Fenofibrate and Lomitapide in PNPLA2-Related Neutral Lipid-Storage Disease with Myopathy: A Single-Patient In Vitro Approach
5 affiliations
- 1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY 10029, USA
- 2Clinic of Pediatrics, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
- 3Institute of Biosciences, Life Sciences Center, Vilnius University, 10257 Vilnius, Lithuania
- 4Department of Anatomy, University of Pecs Medical School, Pecs Szigeti út, 12 7624 Pecs, Hungary
- 5Department of Biophysics, University of Pecs Medical School, Pecs Szigeti út, 12 7624 Pecs, Hungary
Abstract
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.
Related
- Extension of the phenotypic spectrum of GLE1 ‐related disorders to a mild congenital form resembling congenital myopathy
- Case Report: Severe depression and suicidality in a young patient with RYR1-related congenital myopathy
- Clinical, Histological, and Genetic Characterization of a Large Cohort of 49 Patients With Nebulin‐Related Congenital Myopathy
- Disease-related readmission in anti-SRP-positive immune-mediated necrotizing myopathy: Incidence and exploratory associated factors in a retrospective cohort study
- Combined statin and fenofibrate therapy and cardiorenal outcomes in patients with CKD, dyslipidemia, and ischemic heart disease
BibTeX
@article{merkevicius2026fenofibrate,
title = {{Fenofibrate and Lomitapide in PNPLA2-Related Neutral Lipid-Storage Disease with Myopathy: A Single-Patient In Vitro Approach}},
author = {Kajus Merkevicius and Graeme Preston and Sadie Larson and Nathalie S. Houssin and Sander Houten and Tamas Kozicz and Eva Morava},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219609},
url = {https://www.mdpi.com/1422-0067/27/21/9609},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Fenofibrate and Lomitapide in PNPLA2-Related Neutral Lipid-Storage Disease with Myopathy: A Single-Patient In Vitro Approach
AU - Kajus Merkevicius
AU - Graeme Preston
AU - Sadie Larson
AU - Nathalie S. Houssin
AU - Sander Houten
AU - Tamas Kozicz
AU - Eva Morava
PY - 2026
DA - 2026/10/27
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219609
UR - https://www.mdpi.com/1422-0067/27/21/9609
AB - 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.
SN - 1422-0067
ER -