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Effects of bezafibrate treatment in a patient and a carrier with mutations in the PNPLA2 gene, causing neutral lipid storage disease with myopathy.

Neutral lipid storage disease with myopathy (NLSDM) is a rare but severe genetic disorder characterized by excessive lipid accumulation in tissues including skin, bone marrow, heart, liver, and muscles. Clinically, NLSDM patients present with severe dilated cardiomyopathy, skeletal muscle myopathy, and insulin resistance.1 NLSDM is caused by a defect in the PNPLA2 gene encoding the enzyme adipose triglyceride lipase (ATGL),2 which catalyzes the breakdown of triglycerides in multiple tissues and is the rate-limiting step of lipolysis. Although heterozygous carriers and homozygous patients both present with similar clinical symptoms, the severity of these symptoms in homozygous patients is more dramatic, leading to premature death attributed to dilated cardiomyopathy in some patients.1,2 To date, the only available treatment is strict dietary guidelines and is focused on treating the comorbidities rather than targeting the primary defect.

To investigate cardiac lipotoxicity in NLSDM, ATGL-deficient mice have been investigated. Just like NLSDM patients, ATGL-deficient mice are also characterized by excessive lipid storage in skeletal muscle, liver, and heart, and they develop cardiomyopathy at a young age, resulting in premature death.3 Interestingly, we reported recently that a lack of ATGL resulted in a diminished cardiac peroxisome proliferator-activated receptor (PPAR) activity and mitochondrial function, suggesting that lipolysis-derived fatty acids or fatty acid byproducts serve as transcriptional activators of PPARs.4 Subsequently, pharmacological treatment of ATGL-deficient mice with PPAR agonists completely reversed the mitochondrial defects, restored cardiac function, and prevented premature death. These promising findings inspired us to investigate whether PPAR agonist treatment in patients and carriers of a PNPLA2 gene defect could also have beneficial effects.

Although NSLDM is a very rare disease, we had the opportunity to study 2 sisters with PNPLA2 gene mutations. Patient 1 is a 37-year-old woman with a body mass index of 21.4 kg/m2. …