Fenofibrate and Lomitapide in PNPLA2-Related Neutral Lipid-Storage Disease with Myopathy: A Single-Patient In Vitro Approach

Neutral lipid-storage disease with myopathy (NLSD-M), caused by pathogenic PNPLA2 variants, has no established treatment. We report a single-patient in vitro study in a 32-year-old female evaluating fenofibrate and lomitapide in patient-derived fibroblasts, selected based on prior therapeutic evidence. Therapeutic endpoints included lipid-droplet (LD) burden, quantified by volumetric z-stack imaging, and bioenergetic profiling, performed by Seahorse respirometry, citrate synthase (CS) activity, cellular NADH capacity, and complex II activity. Fibroblasts were treated with fenofibrate (20 µM) and lomitapide (5 nM) for two weeks. PNPLA2-mutant fibroblasts exhibited LD burden of median 56 droplets per cell, reduced CS activity, a proxy for mitochondrial content, and a hypometabolic profile. Preserved total NADH oxidase and Complex II activities indicated unaffected intrinsic electron transport chain function. Under fenofibrate exposure, most measured bioenergetic parameters in the patient-derived line were closer to the corresponding values in treated controls, but paradoxically increased LD count 1.5–1.9-fold. Lomitapide did not reduce LD burden and further worsened bioenergetic parameters. Loss of PNPLA2-mediated lipolysis produces a dual phenotype of LD accumulation and bioenergetic impairment. Fenofibrate and lomitapide produced divergent and partially adverse effects across these two endpoints. These findings informed precautionary, patient-specific clinical management decisions. Combined LD and metabolic profiling in patient-derived fibroblasts may complement therapeutic decision-making in NLSD-M, pending validation in larger cohorts.