Lipoprotein lipase deficiency

Signs and symptoms

The disease often presents in infancy with colicky pain, failure to thrive, and other symptoms and signs of the chylomicronemia syndrome. In women the use of estrogens or first pregnancy are also well known trigger factors for initial manifestation of LPLD. At all ages, the most common clinical manifestation is recurrent abdominal pain and acute pancreatitis. The pain may be epigastric, with radiation to the back, or it may be diffuse, with the appearance of an emergent acute abdomen. Other typical symptoms are eruptive xanthomas (in about 50% of patients), lipaemia retinalis and hepatosplenomegaly.

Complications

Patients with LPLD are at high risk of acute pancreatitis, which can be life-threatening, and can lead to chronic pancreatic insufficiency and diabetes.

Diagnosis

Lab tests show massive accumulation of chylomicrons in the plasma and corresponding severe hypertriglyceridemia. Typically, the plasma in a fasting blood sample appears creamy (plasma lactescence).

Familial LPL deficiency should be considered in anyone with severe hypertriglyceridemia and the chylomicronemia syndrome. The absence of secondary causes of severe hypertriglyceridemia (like e.g. diabetes, alcohol, estrogen-, glucocorticoid-, antidepressant- or isotretinoin-therapy, certain antihypertensive agents, and paraproteinemic disorders) increases the possibility of LPL deficiency. In this instance besides LPL also other loss-of-function mutations in genes that regulate catabolism of triglyceride-rich lipoproteins (like e.g. ApoC2, ApoA5, LMF-1, GPIHBP-1 and GPD1) should also be considered

The diagnosis of familial lipoprotein lipase deficiency is finally confirmed by detection of either homozygous or compound heterozygous pathogenic gene variants in LPL with either low or absent lipoprotein lipase enzyme activity.

Lipid measurements

· Milky, lipemic plasma revealing severe hyperchylomicronemia;

· Severely elevated fasting plasma triglycerides (2000 mg/dL);

LPL enzyme

· Low or absent LPL activity in post-heparin plasma;

· LPL mass level reduced or absent in post-heparin plasma;

Molecular genetic testing The LPL gene is located on the short (p) arm of chromosome 8 at position 22. More than 220 mutations in the LPL gene have been found to cause familial lipoprotein lipase deficiency so far.

Treatment

Treatment of LPLD has two different objectives: immediate prevention of pancreatitis attacks and long-term reduction of cardiovascular disease risk.

Olezarsen (Tryngolza) was approved for medical use in the United States in December 2024.

Gene therapy

In 2012, the European Commission approved alipogene tiparvovec (Glybera), a gene therapy for adults with familial LPLD (confirmed by genetic testing) and having severe or multiple pancreatitis attacks despite dietary fat restrictions. It is the first gene therapy to receive marketing authorization in the European Union; it was priced at about $1 million per treatment, and as of 2016, only one person had been treated with it commercially. A total of 31 people were treated with Glybera, most for free in clinical trials before it was taken off the market.

Incidence

The disorder affects about 1 out of 1,000,000 people; however, epidemiological data are limited and there are regional differences due to cofounder effect (e.g. in Canada) or intermarriage.

References

References

1. Santamarina-Fojo, S. (1998). "Familial lipoprotein lipase deficiency.". Endocrinol Metab Clin North Am.
2. James, William D.. (2006). "Andrews' Diseases of the Skin: clinical Dermatology". Saunders Elsevier.
3. Rapini, Ronald P.. (2007). "Dermatology: 2-Volume Set". [[Mosby (publisher).
4. (20 February 1991). "The familial hyperchylomicronemia syndrome. New insights into underlying genetic defects.". JAMA.
5. {{OMIM. 238600. HYPERLIPOPROTEINEMIA, TYPE I, updated 03/18/2004. As of October 2012, mention of type Ia no longer appears in the OMIM record.
6. "Familial lipoprotein lipase deficiency: MedlinePlus Medical Encyclopedia".
7. (June 22, 2017). "GeneReviews". University of Washington.
8. (19 December 2024). "Tryngolza (olezarsen) approved in U.S. as first-ever treatment for adults living with familial chylomicronemia syndrome as an adjunct to diet". Ionis Pharmaceuticals.
9. (May 4, 2016). "The World's Most Expensive Medicine Is a Bust". MIT Technology Review.
10. Crowe, Kelly. (17 November 2018). "The million-dollar drug". CBC (Canadian Broadcasting Corporation).
11. (2011-05-29). "Familial lipoprotein lipase deficiency". [[National Center for Biotechnology Information]].