Familial lipoprotein lipase deficiency is caused by biallelic pathogenic variants in the LPL gene (chromosome 8), which encodes lipoprotein lipase (GeneReviews; OMIM:238600). The condition is inherited in an autosomal recessive pattern: an individual must inherit two pathogenic copies of LPL—one from each parent—to be affected. Heterozygous carriers are typically asymptomatic but may have moderately elevated plasma triglyceride concentrations (GeneReviews). LPL variants account for approximately 95% of monogenic chylomicronemia cases; less common causes involve other genes in the triglyceride clearance pathway, including APOC2, GPIHBP1, APOA5, and LMF1 (GeneReviews). Sequence analysis of LPL detects pathogenic variants in approximately 97% of probands; gene-targeted deletion/duplication analysis accounts for approximately 3% (GeneReviews). According to GeneReviews, no reliable genotype-phenotype correlations have been established, as most pathogenic LPL variants have been reported in individual case reports or small case series. Consanguinity is observed in some families with familial LPL deficiency caused by homozygous pathogenic LPL variants, reflecting the increased likelihood that parents sharing common ancestry will carry the same rare variant (GeneReviews).

According to GeneReviews, familial lipoprotein lipase deficiency is suspected in individuals—particularly those under age 40—presenting with recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly, together with supporting laboratory findings: fasting lipemic plasma, impaired chylomicron clearance from plasma, and plasma triglyceride concentrations exceeding 2,000 mg/dL in the untreated state regardless of fasting status (GeneReviews). The diagnosis is established by identification of biallelic pathogenic variants in LPL on molecular genetic testing. Diagnostic approaches include sequence analysis of LPL (detecting approximately 97% of pathogenic variants) followed, where single-variant testing is inconclusive, by gene-targeted deletion/duplication analysis (GeneReviews). Multigene panels encompassing LPL and other chylomicronemia-associated genes may also be considered. Measurement of lipoprotein lipase enzyme activity in post-heparin plasma can confirm absent or severely reduced enzyme function, though this assay is not routinely available and is generally performed only at specialist centers (GeneReviews).

No treatments specifically approved for familial lipoprotein lipase deficiency appear in this packet. One gene therapy product for LPL deficiency holds orphan designation but is listed as WITHDRAWN and does not represent a current treatment option. Medical nutrition therapy is the cornerstone of management. According to GeneReviews, morbidity can be prevented by maintaining plasma triglyceride concentrations below 2,000 mg/dL, with a clinical goal below 1,000 mg/dL. Restriction of dietary fat to no more than 20 grams per day or 15% of total energy intake is typically sufficient to reduce chylomicronemia and maintain an affected individual free of symptoms (GeneReviews). Medium-chain triglycerides may serve as an alternative fat source because they are absorbed directly into the portal vein without incorporation into chylomicrons (GeneReviews). For acute pancreatitis, management follows established approaches, including discontinuation of oral fat intake and, where necessary, hypocaloric parenteral nutrition to decrease VLDL triglyceride production (GeneReviews). GeneReviews notes that fish oil supplements, effective in certain other hypertriglyceridemia disorders, are not effective in LPL deficiency and are contraindicated. Hepatosplenomegaly may resolve within one week of effective triglyceride lowering, and eruptive xanthomas may clear over weeks to months (GeneReviews).

According to GeneReviews, affected individuals can lead a relatively normal life when dietary fat restriction is maintained. Secondary complications of pancreatitis—including diabetes mellitus, steatorrhea, and pancreatic calcification—are unusual in familial LPL deficiency and rarely occur before middle age (GeneReviews). Pancreatitis may rarely be associated with total pancreatic necrosis and death in severe cases. Prevention of recurrent pancreatitis also reduces the risk of developing diabetes mellitus. Neuropsychiatric manifestations and lipemia retinalis are generally reversible with triglyceride normalization. GeneReviews reports that with stringent dietary fat restriction during pregnancy, delivery of a normal infant with normal essential fatty acid concentrations has been documented. Overall prognosis is closely related to adherence to dietary fat restriction and prevention of pancreatitis episodes.

Familial lipoprotein lipase deficiency is an active area of clinical investigation. Phase 3 trials registered at ClinicalTrials.gov are evaluating olezarsen, an APOC3-targeting therapy, for familial chylomicronemia syndrome in adults (NCT05130450, NCT05185843, Ionis Pharmaceuticals) and in a pediatric population (NCT07727538, Ionis Pharmaceuticals). Early-phase studies are examining APOC3 base editing approaches in adults with familial chylomicronemia syndrome (NCT07176923, CorrectSequence Therapeutics) and in children and adolescents with hyperchylomicronemia (NCT07371767). An additional study is examining postprandial fatty acid metabolism in LPL deficiency (NCT04227678, Universite de Sherbrooke). Published research encompasses 149 classified publications, including case reports, case series, and review articles, with ongoing investigation into gene-based approaches, triglyceride pathway inhibitors, and biomarkers for the condition.