier and more mobile than their non-persister counterparts. Wound healing assays, a standard test of cell migration, showed that the persister cells closed scratches faster, a behavior consistent with the acquisition of invasive traits. Conversely, when the researchers suppressed GDH1, either pharmacologically or through genetic silencing, cell viability dropped and migration slowed. The enzyme was not a passive marker of the persister state; it was actively maintaining it.

One of the most intriguing aspects of the study concerns the physical architecture of mitochondria. Mitochondria are dynamic organelles that constantly fuse and split, and the balance between these two processes shapes their function. The researchers found that GDH1 supports a program of fusion-associated remodeling in persister cells, involving the mitofusin proteins MFN1 and MFN2, which tether neighboring mitochondria together, and the phosphorylation state of dynamin-related protein 1, or DRP1, the master regulator of mitochondrial fission. Specifically, the persister cells showed evidence of increased phosphorylation of DRP1 at serine 637, a modification that inhibits fission and favors elongated, fused mitochondrial networks. This fused state is thought to protect mitochondria during stress, preserving their integrity and their capacity to generate energy when the cell is under attack from chemotherapy. In other words, GDH1 appears to coordinate two survival strategies at once: it supplies the metabolic substrate that keeps the Krebs cycle turning, and it shapes the mitochondrial network into a configuration that is more resilient to damage.

The study also connected GDH1 to epithelial-to-mesenchymal transition, or EMT, the developmental program through which epithelial cancer cells abandon their anchored, orderly identity and adopt the mobile, invasive character of mesenchymal cells. EMT is closely associated with drug tolerance, because the transition suppresses proliferation and activates survival pathways, exactly the phenotype that persister cells display. When the researchers stably knocked down GDH1, they found that EMT markers diminished and the cells lost their ability to form the persister state in the first place. This suggests that GDH1 is not merely a consequence of EMT but an enabler of it, linking glutamine metabolism to the transcriptional and structural changes that allow cancer cells to hunker down under therapy.

Perhaps the most clinically significant experiments came from the animal studies. The team implanted triple-negative breast cancer cells into mice as xenografts and compared tumors with normal GDH1 levels to tumors in which GDH1 had been knocked down. When chemotherapy was administered, the GDH1-deficient tumors responded far more dramatically, demonstrating that removing the enzyme restored chemosensitivity in vivo. Analysis of the tumor tissue showed reduced levels of Ki-67 and PCNA, two well-established markers of cell proliferation, confirming that GDH1 loss impaired the growth machinery of the tumor. Together, these results elevate GDH1 from an interesting biochemical observation to a validated therapeutic target whose inhibition could sensitize tumors to existing drugs.

An important nuance emerged when the researchers followed persister cells over time. After thirty days without drug exposure, GDH1 expression declined back toward baseline, indicating that the enzyme plays a transient, state-dependent role rather than causing a permanent genetic change. This reversibility is characteristic of the non-genetic mechanisms that underpin drug tolerance, and it explains why persister cells can eventually exit their dormant state and resume rapid proliferation, seeding recurrence. It also suggests a therapeutic window: if clinicians could target GDH1 during the period when it is elevated, they might eliminate persisters before they revert to a proliferative, treatment-resistant state.

The implications for patients are considerable. Combination strategies that pair conventional chemotherapy with GDH1 inhibition could, in principle, prevent the establishment of the persister reservoir that so often leads to relapse in triple-negative breast cancer. Because GDH1 acts on both metabolism and mitochondrial dynamics, inhibitors of the enzyme might be particularly effective in tumors that have already adopted a glutamine-dependent survival mode. The work also adds to a growing appreciation that cancer therapy must target not only the dividing cells that dominate a tumor’s bulk but also the quiet, metabolically rewired survivors that hide among them. As the authors conclude, GDH1 stands out as a crucial regulator of persister survival, and drugs aimed at this mitochondrial gatekeeper may represent a promising path toward overcoming chemoresistance in one of breast cancer’s most feared forms.

Subject of Research: Role of glutamate dehydrogenase 1 in the survival of drug-tolerant persister cells in triple-negative breast cancer

Article Title: Glutamate dehydrogenase 1 (GDH1) sustains triple-negative breast cancer persister cell survival by coordinating mitochondrial fusion and anaplerotic flux

Article References: Dey, B., Chatterjee, E., Pandey, N., Singh, H., Basak, S., Kumar, R., Sharma, A., Bhalerao, H. A., Dharavath, A., S., S. L., Singh, P. K., Sonti, R., Naik, P. K., Doijad, N., & Guru, S. K. (2026). Glutamate dehydrogenase 1 (GDH1) sustains triple-negative breast cancer persister cell survival by coordinating mitochondrial fusion and anaplerotic flux. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06316-9

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06316-9

Keywords: triple-negative breast cancer, GDH1, drug-tolerant persister cells, mitochondrial fusion, anaplerotic flux, glutaminolysis, EMT, chemoresistance, cancer metabolism, MFN2, DRP1, tumor recurrence