Abstract
Neutral lipid storage disease with myopathy (NLSDM) presents with skeletal muscle myopathy and severe dilated cardiomyopathy in nearly 40% of cases. NLSDM is caused by mutations in the PNPLA2 gene, which encodes the adipose triglyceride lipase (ATGL). Here we report clinical and genetic findings of a patient carrying two novel PNPLA2 mutations (c.696+4A>G and c.553_565delGTCCCCCTTCTCG). She presented at age 39 with right upper limb abduction weakness slowly progressing over the years with asymmetric involvement of proximal upper and lower limb muscles. Cardiological evaluation through ECG and heart echo scan was normal until the age 53, when mild left ventricular diastolic dysfunction was detected. Molecular analysis revealed that only one type of PNPLA2 transcript, with exon 5 skipping, was expressed in patient cells. Such aberrant mRNA causes the production of a shorter ATGL protein, lacking part of the catalytic domain. This is an intriguing case, displaying severe PNPLA2 mutations with clinical presentation characterized by slight cardiac impairment and full expression of severe asymmetric myopathy.
Highlights
Neutral lipid storage disease with myopathy (NLSDM; MIM 610717) is an autosomal recessive disorder characterized by abnormal accumulation of triacylglycerols (TAGs) in cytoplasmic lipid droplets (LDs) in most tissues, including muscle, heart, liver and peripheral blood
The main clinical feature of NLSDM is skeletal muscle myopathy, which is present in 100% of patients
The first mutation causes the skipping of exon 5 and the production of a mutated protein that loses part of the catalytic site, abrogating adipose triglyceride lipase (ATGL) lipase activity; the second mutation determines complete lack of mRNA expression and protein production (Fig. 3e)
Summary
Neutral lipid storage disease with myopathy (NLSDM; MIM 610717) is an autosomal recessive disorder characterized by abnormal accumulation of triacylglycerols (TAGs) in cytoplasmic lipid droplets (LDs) in most tissues, including muscle, heart, liver and peripheral blood. NLSDM is caused by mutations in PNPLA2 coding for the adipose triglyceride lipase (ATGL), a member of the patatinlike phospholipase domain-containing proteins [3]. This lipase is a lipid droplet-associated protein that catalyses the first step in the hydrolysis of TAGs, stored within LDs [16]. We describe clinical and genetic findings in a woman harbouring two novel mutations in PNPLA2 These mutations completely abolish lipase activity, our patient showed slowly progressive skeletal muscle weakness with late presentation, in association with mild cardiac impairment
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