Case Report: a novel PNPLA2 homozygous frameshift variant causing severe neutral lipid storage disease with myopathy (NLSDM) in a Moroccan patient

Neutral lipid storage disease with myopathy (NLSDM) is an ultra-rare autosomal\r\nrecessive lipid metabolism disorder caused by PNPLA2 variants, leading to\r\ndefective adipose triglyceride lipase (ATGL) function and pathological\r\ntriglyceride accumulation in multiple tissues. Fewer than 150 cases have been\r\nreported worldwide, and the clinical spectrum remains incompletely defined. A\r\n57-year-old Moroccan man presented with diabetes, hearing loss, cataracts,\r\nhypertrophic cardiomyopathy, and asymmetric weakness. Whole-body muscle\r\nMRI revealed severe fatty infiltration of the supraspinatus muscles in the upper\r\nlimbs and asymmetric right biceps femoris and left lateral gastrocnemius muscle\r\nwith a patchy pattern in the lower limbs. A deltoid muscle biopsy revealed\r\nvacuoles filled with lipids. Peripheral blood smear analysis showed Jordans’\r\nanomaly. Next-generation sequencing disclosed the novel homozygous\r\nc.1043del, p.Phe348SerfsTer18 PNPLA2 frameshift variant predicted to disrupt\r\nthe adipose triglyceride lipase (ATGL) patatin domain. Bioinformatics protein\r\nmodeling predicted disruption of the patatin domain and global structural\r\ninstability, likely abolishing enzymatic activity. Western blotting performed on\r\npatient-derived muscle tissue revealed a truncated ATGL protein, functionally\r\nvalidating the truncating effect of this novel variant. This case broadens the\r\nphenotypic and molecular understanding of NLSDM.