Lipoprotein lipase deficiency
|Lipoprotein lipase deficiency|
|Lipoprotein lipase deficiency is inherited via autosomal recessive manner|
Lipoprotein lipase deficiency (also known as "familial chylomicronemia syndrome", "chylomicronemia", "chylomicronemia syndrome" and "hyperlipoproteinemia type Ia") is a rare autosomal recessive lipid disorder caused by a mutation in the gene which codes lipoprotein lipase.:533 As a result, afflicted individuals lack the ability to produce lipoprotein lipase enzymes necessary for effective breakdown of triglycerides.
Signs and symptoms
Laboratory changes: massive accumulation of chylomicrons in the plasma and corresponding severe hypertriglyceridemia. Typically, the plasma in a fasting blood sample appears creamy (plasma lactescence).
Clinical 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), lipemia retinalis and hepatosplenomegaly.
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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.
· Milky, lipemic plasma revealing severe hyperchylomicronemia;
· Severely elevated fasting plasma triglycerides (>2000 mg/dL);
· 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 of LPLD has two different objectives: immediate prevention of pancreatitis attacks and long term reduction of cardiovascular disease risk. Treatment is mainly based on medical nutrition therapy to maintain plasma triglyceride concentration below 11,3 mmol/L (1000 mg/dL). Maintenance of triglyceride levels below 22,6 mmol/L (2000 mg/dL) prevents in general from recurrent abdominal pain.
Strict low fat diet and avoidance of simple carbohydrates
Restriction of dietary fat to not more than 20 g/day or 15% of the total energy intake is usually sufficient to reduce plasma triglyceride concentration, although many patients report that to be symptom free a limit of less than 10g/day is optimal. Simple carbohydrates should be avoided as well. Medium-chain triglycerides can be used for cooking, because they are absorbed into the portal vein without becoming incorporated into chylomicrons. Fat-soluble vitamins A, D, E, and K, and minerals should be supplemented in patients with recurrent pancreatitis since they often have deficiencies as a result of malabsorption of fat. However, the diet approach is difficult to sustain for many of the patients.
Lipid lowering drugs
Lipid-lowering agents such as fibrates and omega-3-fatty acids can be used to lower TG levels in LPLD, however those drugs are very often not effective enough to reach treatment goals in LPLD patients. Statins should be considered to lower elevated non-HDL-Cholesterol.
Additional measures are avoidance of agents known to increase endogenous triglyceride levels, such as alcohol, estrogens, diuretics, isotretinoin, anidepressants (e.g. sertraline) and b-adrenergic blocking agents.
In 2012, the European Commission approved alipogene tiparvovec (Glybera), a gene therapy for adults diagnosed with familial LPLD (confirmed by genetic testing) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. It was the first gene therapy to receive marketing authorization in Europe; it was priced at about $1 million per treatment, and as of 2016, only one person had been treated with it.
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.
Society and culture
In October 2012, a patient with LPLD together with RareConnect launched an international online patient community for Lipoprotein Lipase Deficiency, subsequently supported by 3 officially recognised patient groups (Heart UK, CholCo & Association Pancréatites Chroniques). The LPLD Community can be found on the RareConnect.org platform.
- Santamarina-Fojo, S (1998). "Familial lipoprotein lipase deficiency". Endocrinol Metab Clin North Am. 27 (3): 551–567. PMID 9785052.
- James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. OCLC 62736861.
- Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. OCLC 212399895.
- Online Mendelian Inheritance in Man (OMIM) HYPERLIPOPROTEINEMIA, TYPE I -238600, updated 03/18/2004. As of October 2012, mention of type Ia no longer appears in the OMIM record.
- Regalado, Antonio (May 4, 2016). "The World's Most Expensive Medicine Is a Bust". MIT Technology Review.
- A.D.A.M. Editorial Board (2011-05-29). Dugdale, III, David C.; Zieve, David, eds. Familial lipoprotein lipase deficiency. A.D.A.M. Medical Encyclopedia. National Center for Biotechnology Information (published May 29, 2011). Retrieved October 15, 2012
- Gaudet D, de Wal J, Tremblay K, Déry S, van Deventer S, Freidig A, Brisson D, Méthot J. Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency. Atheroscler Suppl. 2010;11(1):55-60.
- Bruno MJ. Gene Therapy Coming of Age – Prevention of acute pancreatitis in lipoprotein lipase deficiency through alipogene tiparvovec. Eur Gastroenterol & Hepatol Rev. 2010; 48-53.
- Brunzell JD “Familial Lipoprotein Lipase Deficiency” in GeneReviews® [Internet]. Initial Posting: October 12, 1999; Last Update: April 24, 2014. https://www.ncbi.nlm.nih.gov/books/NBK1308/
- Genetic Home Reference – a service of the US Library of Medicine accessible via http://ghr.nlm.nih.gov/gene/LPL;
- Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard BG, Kuivenhoven JA, Averna M, Borén J, Bruckert E, Catapano AL, Descamps OS, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Raal FJ, Ray KK, Santos RD, Stalenhoef AF, Stroes E, Taskinen MR, Tybjærg-Hansen A, Watts GF, Wiklund O; European Atherosclerosis Society Consensus Panel. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014 Aug;2(8):655-66. PMID 24731657;
- Brunzell JD, Deeb SS “Familial Lipoprotein Lipase Deficiency, Apo C-II Deficiency, and Hepatic Lipase Deficiency” Chapter 117, The Online Metabolic & Molecular Bases of Inherited Disease. DOI:10.1036/ommbid.145 http://ommbid.mhmedical.com/content.aspx?sectionid=62637184&bookid=971&Resultclick=2&q=Lipoprotein+Lipase+Deficiency
- Glybera (alipogene tiparvovec). Summary of Product Characteristics. uniQure biopharma B.V. Amsterdam, The Netherlands. Accessed at: http://www.ema.europa.eu/. April 2015.
- Carpentier AC, Frisch F, Labbé SM, Gagnon R, de Wal J, Greentree S, Petry H, Twisk J, Brisson D, Gaudet D. Effect of alipogene tiparvovec (AAV1-LPL(S447X)) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J Clin Endocrinol Metab. 2012 May;97(5):1635-44.
- Gaudet D, Méthot J, Kastelein J. Gene therapy for lipoprotein lipase deficiency. Curr Opin Lipidol. 2012;23(4):310-20.
- Gaudet D, Méthot J, Déry S, Brisson D, Essiembre C, Tremblay G, Tremblay K, de Wal J, Twisk J, van den Bulk N, Sier-Ferreira V, van Deventer S. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther. 2013;20(4):361-9.
- Gaudet D, Stroes E, Bruno M, Andersen M, Petry H, Meyer C. Gene therapy with alipogene tiparvovec (Glybera®) for the prevention of LPLD induced pancreatitis: Follow-up data suggests long-term clinical benefit. Atherosclerosis. 2014; 235(2):e13.
- E. Steinhagen-Thiessen, E. Stroes, H. Soran, C. Johnson, P. Moulin, G. Iotti, M. Zibellini, B. Ossenkoppele, M. Dippel, M.R. Averna on behalf of the GENIALL Investigators: First global, longitudinal, pharmaco-epidemiologic, observational registry on GENe therapy In the ManAgement of Lipoprotein Lipase Deficiency (GENIALL); Atherosclerosis 2015; Volume 241, Issue 1, Abstract # 0854 presented as Poster at EAS Congress 2015 in Glasgow