NORD gratefully acknowledges John JP Kastelein, MD, PhD, Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, for assistance in the preparation of this report.
Familial lipoprotein lipase (LPL) deficiency is a rare genetic metabolic disorder characterized by a deficiency of the enzyme lipoprotein lipase. Deficiency of this enzyme prevents affected individuals from properly digesting certain fats and results in massive accumulation of fatty droplets called chylomicrons in the circulation (chylomicronemia) and consequently also an increase of the plasma concentration of fatty substances called triglycerides. Affected individuals often experience episodes of abdominal pain, acute recurrent inflammation of the pancreas (pancreatitis), abnormal enlargement of the liver and/or spleen (hepatosplenomegaly), and the development of skin lesions known as eruptive xanthomas. Familial LPL deficiency is caused by changes (mutations) in the lipoprotein lipase (LPL) gene and is inherited in an autosomal recessive pattern. Recently, mutations in other genes besides LPL were found to cause a clinical picture similar to LPL deficiency.
Chylomicronemia syndrome is a general term for the symptoms that develop due to the accumulation of chylomicrons in the plasma. There are many causes of chylomicronemia syndrome. The term familial chylomicronemia is sometimes used synonymously with familial lipoprotein lipase deficiency. However, there are different causes of familial chylomicronemia. In the past, familial lipoprotein lipase deficiency has also been called hyperlipoproteinemia type I. Familial LPL deficiency was first described in the medical literature in 1932 by Drs. Burger and Grutz.
Most cases of familial LPL deficiency are identified during childhood, usually before the age of 10. In approximately 25 percent of patients, the disorder is identified during the first year of life. Some affected individuals may not be identified until adulthood. For example, some women may not be diagnosed until after becoming pregnant or when they begin taking contraceptive medication.
The severity of familial LPL deficiency varies depending upon the degree of chylomicronemia, which fluctuates depending upon the amount fat in an individual’s diet. The main symptoms are abdominal pain, pancreatitis, eruptive xanthomas and hepatosplenomegaly.
The most common symptom of familial LPL deficiency is episodic abdominal pain. The severity of abdominal pain can vary, ranging from mild to severe and, in some people, can be incapacitating. The pain may be located in the upper, central region (epigastric area) of the abdomen and can radiate to cause back pain. In some people, the pain may be widespread (diffuse) and can potentially resemble acute abdomen (peritonitis). In the past, this has led to unnecessary surgery.
Abdominal pain in individuals with familial LPL deficiency may result from recurrent episodes of inflammation of the pancreas (pancreatitis). The pancreas is a small gland located behind the stomach. The pancreas secretes enzymes that travel to the intestines to aid in digestion and hormones that have specialized roles in the body. The main symptom of pancreatitis is pain, which is sometimes intense, and is most often felt in the upper left side or middle of the abdomen. Pancreatitis can also cause nausea, sweating, weakness, chills, clammy skin, and mild yellowing of the skin or whites of the eyes (jaundice). Some individuals will develop acute, recurrent pancreatitis, which can potentially be lethal.
Chronic pancreatitis can be associated with additional complications including diabetes, hardening of the pancreas due to the accumulation of calcium salts (pancreatic calcification) and stools containing excess amounts of fat causing them to be frothy, foul smelling and to float (steatorrhea). However, these complications are unusual in individuals with familial LPL deficiency. Even in individuals with recurrent episodes of pancreatitis, such complications rarely develop until middle age. Although rare, pancreatitis in LPL deficiency can cause severe, life-threatening complications.
Enlargement of the liver and spleen (hepatosplenomegaly) can also occur, especially in infants and young children. The degree of enlargement varies, often in conjunction with the amount of fat in the diet. Hepatosplenomegaly is caused by the accumulation of a special type of macrophage. Macrophages are white blood cells that ingest foreign or harmful substances. In familial LPL deficiency, macrophages ingest excess triglyceride and transform into foam cells. Foam cells are specialized macrophages that attempt to deal with excess fat in the body and usually contain fatty materials. Foam cells in individuals with familial LPL deficiency abnormally accumulate in the bone marrow, liver and spleen.
Approximately 50 percent of affected individuals develop eruptive cutaneous xanthomas, which are skin lesions make up of certain fats (lipids). Xanthomas may appear as raised, reddish-yellow bumps or nodules on the skin. They often occur on the buttocks, knees and outer arms. Individuals lesions may measure about 1 millimeter in size, but xanthomas often cluster and may grow together (coalesce) to form larger lesions. Eruptive xanthomas are generally not painful or tender, unless they develop on an area of the body where they suffer repeated trauma or abrasion. Xanthomas usually appear within a few days after triglyceride levels in the plasma have begun to increase. They may contain a greasy, yellowish substance and sometimes a milky fluid. Xanthomas will disappear over a period of weeks to months as the amount of triglyceride in the plasma decreases. The persistent presence of xanthomas in individuals with familial LPL deficiency indicates inadequate therapy to lower triglyceride levels.
In the presence of excessive fatty substances in the circulation the small arteries (arterioles) and small veins (venules) in the outer parts of the retina and the back of the eyeball (fundus) may appear pale pink upon examination by an eye specialist (ophthalmologist). This condition may be referred to as “lipemia retinalis”. The change is related to the degree of fatty build up (i.e., large chylomicrons), which causes incoming light to scatter. This discoloration is reversible and does not affect the vision of individuals with familial LPL deficiency.
Additional symptoms have been reported in some individuals with familial LPL deficiency including a variety of reversible neuropsychiatric findings such as depression, memory loss and dementia.
Some individuals with familial LPL deficiency have developed premature atherosclerosis, which is characterized by thickening and obstruction of various blood vessels due to the accumulation of fatty material, potentially causing coronary heart disease or peripheral vascular disease. However, most researchers do not believe that individuals with familial LPL deficiency have an increased risk of developing atherosclerosis.
Familial LPL deficiency is caused by changes (mutations) in the LPL gene. The LPL gene contains instructions for creating (encoding) an enzyme known as lipoprotein lipase. This enzyme is essential for the proper breakdown of certain fats in the body. Fat is obtained through the diet and is absorbed by the intestines. It is transported in the form of triglyceride by large lipoproteins known as chylomicrons. (Triglycerides are fatty molecules that are used by the cells of the body for fuel.) When chylomicrons are released into the bloodstream, a protein within chylomicrons called apolipoprotein C2 is activated. This protein is recognized by the enzyme lipoprotein lipase, ultimately resulting in the breakdown of triglyceride. When lipoprotein lipase is inadequate or impaired, chylomicrons accumulate in the plasma, which, in turn, causes abnormal amounts of triglyceride to accumulate in the plasma as well. The accumulation of excess.
Familial LPL deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Individuals who inherit one mutated gene and one normal gene (heterozygotes) do not develop familial LPL deficiency. However, these individuals may have a slightly increased risk of developing mixed dyslipidemia with low HDL cholesterol levels. Heterozygotes may also be more susceptible to developing atherosclerosis than non-carriers, especially if they gain weight or remain on a high fat diet.
Familial LPL deficiency affects males and females in equal numbers. It is estimated to occur in approximately 1 in 250,000 people in the general population and has been described in all races. The prevalence is much higher in Quebec, Canada due to a founder effect. A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a particular genetic trait.
A diagnosis of familial LPL deficiency may be suspected based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and certain tests including blood tests.
Clinical Testing and Workup
Blood tests can reveal reduced activity of the lipoprotein lipase enzyme in the plasma, following intravenous administration of heparin. Heparin is a substance normally found in the liver that stimulates the release of lipoprotein lipase in the body.
A diagnosis of familial LPL deficiency can be confirmed by the molecular genetic testing for mutations in the LPL gene. Molecular genetic testing is available through commercial and academic research laboratories.
A proportion of LPL deficient individuals can be successfully treated by dietary restriction of fats, but many are still plagued by recurrent abdominal pain and episodes of acute pancreatitis. The goal of restricting fat intake is to reduce chylomicronemia and hypertriglyceridemia enough to prevent symptoms. Many individuals learn on their own to avoid foods containing fat. However, many physicians recommend reducing fat intake significantly to no more than 20 g/day or 15 percent of total energy intake in order to prevent symptoms.
Drugs that lower lipid levels in the body are not effective in reducing fat levels in individuals with familial LPL deficiency. Alcohol and drugs that increase triglyceride levels should be avoided. Such drugs include oral contraceptives, diuretics, beta-adrenergic blocking agents, isotretinoin and Zoloft®.
Medium chain fatty acids can be used for cooking because they are absorbed directly by the portal vein of the liver. Many individuals have been successfully treated with a diet rich in medium chain fatty acids. Fish oil supplements are not effective for individuals with familial LPL deficiency and are contraindicated.
An enlarged liver or spleen will usually shrink to normal size within one week of reducing triglyceride levels. Eruptive xanthomas usually clear up within several weeks to months. If xanthomas persist or recur despite treatment, it indicates inadequate therapeutic efforts.
Pancreatitis is treated following standard guidelines.
Genetic counseling is recommended for affected individuals and their families.
In 2012, the European Commission approved the marketing authorization of alipogene tiparvovec gene therapy (Glybera®) developed UniQure for the treatment of individuals with familial LPL deficiency. Glybera was the first approved gene therapy in the Western world but was never approved in the US. In 2017, Glybera was taken off the market by UniQure due to low demand from the patient community.
The Foundation of the National Lipid Association has established a patient registry for individuals who have rare conditions that involve high levels of triglycerides. More information is available in the following link:
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact:
For information about clinical trials conducted in Europe, contact:
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
Davidson MH, Toth PP, Maki KC. Familial lipoprotein lipase deficiency. Therapeutic Lipidology. Humana Press. Totowa, NJ. 2007:465-466.
Demacker PNM, Stalenhoef AFH. Familial lipoprotein lipase deficiency. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:465-466.
Brunzell JD, Deeb SS. Familial lipoprotein lipase deficiency, apo CII deficiency and hepatic lipase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease, 8th ed. McGraw-Hill, New York, 2001:2789-2816.
Gaudet D, Methot J, Kastelein J. Gene therapy for lipoprotein lipase deficiency. Curr Opin Lipidol. 2012;23:310-320. http://www.ncbi.nlm.nih.gov/pubmed/22691709
Gaudet D, Methot J, Dery S, et al Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPL[S447X]) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther. 2012;[Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/22717743
Gaudet D, de Wal J, Tremblay K, et al. Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency. Atheroscler Suppl. 2010;11:55-60. http://www.ncbi.nlm.nih.gov/pubmed/20427244
Stroes ES, Nierman MC, Meulenberg JJ, et al. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler Thromb Vasc Biol. 2008;28:2303-2304. http://www.ncbi.nlm.nih.gov/pubmed/18802015
Kawashiri MA, Higashikata T, Mizuno M, et al. Long-term course of lipoprotein lipase (LPL) deficiency due to homozygous LPL(Arita) in a patient with recurrent pancreatitis, retained glucose tolerance, and atherosclerosis. J Clin Endocrinol Metab. 2005;90:6541-6544. http://www.ncbi.nlm.nih.gov/pubmed/16174715
Nieman MC, Twisk RJ, Meulenberg JJ, et al. Gene therapy for genetic lipoprotein lipase deficiency: from promise to practice. Neth J Med. 2005;63:14-19. http://www.ncbi.nlm.nih.gov/pubmed/16259561
Wilson DE, Emi M, Iverius PH, et al. Phenotypic expression of heterozygous lipoprotein lipase deficiency in the extended pedigree of a proband homozygous for a missense mutation. J Clin Invest. 1990;86:735-750. http://www.ncbi.nlm.nih.gov/pubmed/2394828
Emi M, Hata A, Robertson M, et al. Lipoprotein lipase deficiency resulting from a nonsense mutation in exon 3 of the lipoprotein lipase gene. Am J Hum Genet. 1990;47:107-111. http://www.ncbi.nlm.nih.gov/pubmed/2349938
Burnett JR, Hooper AJ, Hegele RA. Familial Lipoprotein Lipase Deficiency. 1999 Oct 12 [Updated 2017 Jun 22]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1308/ Accessed May 30, 2019.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:238600; Last Update: 07/09/2016. Available at: http://omim.org/entry/238600 Accessed May 30, 2019.
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