Clinical findings and autophagic pathology in neutral lipid storage disease with myopathy

Neutral lipid storage disease with myopathy (NLSDM) is a triglyceride metabolic disorder caused by defects of adipose triglyceride lipases (ATGL). The coexistence of lipid vacuoles and rimmed vacuoles in the myofibers is a characteristic pathological change in some NLSDM cases. However, it has not been explored whether autophagic abnormalities exist in the NLSDM myofibers with rimmed vacuole. Herein, we report that 5 patients with NLSDM initially presented with muscle weakness in the right arm related to long-term physical efforts, then developed muscle weakness of other limbs. Pathogenic mutations in the PNPLA2 gene were identified in all patients. Myopathological analysis showed a coexistence of massive lipid vacuoles and rimmed vacuoles, which was not associated with the age of onset or mutation sites, but closely related to the severity of muscle degeneration. The rimmed vacuoles showed strong immunopositivity to autophagic markers, but were negative to apoptotic markers. Significant immunoreactivity of p62 was observed in the rimmed vacuoles, while the lysosomal marker LAMP1 was severely decreased. Our study expanded the clinical and genetic spectrum of NLSDM. Loss of ATGL activity in muscle fibers with rimmed vacuoles induced a marked increase in autophagic formation, but lowered down the turnover of autolysosomes due to malfunction of lysosomes.