PNPLA2 – Neutral Lipid Storage Myopathy

Neutral lipid storage myopathy (NLSDM) is an ultra-rare autosomal recessive disorder caused by biallelic pathogenic variants in PNPLA2, which encodes adipose triglyceride lipase (ATGL). Affected individuals typically present in adulthood with elevated serum creatine kinase, progressive proximal muscle weakness, exercise intolerance, and variable cardiomyopathy and hepatomegaly. Jordans’ anomaly on peripheral blood smear and lipid droplets with rimmed vacuoles on muscle biopsy are consistent pathognomonic findings.

Genetic studies have identified recessive PNPLA2 variants in 45 unrelated NLSDM patients from 40 families demonstrating loss-of-function alleles and multi-family segregation [PMID:31655616]. Thirteen patients arose from consanguineous unions, supporting autosomal recessive inheritance. Additional case reports and series have expanded the cohort to over 56 genetically confirmed NLSDM cases worldwide [PMID:32564019].

Segregation analyses in familial reports include an Italian kindred with three affected siblings carrying compound heterozygous PNPLA2 missense alleles, confirming cosegregation of disease with variants in multiple relatives [PMID:25956450]. No significant phenotypic rescue was observed in unaffected heterozygous carriers, consistent with recessive inheritance.

The PNPLA2 variant spectrum includes frameshift, splice site, nonsense, and missense mutations across exons 4–7. Reported variants comprise c.167T>G (p.Leu56Arg) (p.Leu56Arg) [PMID:25956450], c.576del (p.Asp192GlufsTer?), and c.757+1G>T, among others, leading to truncated or catalytically impaired ATGL proteins.

Functional assays in patient fibroblasts and in vitro models demonstrate that loss of ATGL activity results in massive triglyceride accumulation in lipid droplets. Missense mutations such as p.Arg221Pro and p.Asn172Lys abrogate lipolytic function despite preserved droplet binding, while overexpression of wild-type ATGL restores normal lipolysis and reduces lipid vacuoles [PMID:22990388]. Induced pluripotent stem cell models recapitulate the lipid storage phenotype and serve as platforms for therapeutic screening.

Collectively, the abundant genetic and experimental concordance fulfills ClinGen criteria for a Definitive gene–disease association. Key take-home: PNPLA2 genetic testing is essential for timely diagnosis of NLSDM and guides clinical management, including monitoring for cardiomyopathy.

References

• Orphanet Journal of Rare Diseases • 2019 • Neutral lipid storage disease with myopathy in China: a large multicentric cohort study. PMID:31655616
• Molecular Genetics and Metabolism • 2015 • Novel missense mutations in PNPLA2 causing late onset and clinical heterogeneity of neutral lipid storage disease with myopathy in three siblings. PMID:25956450
• Human Molecular Genetics • 2012 • Contribution of novel ATGL missense mutations to the clinical phenotype of NLSD-M: a strikingly low amount of lipase activity may preserve cardiac function. PMID:22990388

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