Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
[Familial LPL deficiency, Type I Hyperlipoproteinemia]
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Author:
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John D Brunzell, MD
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Initial Posting:
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Last Revision:
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Disease characteristics. Familial lipoprotein lipase (LPL) deficiency usually presents in childhood and is characterized by hypertriglyceridemia with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Clearance of chylomicrons from the plasma is impaired, causing triglycerides to accumulate in plasma and the plasma to have a milky ("lactescent" or "lipemic") appearance. Symptoms resolve with restriction of dietary fat to 20 grams/day or less.
Diagnosis/testing. Familial LPL deficiency is caused by very low or absent activity of LPL encoded by the gene LPL. The diagnosis of familial LPL deficiency is based on the assay of LPL enzyme activity in plasma following intravenous administration of heparin. Detection of very low or absent LPL enzyme activity in an assay system that contains either normal plasma or apoprotein C-II and excludes hepatic lipase is diagnostic of familial LPL deficiency. Molecular genetic testing of LPL is available on a clinical basis.
Management. Treatment is based on medical nutrition therapy to maintain plasma triglyceride concentration at less than 2000 mg/dL. Restriction of dietary fat to no more than 20 g/day or 15% of a total energy intake is usually sufficient to reduce plasma triglyceride concentration and to keep the individual with familial LPL deficiency free of symptoms. Pancreatitis is treated with standard care. Surveillance includes monitoring of plasma triglycerides. Avoidance of agents known to increase endogenous triglyceride concentration such as alcohol, oral estrogens, diuretics, isotretinoin, Zoloft®, and beta-adrenergic blocking agents is recommended.
Genetic counseling. Familial lipoprotein lipase deficiency is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing is available on a clinical basis once the LPL mutations have been identified in the proband. Prenatal testing is available on a limited basis.
Familial lipoprotein lipase deficiency is suspected in individuals with:
Affected individuals
Chylomicrons are large lipoprotein particles that appear in the circulation shortly after the ingestion of dietary fat; normally, they are cleared from plasma after an overnight fast. In familial LPL deficiency, clearance of chylomicrons from the plasma is impaired, causing triglycerides to accumulate in plasma and the plasma to have a milky ("lactescent" or "lipemic") appearance. Plasma triglyceride levels in the presence of chylomicrons can be estimated fairly accurately by visual inspection. It is important to measure the plasma triglyceride concentration once as a baseline.
Plasma triglyceride concentrations
Carriers. Heterozygotes have normal or only slightly elevated plasma lipid concentrations.
Affected individuals. The diagnosis of familial lipoprotein lipase deficiency is based on detection of low or absent LPL enzyme activity in an assay system that contains either normal plasma or apoprotein C-II (a cofactor of LPL) and excludes hepatic lipase (HL).
Carriers. Heterozygotes exhibit a 50% decrease of LPL enzyme activity in plasma following intravenous administration of heparin.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.
Gene. LPL is the only gene associated with familial lipoprotein lipase deficiency.
Clinical uses
Carrier detection. Molecular genetic testing is used primarily for genetic counseling purposes for those individuals in whom the diagnosis is confirmed by biochemical testing.
Clinical testing
Table 1
summarizes molecular genetic testing for this disorder.
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1. Percent of alleles in individuals confirmed by biochemical testing to have familial LPL deficiency
2. Brunzell & Deeb 2001 , Gilbert et al 2001 |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Persistant severe hypertriglyceridemia (1000-2000 mg/dL) in an infant or child that is responsive to dietary fat intake is indicative of LPL deficiency. When LPL deficiency is first suspected, a history of failure to thrive as an infant or recurrent abdominal pain as a child should be sought. A fasting plasma triglyceride concentration should be obtained at lease once for documentation.
Neither measurement of plasma post-heparin LPL enzyme activity nor, in particular, LPL molecular genetic testing is required to make a presumptive clinical diagnosis.
No other phenotypes are associated with mutations in LPL.
Familial lipoprotein lipase deficiency usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Males and females affected equally.
About 25% of affected individuals develop symptoms before the age of one year and the majority develops symptoms before the age of ten years; however, some individuals present for the first time during pregnancy. The severity of symptoms correlates with the degree of chylomicronemia, which varies by dietary fat intake.
The abdominal pain can vary from mildly bothersome to incapacitating. It is usually mid-epigastric with radiation to the back. It may be diffuse and mimic an acute abdomen, often leading to unnecessary abdominal exploratory surgery. The pain may result from chylomicronemia leading to pancreatitis.
Kawashiri et al (2005) reported that individuals with LPL deficiency can lead a fairly normal life on a diet very low in total fat content. The secondary complications of pancreatitis — diabetes mellitus, steatorrhea, and pancreatic calcification — are unusual in familial lipoprotein lipase deficiency and rarely occur before middle age. Pancreatitis may rarely be associated with total pancreatic necrosis and death.
About 50% of individuals with familial LPL deficiency have eruptive xanthomas, small yellow papules localized over the trunk, buttocks, knees, and extensor surfaces of the arms. They may become generalized. As a single lesion, they may be several millimeters in diameter; rarely, they may coalesce into plaques. They are usually not tender unless they occur at a site susceptible to repeated trauma. Xanthomas are deposits of lipid in the skin that result from the extravascular phagocytosis of chylomicrons by macrophages. They can appear rapidly when plasma triglyceride concentration exceeds 2000 mg/dL.
Hepatomegaly and splenomegaly often occur when plasma triglyceride levels are markedly increased. The organomegaly results from triglyceride uptake by macrophages, which become foam cells.
With triglyceride concentrations above 4000 mg/dL, the retinal arterioles and venules, and often the fundus itself, develop a pale pink color ("lipemia retinalis"), caused by light scattering by large chylomicrons. This coloration is reversible and vision is not affected.
Neuropsychiatric findings, including mild dementia, depression, and memory loss, have also been reported with chylomicronemia [Chait et al 1981].
Mild lipid abnormalities not associated with familial LPL deficiency have been reported with common variants of the LPL gene, such as the p.Asn291Ser allele [Hokanson 1997]. The p.Asn291Ser allele does not seem to have a major effect on plasma lipid concentration or on risk for coronary disease in the general population; however, it may be associated with hypertriglyceridemia in the presence of apoE2, diabetes mellitus [Knudsen et al 1997], familial combined hyperlipidemia [de Bruin et al 1996 , Hoffer et al 1996], hepatic lipase deficiency, and glycogen storage disease type Ib . It is possible that the association of the p.Asn291Ser allele with these disorders is only a reflection of the relatively high frequency of this allele in the general population.
There are no known genotype-phenotype correlations.
Familial LPL deficiency was previously included in the term "type 1 hyperlipoproteinemia."
The prevalence of familial LPL deficiency is approximately one per 1,000,000 in the general population.
The disease has been described in all races. The prevalence is much higher in some areas of Quebec, Canada, as a result of a founder effect [Bergeron et al 1992].
Consanguinity is often observed in families with familial LPL deficiency.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Familial LPL deficiency should be considered in young individuals with the chylomicronemia syndrome, defined as abdominal pain, eruptive xanthomata, and plasma triglyceride concentrations greater than 2000 mg/dL. However, the majority of individuals with chylomicronemia and plasma triglyceride concentration greater than 2000 mg/dL do not have familial LPL deficiency; rather, they have one of the more common genetic disorders of triglyceride metabolism (i.e., familial combined hyperlipidemia and monogenic familial hypertriglyceridemia) occurring simultaneously with, and independently of, a common, acquired, secondary form of hypertriglyceridemia [Brunzell & Deeb 2001].
Secondary causes of hypertriglyceridemia are diabetes mellitus, paraproteinemic disorders, use of alcohol, and therapy with estrogen, glucocorticoids, Zoloft®, isotretinoin, and certain antihypertensive agents. In one series of 123 individuals evaluated for marked hypertriglyceridemia [Chait & Brunzell 1983], 110 had an acquired cause of hypertriglyceridemia combined with a common genetic form of hypertriglyceridemia, five had familial LPL deficiency, five had other rare genetic forms of hypertriglyceridemia, and three had an unknown cause.
Familial apolipoprotein C-II deficiency and familial apoAV deficiency can present with chylomicronemia with severe hypertriglyceridemia.
Familial apolipoprotein C-II deficiency. Apolipoprotein C-II is a cofactor for lipoprotein lipase. Familial apolipoprotein C-II deficiency is an extremely rare autosomal recessive disorder that differs from familial LPL deficiency in that (1) symptoms generally develop at a later age (13-60 years) and (2) individuals may develop chronic pancreatic insufficiency with steatorrhea and insulin-dependent diabetes mellitus. The diagnosis is based on assay of plasma apo C-II concentration or activation of a purified LPL standard and on gel electrophoresis of VLDL apolipoproteins. Infusion of normal plasma into an individual with familial apolipoprotein C-II deficiency results in dramatic reduction of the plasma triglyceride level. Treatment is a low-fat diet throughout life.
Familial apoAV deficiency. It has been suggested that apoAV facilitates the interaction of apoCII with heparan sulfate on triglyceride-rich lipoproteins and the interaction of apoCII with LPL on the vascular endothelium. Several families with apoAV deficiency have been reported to have severe hypertriglyceridemia [Marcais et al 2005]; this observation needs to be confirmed.
To establish the extent of disease in an individual diagnosed with familial lipoprotein lipase (LPL) deficiency, plasma triglyceride concentration should be measured.
Medical nutrition therapy. Morbidity and mortality can be reduced by maintaining plasma triglyceride concentration at less than 2000 mg/dL. Restriction of dietary fat to no more than 20 g/day or 15% of total energy intake is usually sufficient to reduce plasma triglyceride concentration and to keep the individual with familial LPL deficiency free of symptoms.
Medium-chain triglycerides can be used for cooking, as they are absorbed directly into the portal vein without becoming incorporated into chylomicron triglyceride.
The success of therapy depends on the individual's acceptance of the fat restriction, including both unsaturated and saturated fat.
The enlarged liver and spleen can return to normal size within one week of lowering of triglyceride concentrations.
The xanthomas can clear over the course of weeks to months. Recurrent or persistent eruptive xanthomas indicate inadequate therapy.
Pancreatitis associated with the chylomicronemia syndrome is treated in the manner typical for other forms of pancreatitis.
If recurrent pancreatitis with severe hypertriglyceridemia occurs, total dietary fat intake needs to be reduced.
Medical nutrition therapy. Maintaining the plasma triglyceride concentration at less than 2000 mg/dL keeps the individual with familial LPL deficiency free of symptoms. This can be accomplished by restriction of dietary fat to no more than 20 g/day or 15% of total energy intake.
During pregnancy in a woman with LPL deficiency, extreme dietary fat restriction to less than two grams per day during the second and third trimester with close monitoring of plasma triglyceride concentration can result in delivery of a normal infant with normal plasma concentrations of essential fatty acids [Al-Shali et al 2002].
One woman with LPL deficiency delivered a normal child following a one-gram fat diet and treatment with gemfibrozil (600 mg twice a day) [Tsai et al 2004]. Despite concerns about the possibility of essential fatty acid deficiency in the newborn, normal essential fatty acids were found in cord blood, as were normal levels of fibrate metabolites.
Plasma triglyceride levels can be followed over time.
Affected individuals who develop abdominal pain need to contact their physician.
Avoidance of agents known to increase endogenous triglyceride concentration such as alcohol, oral estrogens, diuretics, isotretinoin, Zoloft®, and beta-adrenergic blocking agents is recommended.
It is appropriate to measure the plasma triglyceride concentration of at-risk sibs during infancy; early diagnosis and implementation of dietary fat intake restriction can prevent symptoms and related medical complications.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Investigations underway are aimed at determining the feasibility of gene replacement therapy [Excoffon et al 1997 , Zsigmond et al 1997 , Nierman et al 2005]. Such studies are strictly experimental at this time.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
The lipid-lowering drugs that are used to treat other disorders of lipid metabolism are not effective in children with familial LPL deficiency.
Although plasmaphoresis, incorporation of omega-3 fatty acids into the diet, and antioxidant therapy have been suggested as treatment for pancreatitis, they do not seem to be indicated.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.
Familial LPL deficiency is inherited in an autosomal recessive manner.
Parents of a proband
Sibs of a proband
Offspring of a proband. The offspring of an individual with familial lipoprotein lipase deficiency are obligate heterozygotes (carriers) for a disease-causing mutation in the LPL gene.
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing is available on a clinical basis once the LPL mutations have been identified in the proband.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for conditions such as familial lipoprotein lipase deficiency that do not affect intellect and have effective treatment available are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion is appropriate. In practice, prenatal testing is rarely requested because of the availability of effective treatment.
Preimplantation genetic diagnosis (PGD)
may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.
Gene Symbol | Chromosomal Locus | Protein Name |
LPL | 8p22 | Lipoprotein lipase |
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Data are compiled from the following standard references: Gene symbol from HUGO;
chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
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Gene Symbol | HGMD |
LPL |
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For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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Normal allelic variants: The LPL gene is 30 kb in length and contains ten exons, from which two mRNAs are transcribed due to alternative sites of polyadenylation. The vertebrate family of lipase genes includes lipoprotein lipase (LPL), hepatic lipase (HL), endothelial lipase (EL), and pancreatic lipase (PL). These lipase genes have similar exon/intron boundaries and the encoded proteins have significant amino acid sequence similarity. The sequence of LPL is highly conserved among mammalian species.
Pathologic allelic variants:
Over 220 disease-causing mutations have been identified [Brunzell & Deeb 2001
, Gilbert et al 2001]. Approximately 70% are missense, 10% nonsense, 18% gene rearrangements, and 2% unknown. At least 28 missense mutations associated with markedly reduced or absent LPL activity have been described. Five single base-pair substitutions causing stop codons have been noted. One involves residue 447 and may be associated with elevated LPL activity. In addition to the original individual with two major gene rearrangements, a 3-kb deletion involving exon 9 and four smaller insertion-deletion defects have been noted. An acceptor splice site defect and a donor splice site defect, both involving intron 2, have been reported. To date, very few
LPL mutant alleles from studied individuals with classic familial lipoprotein lipase deficiency remain uncharacterized.
The insertion-deletion mutations, the splice site defects, and the nonsense mutations presumably lead to absent or truncated LPL protein with defective catalytic activity. Most of the mutations are in the highly conserved central homology region [Brunzell & Deeb 2001
, Gilbert et al 2001], involving
LPL exons 4, 5, and 6. The two mutations at residue 156 involve aspartic acid of the catalytic triad. Many of the mutations change hydrophobic residues to ones that are less so, particularly those involving residues 142, 157, 176, 188, 194, 205, and 225. Some are part of beta-sheet strands (residues 154, 204, 205, and 207) and some involve alpha-helical structures (residues 136, 139, 142, 243, 244, 250, and 251). In addition to the structural mutations, regulatory variants of the
LPL promoter have been identified [Yang et al 1996
, Ehrenborg et al 1997].
Normal gene product: Lipoprotein lipase is a glycoprotein that is synthesized in adipose tissue and cardiac and skeletal muscle, but not in the postpartum liver. It is transported to the luminal surface of the capillary endothelium of extrahepatic tissues. It is essential for hydrolysis of chylomicron and VLDL triglycerides to provide free fatty acids to tissue for energy production. LPL has two major domains: a larger NH2-terminal domain linked by a short region to a COOH-terminal domain of approximately half its size. The globular NH2-terminal domain, which contains the catalytic triad, specifies the catalytic properties of the lipase, whereas the COOH-terminal domain specifies substrate specificity and heparin-binding properties. The protein is 448 amino acids.
Abnormal gene product: In individuals with missense mutations, catalytically inactive protein can sometimes be found in post-heparin plasma. However, since the defective protein is unstable, protein mass is usually absent and LPL activity is deficient [Peterson et al 2002].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.
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No specific guidelines regarding genetic testing for this disorder have been developed.
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