Diagnosis Clinical DiagnosisFamilial lipoprotein lipase (LPL) deficiency is suspected in individuals with the following:Childhood-onset very severe hypertriglyceridemia (>2000 mg/dL) with episodic abdominal pain Recurrent acute pancreatitis Eruptive cutaneous xanthomata Hepatosplenomegaly TestingChylomicronemia / plasma triglyceride concentrationAffected 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 concentrations In the presence of chylomicrons plasma triglyceride concentrations can be estimated fairly accurately by visual inspection. Plasma triglyceride concentrations are usually greater than 2000 mg/dL in the untreated state. It is important to measure the plasma triglyceride concentration once as a baseline. Routine measurement of non-fasting plasma triglyceride concentration can be used when fasting samples are difficult to obtain (e.g., in infants). Plasma triglyceride concentration is an excellent measure of compliance with dietary fat restrictions. Carriers. Heterozygotes have normal to moderately elevated plasma triglyceride concentrations. Measurement of lipoprotein lipase enzyme activityAffected individuals. The diagnosis of familial lipoprotein lipase deficiency is confirmed by 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). LPL enzyme activity can be assayed in plasma ten minutes following intravenous administration of heparin (60 U/kg body wt). The absence of lipoprotein lipase enzyme activity in postheparin plasma is diagnostic of familial LPL deficiency. LPL enzyme activity may be assayed directly in biopsies of adipose tissue. LPL enzyme activity can be measured in selected children and young adults. For more information, contact the author at brunzell/at/u.washington.edu/*/*]]>*/.Carriers. Heterozygotes exhibit a 50% decrease of LPL enzyme activity in plasma following intravenous administration of heparin. Molecular Genetic TestingGene. LPL is the only gene in which mutations are known to cause familial lipoprotein lipase deficiency. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Familial Lipoprotein Lipase Deficiency View in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityLPLSequence analysisSequence variants 2 (including p.Gly188Glu 3)~97% 4Clinical Deletion / duplication analysis 5Partial- and whole-gene deletions and duplications~3% 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. The mutation p.Gly188Glu, common in Europe, is present in fewer than 40% of individuals with LPL deficiency.4. Brunzell & Deeb [2001], Gilbert et al [2001]5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. 6. Brunzell & Deeb [2001]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. Persistent 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 least once for documentation. Note: Neither measurement of post-heparin plasma LPL enzyme activity nor LPL molecular genetic testing is required to make a presumptive clinical diagnosis. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in LPL.Mild lipid abnormalities not associated with familial LPL deficiency have been reported with common variants of LPL, such as the p.Asn291Ser allele. 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, familial combined hyperlipidemia, 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.}

Natural HistoryFamilial lipoprotein lipase (LPL) deficiency usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Males and females are affected equally. Approximately 25% of affected children develop symptoms before age one year and the majority develop symptoms before age 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, which can vary from mildly bothersome to incapacitating, 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 probably results 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 individuals with familial LPL deficiency and rarely occur before middle age. Pancreatitis in LPL deficiency 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. 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.Xanthomas 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 abrasion. Hepatomegaly and splenomegaly often occur when plasma triglyceride concentrations are markedly increased. The organomegaly results from triglyceride uptake by macrophages, which become foam cells.When triglyceride concentrations exceed 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.Reversible neuropsychiatric findings, including mild dementia, depression, and memory loss, have also been reported with chylomicronemia.

Genotype-Phenotype CorrelationsThere are no known genotype-phenotype correlations.

Differential DiagnosisFamilial LPL deficiency should be considered in young persons 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, 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.Other extremely rare genetic disorders can present with chylomicronemia with severe hypertriglyceridemia [Brunzell & Deeb 2001, Deeb & Brunzell 2009]. Compared to LPL deficiency, apoCIII deficiency, LMF1 deficiency and GPIHBP1 deficiency are very rare, as are deletions and duplications in APOA5, which encodes apo5.Familial apolipoprotein C-II (apoC-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 concentration. Treatment is a low-fat diet throughout life. Apolipoprotein C-II is encoded by APOA2C.Familial lipase maturation factor 1 (LMF1) deficiency. LMF1 is a transmembrane protein localized to the endoplasmic reticulum involved in the maturation of both LPL and hepatic lipase. One patient, homozygous for a deleterious mutation, has very low LPL activity, modestly low hepatic lipase activity, and chylomicronemia [Péterfy et al 2007].Familial glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) deficiency. GPIHBP1 appears to be a binding site for LPL on the capillary endothelial surface, perhaps through binding with apoAV [Beigneux et al 2007]. Several individuals with GPIHBP1 deficiency have been described. Familial apolipoprotein A-V (apoA5) deficiency. It has been suggested that apoA5 facilitates the interaction of endothelial heparan sulfate with apoCII on triglyceride-rich lipoproteins and the interaction of apoCII with LPL on the vascular endothelium. Several families with apoA5 deficiency have been reported to have severe hypertriglyceridemia. These defects may be more prevalent among Asians [Pullinger et al 2008].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Affected individualsHeterozygotes

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with familial lipoprotein lipase (LPL) deficiency, measurement of plasma triglyceride concentration is recommended.Treatment of ManifestationsMedical nutrition therapy. Morbidity and mortality can be prevented by maintaining plasma triglyceride concentration at less than 2000 mg/dL. A good clinical goal is less than 1000 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 may 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. Note: Fish oil supplements, which are effective in disorders of excess hepatic triglyceride production, are not effective in LPL deficiency and are contraindicated.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. Discontinuation of oral intake stops chylomicron triglyceride formation, and replacement with hypocaloric parenteral nutrition decreases VLDL triglyceride production. Administration of excess calories, as in hyperalimentation, is contraindicated in the acute state. The intravenous administration of lipid emulsions may lead to persistent or recurrent pancreatitis. If recurrent pancreatitis with severe hypertriglyceridemia occurs, total dietary fat intake needs to be reduced.Prevention of Primary ManifestationsMedical 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. Prevention of Secondary ComplicationsPrevention of acute recurrent pancreatitis decreases the risk of development of diabetes mellitus. Fat malabsorption is very rare.SurveillancePlasma triglyceride levels need to be followed over time to evaluate the patient’s success in following the very low-fat dietary recommendations. When the triglyceride level is above 1000 mg/dL, the sample does not need to be fasting for this evaluation. Other components of the lipid profile do not need to be routinely measured.Affected individuals who develop abdominal pain need to contact their physician. Agents/Circumstances to AvoidAvoidance of agents known to increase endogenous triglyceride concentration such as alcohol, oral estrogens, diuretics, isotretinoin, glucocorticoids, Zoloft^®, and beta-adrenergic blocking agents is recommended.Fish oil supplements are contraindicated as they contribute to chylomicron levels.Evaluation of Relatives at RiskIt is appropriate to measure plasma triglyceride concentration in 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 evaluation of at-risk relatives for genetic counseling purposes.Pregnancy ManagementDuring 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 1x/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. Therapies Under InvestigationInvestigations aimed at determining the feasibility of gene replacement therapy are underway [Nierman et al 2005]. Such studies remain strictly experimental at this time. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherThe lipid-lowering drugs that are used to treat other disorders of lipid metabolism are not effective in individuals with familial LPL deficiency.Although plasmapheresis and antioxidant therapy have been suggested as treatment for pancreatitis, they do not seem to be needed for either acute therapy or long-term care.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Lipoprotein Lipase Deficiency, Familial: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDLPL8p21​.3Lipoprotein lipaseLPL homepage - Mendelian genesLPLData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Lipoprotein Lipase Deficiency, Familial (View All in OMIM) View in own window 238600HYPERLIPOPROTEINEMIA, TYPE I 609708LIPOPROTEIN LIPASE; LPLNormal allelic variants. LPL is 30 kb in length and contains ten exons, from which two mRNAs are transcribed because of alternative sites of polyadenylation. The vertebrate family of lipase genes includes LPL (encoding lipoprotein lipase [LPL]), LIPC (hepatic lipase [HL]), LIPG (endothelial lipase [EL]), and PNLIP (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. More than 220 disease-causing mutations have been identified [Brunzell & Deeb 2001, Gilbert et al 2001]. Approximately 70% of these mutations 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. Many missense mutations result in LPL deficiency secondary to LPL homodimer instability. 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.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 the 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].