Neutral Lipid Storage Disease with Myopathy via the PNPLA2 Gene

Neutral lipid storage disease with myopathy (NLSDM, OMIM 610717) is characterized by the accumulation of cytoplasmic lipid droplets in a wide range of cells types, including muscle cells and blood granulocytes; the absence of skin findings; and the presence of mild myopathy. NLSDM is typically a slowly progressive myopathy with onset around the third decade of life. Cardiomyopathy, as a finding later in the disease course, is common in NLSDM. Muscle weakness is most notable in the shoulder girdle and less so in the pelvic girdle and distal muscle groups. Patients exhibit exercise intolerance and highly elevated serum CpK levels. Muscle biopsies reveal massive accumulation of neutral lipid droplets, while peripheral blood smears exhibit persistent vacuoles in the cytoplasm of granulocytes (Reilich et al. J Neurol 258:1987-1997, 2011; Campagna et al. Biochem Biophys Res Commun 377:843-846, 2008). Rimmed vacuoles in muscle fibers have also been noted in one case of NLSDM (Chen et al. Clin Neuropathol 29:351-366, 2010). Although myopathy associated with NLSDM is generally considered to be mild, one case of severe myopathy in NLSDM was reported, in which a homozygous truncating variant affecting the adipose triglyceride lipase active site was found (Akiyama et al. Muscle Nerve 36:856-859, 2007).

Neutral lipid storage disease with myopathy is inherited as an autosomal recessive disorder. The only gene known to be associated with this disorder is the adipose triglyceride lipase gene (PNPLA2, OMIM 609059; Fischer et al. Nat Genet 39:28-30, 2007). PNPLA2 (patatin-like phospholipase domain-containing protein 2) encodes adipose triglyceride lipase, the enzyme that catalyzes the rate-limiting step of lipolysis. Most NLSDM-causing variants of the PNPLA2 gene are small deletions resulting in loss of function.

Adipose triglyceride lipase is coded by exons 2-10 of the PNPLA2 gene on chromosome 11p15.

Clinical sensitivity should be high in patients meeting clinical and histological criteria for this disorder. Analytical sensitivity should also be high because nearly all reported PNPLA2 variants are detectable by direct sequencing of genomic DNA.

This test provides full coverage of all coding exons of the PNPLA2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).