Delving into the clinical and genetic spectrum of NLSDM: A case study.

Mutations in the PNPLA2 gene, which encodes adipose triglyceride lipase (ATGL), are linked to neutral lipid storage disease with myopathy (NLSDM). This rare genetic disorder is marked by abnormal accumulation of neutral lipids in cytoplasmic lipid droplets, leading to muscle-related symptoms such as weakness, cramps and progressive myopathy in almost all patients, and cardiomyopathy in about half of the patients. Here, we report a novel PNPLA2 variant and the clinical and MRI findings of a 42-year-old Italian male with NLSDM, revealing a myopathic pattern involving both proximal and distal muscles of all four limbs, as well as axial and facial muscles, without detectable cardiac abnormalities. Genetic testing uncovered a novel PNPLA2 homozygous mutation, resulting in the deletion of a single amino acid in the first ATGL LC3-interacting region (LIR) motif. In addition, bioinformatic analyses predicted changes in mutated ATGL's structure that could affect its enzymatic function and impair both lipolysis and lipophagy by disrupting ATGL-LC3 interaction. Western blot analysis confirmed a block in lipophagic flux. This study broadens our understanding of the genetic and clinical heterogeneity of NLSDM, highlighting the complexity of the disease.