Lipoprotein lipase deficiency

Lipoprotein lipase deficiency
Classification and external resources
Specialty
ICD-10	E78
OMIM	238600
DiseasesDB	4697
MedlinePlus	000408
Patient UK	Lipoprotein lipase deficiency
MeSH	D008072
GeneReviews	Familial Lipoprotein Lipase Deficiency

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. As a result, afflicted individuals lack the ability to produce lipoprotein lipase enzymes necessary for effective breakdown of fatty acids.

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.

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.

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.

Diagnosis

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. 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.

Genetherapy

In 2012, the European Commission approved Glybera (alipogene tiparvovec) for adult patients diagnosed with familial LPLD (confirmed by genetic testing) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions,

It addresses the underlying genetic cause of the disease by introducing a LPL gain-of-function allele delivered by an adeno-associated virus type vector. Clinical experience has shown a long term expression of LPL-protein in injected muscles, improved postprandial chylomicron metabolism, and a decreased incidence and severity of pancreatitis attacks.

Glybera is the first gene therapy to receive marketing authorization in Europe (2012). It was developed by uniQure biopharma B.V. and is marketed in Europe and in other specific countries by Chiesi Farmaceutici S.p.A. since April 2013. The first patient has been treated with commercially available Glybera at the Charité in Berlin (Germany) in September 2015.

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.^[8]

See also

• Primary hyperlipoproteinemia
• Familial apoprotein CII deficiency
• List of cutaneous conditions

References

[http://]

Sources

1. 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.
2. 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.
3. Brunzell JD “Familial Lipoprotein Lipase Deficiency” in GeneReviews® [Internet]. Initial Posting: October 12, 1999; Last Update: April 24, 2014. http://www.ncbi.nlm.nih.gov/books/NBK1308/
4. Genetic Home Reference – a service of the US Library of Medicine accessible via http://ghr.nlm.nih.gov/gene/LPL;
5. 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;
6. 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
7. Glybera (alipogene tiparvovec). Summary of Product Characteristics. uniQure biopharma B.V. Amsterdam, The Netherlands. Accessed at: http://www.ema.europa.eu/. April 2015.
8. 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.
9. Gaudet D, Méthot J, Kastelein J. Gene therapy for lipoprotein lipase deficiency. Curr Opin Lipidol. 2012;23(4):310-20.
10. 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.
11. 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.
12. www.encepp.eu
13. www.clinicaltrial.gov
14. 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

External links

• Familial Chylomicronemia Syndrome is an online educational initiative to provide clinicians with peer reviewed information on how to diagnose and treat patients with familial chylomicronemia syndrome (FCS) [also known as hyperlipoproteinemia type 1 or lipoprotein lipase deficiency].
• LPLD Community is an online community for people living with lipoprotein lipase deficiency or their loved ones].
• LPLD Alliance is a patient-led charity registered in England and Wales for patients with LPLD and related conditions.