Novel mutations in the PNPLA2 gene causing late one-set of neutral lipid storage disease with myopathy in an 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). Mutations in the PNPLA2 gene cause the onset of NLSDM. PNPLA2 codes for adipose triglyceride lipase (ATGL), an enzyme that hydrolyses fatty acids from triacylglycerol. NLSDM patients are mainly affected by progressive myopathy, cardiomyopathy and hepatomegaly. Other clinical symptoms may include diabetes, chronic pancreatitis and short stature. To our best knowledge, twenty six different PNPLA2 mutations have been described in thirty two NLSDM patients. Here we report the clinical and genetic findings of a NLSDM Italian family with different affected members. In our patients we identified two novel PNPLA2 missense mutations (pL56R and pI193F). 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 pL56R and pI193F 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.