Faedo_2026_Front.Genet_17_1701218

Neutral lipid storage disease with myopathy (NLSDM) is an ultra-rare autosomal recessive lipid metabolism disorder caused by PNPLA2 variants, leading to defective adipose triglyceride lipase (ATGL) function and pathological triglyceride accumulation in multiple tissues. Fewer than 150 cases have been reported worldwide, and the clinical spectrum remains incompletely defined. A 57-year-old Moroccan man presented with diabetes, hearing loss, cataracts, hypertrophic cardiomyopathy, and asymmetric weakness. Whole-body muscle MRI revealed severe fatty infiltration of the supraspinatus muscles in the upper limbs and asymmetric right biceps femoris and left lateral gastrocnemius muscle with a patchy pattern in the lower limbs. A deltoid muscle biopsy revealed vacuoles filled with lipids. Peripheral blood smear analysis showed Jordans' anomaly. Next-generation sequencing disclosed the novel homozygous c.1043del, p.Phe348SerfsTer18 PNPLA2 frameshift variant predicted to disrupt the adipose triglyceride lipase (ATGL) patatin domain. Bioinformatics protein modeling predicted disruption of the patatin domain and global structural instability, likely abolishing enzymatic activity. Western blotting performed on patient-derived muscle tissue revealed a truncated ATGL protein, functionally validating the truncating effect of this novel variant. This case broadens the phenotypic and molecular understanding of NLSDM.