Late onset and heterogeneous clinical presentation in three affected members of a NLSDM Italian family

Neutral Lipid Storage Disease with Myopathy (NLSDM), is a rare autosomal recessive disorder characterized by an abnormal accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). LDs metabolic functions are mediated by proteins bound to their surface. In particular, the lipase that catalyzes the removal of the first acyl chain from triacylglycerol is the patatin-like phospholipase domain-containing protein 2 (PNPLA2). Mutations in the PNPLA2 cause the onset of NLSDM. Patients are mainly affected by progressive myopathy, cardiomyopathy and hepatomegaly. To our best knowledge, 27 different PNPLA2 mutations have been described in 41 NLSDM patients. Here we report the clinical and genetic findings of a NLSDM Italian family with three affected siblings. In our patients we identified two novel PNPLA2 missense mutations. Since age of 38 years, the oldest brother had weakness and hypotrophy of right upper arm and kyphosis. He is now unable to raise arms in horizontal position (61 years old). The second brother, since 44 years of age, had exercise intolerance, cramps and pain in lower limbs. He currently has a distal amyotrophy. Genetic analysis revealed that also one of the two sisters presents the PNPLA2 mutations, but she is still barely symptomatic. Using a functional in vitro assay, we have observed that these mutations caused the production of ATGL proteins with diminish lipase activity, but able to bind to LDs. This is a very interesting family since it shows heterogeneity of clinical presentation from relatively asymptomatic phenotype to full expression of a severe myopathy.