PNPLA2 – Triglyceride Deposit Cardiomyovasculopathy

Adipose triglyceride lipase (ATGL), encoded by PNPLA2, catalyzes the first step in intracellular triglyceride hydrolysis. Biallelic loss-of-function variants in PNPLA2 cause a recessive cardiomyopathy—triglyceride deposit cardiomyovasculopathy (TGCV; MONDO:0035423)—characterized by massive myocardial lipid accumulation and heart failure. Clinical onset is typically in mid-adult life, with progressive heart failure and arrhythmias prompting transplantation in severe cases.

Genetic evidence supports an autosomal recessive inheritance. A 59-year-old patient with NLSDM/TGCV carried a homozygous c.576delC (p.Asp192GlufsTer?) frameshift variant (PMID:24836204). A larger series of 56 genetically-confirmed patients—including 55 published cases and one index patient—harbored homozygous or compound heterozygous PNPLA2 truncating mutations (56 probands) (PMID:32564019).

Variant spectrum encompasses frameshift, nonsense, and missense alleles concentrated in exons 4–7. Pathogenic missense c.446C>G (p.Pro149Arg) in the catalytic domain was identified in a patient with primary TGCV, demonstrating impaired lipolysis despite preserved lipid binding (PMID:36846631).

Functional assays reveal concordant evidence: selective immunoinactivation assays show markedly reduced ATGL activity in idiopathic TGCV leucocytes (PMID:29146190), and in vitro expression of p.Pro149Arg confirms decreased lipolytic function. These data support a loss-of-function mechanism.

Clinically, TGCV presents with congestive heart failure (HP:0001635), angina pectoris (HP:0001681), chest pain (HP:0100749), and exertional dyspnea (HP:0002875). Early suspicion based on cardiac steatosis by imaging and genetic testing of PNPLA2 enables prompt diagnosis and can guide potential lipolysis-enhancing therapies.

Integration of robust genetic segregation, a consistent recessive phenotype, and functional concordance establishes a Strong gene-disease association for PNPLA2 in TGCV. Key take-home: PNPLA2 mutation analysis should be incorporated into the diagnostic workup of adult-onset cardiomyopathies with myocardial lipid accumulation.

References

• Neuromuscular disorders • 2014 • A novel mutation in PNPLA2 causes neutral lipid storage disease with myopathy and triglyceride deposit cardiomyovasculopathy: a case report and literature review. PMID:24836204
• European neurology • 2020 • Neutral Lipid Storage Disease Associated with the PNPLA2 Gene: Case Report and Literature Review. PMID:32564019
• Molecular genetics and metabolism reports • 2023 • A novel homozygous missense mutation in PNPLA2 in a patient manifesting primary triglyceride deposit cardiomyovasculopathy. PMID:36846631
• Biochemical and biophysical research communications • 2018 • Newly developed selective immunoinactivation assay revealed reduction in adipose triglyceride lipase activity in peripheral leucocytes from patients with idiopathic triglyceride deposit cardiomyovasculopathy. PMID:29146190
• Orphanet journal of rare diseases • 2019 • Triglyceride deposit cardiomyovasculopathy: a rare cardiovascular disorder. PMID:31186072

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