Familial lipoprotein lipase deficiency

Lipoprotein lipase deficiency is a rare condition and inherited as an autosomal recessive condition. It is characterised by the presence of chylomicrons in fasting plasma. Fasting tryglyceride levels are characteristically > 10 mmol/L.

Characteristically there is a fasting hypertriglyceridaemia and chylomicronaemia (1):

• familial chylomicronaemia syndrome (FCS) is a rare genetic disorder characterized by reduced or absent lipoprotein lipase (LPL) activity
  • LPL mediates lipolysis of plasma triglycerides in chylomicrons and other triglyceride-rich lipoproteins
  • absence of LPL leads to marked fasting and postprandial chylomicronemia, with triglyceride levels 10 to 100 times above the normal level of 150 mg per deciliter (1.7 mmol per liter)
  • results from inactivating mutations in both alleles of the LPL gene or from mutations in other genes encoding proteins required for LPL activity, such as apolipoproteins C-II and A-5 (APOC2 and APOA5), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1) (2,3)
  • occasionally, patients with FCS phenotypes do not present with mutations in these genes (4,5)
  • prevalence of FCS is estimated to be 1 to 2 per million people, which equates to about 55 to 110 people in England (6)

Possible clinical features include:

• hepatosplenomegaly
• eruptive xanthomas
• lipaemia retinalis (turbid blood in the retinal vessels).
• pancreatitis

Management:

• lipoprotein apheresis can lower greatly elevated triglyceride levels in the short term
• dietary intervention:
  • restriction of total fat intake to less than 10 to 15% of daily calories (15 to 20 g per day) - people on a fat-restricted diet need supplements of essential fatty acids (linoleic and alpha linolenic acids) and fat-soluble vitamins (vitamins A, D, E and K).The strict dietary regimen is highly restrictive and often challenging for people with the condition and their families (6)
• treatments for hypercholesterolaemia (such as fibrates, nicotinic acids and statins) may be prescribed but are of limited value
• NICE state that "Volanesorsen is recommended, within its marketing authorisation, as an option for treating familial chylomicronaemia syndrome in adults with genetically confirmed familial chylomicronaemia syndrome who are at high risk of pancreatitis, and when response to diet and triglyceride-lowering therapy has been inadequate" (5)
  • volanesorsen is an antisense oligonucleotide inhibitor of apolipoprotein C-III (apoC-III) production. ApoC-III inhibits the metabolism of triglycerides via the actions of both the lipoprotein lipase and lipoprotein lipase-independent pathways. It selectively binds to apoC-III mRNA to prevent the production of the apoC-III protein, so increasing metabolism of triglycerides
  • adverse reactions listed as very common (that is, occurring in 1 in 10 people or more) in the summary of product characteristics for volanesorsen include thrombocytopenia and injection site reactions

Note that there is an overlap between lipoprotein lipase deficiency and apolipoprotein C-II Deficiency (familial inhibitor to lipoprotein lipase is a rare autosomal recessive hereditary disorder) (1)

• apolipoprotein C-II (apoC-II) is a necessary cofactor for the activation of LPL
• this condition is characterized by a deficiency of apolipoprotein C-II, causing an accumulation of chylomicrons and very low density lipoproteins (VLDL)
• xanthomas and hepatosplenomegaly are less common in C-II anapolipoproteinemia than in lipoprotein lipase deficiency (1)

Reference:

1. Saku, K.; Cedres, C.; McDonald, B.; Hynd, B. A.; Liu, B. W.; Srivastava, L. S.; Kashyap, M. L. : 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. 77: 457-462, 1984.
2. Brahm AJ, Hegele RA. Chylomicronaemia — current diagnosis and future therapies. Nat Rev Endocrinol 2015; 11: 352-62.
3. Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. J Intern Med 2012;272: 185-96.
4. Shetty S, Xing C, Garg A. Type 1 hyperlipoproteinemia due to compound heterozygous rare variants in GCKR. J Clin Endocrinol Metab 2016; 101: 3884-7.
5. Beigneux AP, Miyashita K, Ploug M, et al. Autoantibodies against GPIHBP1 as a cause of hypertriglyceridemia. N Engl J Med 2017; 376: 1647-58.
6. NICE (November 2020). Volanesorsen for treating familial chylomicronaemia syndrome