Neutral Lipid Storage Disease with Myopathy: A Case Report with a Novel PNPLA2 Mutation

ABSTRACT Neutral lipid storage disease with myopathy (NLSDM) is a rare autosomal recessive disorder caused by mutations in the PNPLA2 gene, leading to defective triglyceride hydrolysis and lipid accumulation in tissues. We report a 28-year-old Indian female presented with a 4-year history of progressive, asymmetric limb weakness, elevated creatine kinase (1000 U/L), and vitiligo. Muscle magnetic resonance imaging (MRI) revealed asymmetric fatty infiltration. Muscle biopsy showed subtle vacuolar changes; notably, oil red O staining was negative, a known limitation in formalin-fixed tissue. Whole-exome sequencing identified a novel, likely pathogenic homozygous frameshift mutation, c. 212del, in exon 3 of PNPLA2, absent in population databases (gnomAD, ClinVar) and classified as likely pathogenic as per American College of Medical Genetics and Genomics (ACMG) criteria (PVS1, PM2). This case underscores the phenotypic variability of NLSDM and expands the genetic spectrum of the disease in the Indian population, highlighting the critical role of genetic testing for definitive diagnosis-particularly when histopathological lipid staining is unrevealing.