Posters

Charcot-Marie-Tooth Disease is a clinically and genetically heterogeneous group of hereditary neuropathies. Using next-generation sequencing, we identified biallelic variants in ARHGAP19, encoding for a RhoA-specific GTPase-activating protein, in 25 individuals from 20 unrelated families presenting with motor-predominant neuropathy. In-vitro biochemical and cellular assays revealed that patient variants impair the GTPase-activating protein (GAP) activity of ARHGAP19 and reduce ARHGAP19 protein levels. Parallel in-vivo studies using Drosophila and zebrafish models revealed a conserved role for ARHGAP19 orthologs in regulating locomotor function, motoneuron axon length and branching, and neuromuscular junction morphology. Leveraging these models and to address the limited therapeutic options, we established an in vivo movement-based drug screen to identify novel therapies, using a Drosophila model of ARHGAP19 ortholog, RhoGAP54D, loss of function. RhoGAP54D knock out flies exhibit motor defects that recapitulate patient phenotypes. To date, we have acutely fed the flies 120 drugs from a library of FDA-approved compounds and screened for drugs that rescued locomotor dysfunction. Any candidate compounds will be validated in patient-derived tissues to assess their clinical potential. This screening algorithm is adaptable and may accelerate therapeutic discovery across diverse CMT subtypes. Our findings reveal ARHGAP19 loss-of-function as a novel driver of inherited neuropathy and support integrated Drosophila and cell-based studies as a means to enable drug repurposing in CMT.

Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy and may remain subclinical until exposure to neurological stressors. Chemotherapy-induced peripheral neuropathy (CIPN) is a recognised toxicity of several anticancer agents, particularly vinca alkaloids, taxanes and platinum compounds; however, capecitabine is not typically considered neurotoxic. We report a 51-year-old woman with microsatellite-stable, stage III (pT4aN1bM0R1) ascending colon adenocarcinoma and genetically confirmed CMT1A (PMP22 duplication). Given concern for CIPN, oxaliplatin was omitted and she commenced empirically dose-reduced adjuvant capecitabine. Within 72 hours she developed profound generalised motor weakness, becoming bedridden. Capecitabine was immediately discontinued, with near-complete neurological recovery within 48 hours. At later relapse, she tolerated fluoropyrimidine-based regimens (5-fluorouracil/leucovorin and dose-reduced FOLFIRI) without significant neurotoxicity, supporting a drug–gene interaction rather than inevitable fluoropyrimidine intolerance. To contextualise this case, we performed a structured mini review of PubMed and Scopus (1985–2025). Of 52 records screened, 34 reports describing chemotherapy-related neuropathy in clinically or genetically confirmed CMT were included. Vincristine was most frequently implicated, often causing early irreversible paralysis in CMT1A; taxanes and less consistently platinum agents were also associated with severe CIPN. No prior cases of capecitabine-triggered acute motor neuropathy in genetically confirmed CMT were identified. This case highlights that “low-risk” agents for CIPN may precipitate severe neurotoxicity in genetically susceptible individuals and supports careful neurological assessment and selective baseline neurophysiology/genetic testing before potentially neurotoxic chemotherapy.