Lipoprotein lipase deficiency

LipoproteinLipase Deficiency and Familial Chylomicronaemia Syndrome

• Familial Chylomicronaemia Syndrome (FCS) is a rare autosomal recessive genetic disorder characterized by severely impaired or absent lipoprotein lipase (LPL) activity, leading to extreme fasting and postprandial hypertriglyceridaemia (>10 mmol/L) (1, 2)
• traditional lipid-lowering therapies (statins, fibrates) are of limited clinical efficacy in FCS due to the underlying LPL enzyme deficiency (1, 3)
• National Institute for Health and Care Excellence (NICE) guidance recommends apolipoprotein C-III (APOC-3) targeted therapies - including olezarsen (TA1203), plozasiran (TA1204), and volanesorsen (HST13) - as options for genetically confirmed FCS in adults after inadequate response to diet and conventional treatments (3, 4, 5)

Clinical Presentation and Etiology

Aetiology and Genetics

• cause: loss-of-function mutations in both alleles of the LPL gene or supporting genes necessary for LPL function, such as APOC2, APOA5, GPIHBP1, and LMF1 (2)
• pathophysiology: LPL mediates lipolysis of plasma triglycerides in chylomicrons; lack of functional LPL leads to massive accumulation of circulating triglyceride-rich lipoproteins (1, 2)
• apolipoprotein C-II deficiency overlap: ApoC-II serves as an essential cofactor for LPL; deficiency causes accumulation of chylomicrons and VLDL, though eruptive xanthomas and hepatosplenomegaly occur less frequently than in primary LPL deficiency (1)

Clinical Features

• severe hypertriglyceridaemia (typically >10 to 100 times normal threshold levels) (1, 2)
• acute, recurrent pancreatitis (primary life-threatening complication) (1, 2)
• eruptive xanthomas (cutaneos fat deposits)
• lipaemia retinalis (milky appearance of retinal vessels)
• hepatosplenomegaly and abdominal pain

Management and NICE Recommendations

Supportive and Dietary Interventions

• strict dietary fat restriction: restriction of total dietary fat intake to less than 10% to 15% of daily energy intake (15 to 20 g per day) combined with essential fatty acid and fat-soluble vitamin supplementation (A, D, E, K) (3)
• conventional lipid-lowering agents: fibrates, statins, and omega-3 fatty acids are generally ineffective in FCS due to reliance on the LPL pathway (1, 3)
• acute clearance: lipoprotein apheresis can rapidly reduce circulating triglycerides during acute severe exacerbations (3)

NICE Targeted Therapies (APOC-3 Inhibitors)

• olezarsen (NICE TA1203): GalNAc3-conjugated antisense oligonucleotide recommended as an option for genetically confirmed FCS in adults when response to diet and conventional treatments is inadequate; administered monthly with no requirement for routine platelet monitoring (4)
• plozasiran (NICE TA1204): GalNAc-conjugated small interfering RNA (siRNA) recommended as an option for genetically confirmed FCS in adults when response to diet and conventional treatments is inadequate; administered quarterly with no requirement for routine platelet monitoring (5)
• volanesorsen (NICE HST13): first-generation antisense oligonucleotide recommended for genetically confirmed FCS in adults at high risk of pancreatitis with inadequate response to diet and conventional therapies; requires routine monitoring due to risks of severe thrombocytopenia (3)

Reference:

1. Saku K, Cedres C, McDonald B, et al. C-II anapolipoproteinemia and severe hypertriglyceridemia: report of a rare case with absence of C-II apolipoprotein isoforms and review of the literature. Am J Med. 1984;77(3):457-462.
2. Brahm AJ, Hegele RA. Chylomicronaemia — current diagnosis and future therapies. Nat Rev Endocrinol. 2015;11(6):352-362.
3. National Institute for Health and Care Excellence (NICE). Volanesorsen for treating familial chylomicronaemia syndrome. NICE Highly Specialised Technologies Guidance [HST13]. Published November 2020.
4. National Institute for Health and Care Excellence (NICE). Olezarsen for treating familial chylomicronemia syndrome. NICE Technology Appraisal Guidance [TA1203]. Published 27 October 2026.
5. National Institute for Health and Care Excellence (NICE). Plozasiran for treating familial chylomicronemia syndrome. NICE Technology Appraisal Guidance [TA1204]. Published 27 October 2026.