# 238600

HYPERLIPOPROTEINEMIA, TYPE I


Alternative titles; symbols

LIPOPROTEIN LIPASE DEFICIENCY
LPL DEFICIENCY
HYPERCHYLOMICRONEMIA, FAMILIAL
HYPERLIPEMIA, IDIOPATHIC, BURGER-GRUTZ TYPE
HYPERLIPEMIA, ESSENTIAL FAMILIAL
LIPASE D DEFICIENCY
LIPD DEFICIENCY
HYPERLIPOPROTEINEMIA, TYPE IA
CHYLOMICRONEMIA, FAMILIAL


Other entities represented in this entry:

HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 11, INCLUDED; HDLCQ11, INCLUDED

Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
8p21.3 Lipoprotein lipase deficiency 238600 AR 3 LPL 609708
8p21.3 [High density lipoprotein cholesterol level QTL 11] 238600 AR 3 LPL 609708
Clinical Synopsis
 

GI
- Pancreatitis
- Episodic abdominal pain
- Hepatosplenomegaly
- Splenomegaly
- Nausea and vomiting
- Bile duct stenosis
Cardiac
- No precocious atherosclerosis
Skin
- Eruptive xanthomas
- Jaundice
Eyes
- Lipemia retinalis
Lab
- Hyperlipemia
- Hyperchylomicronemia
- Fat-induced hyperlipemia
- Hypercholesterolemia
- Hyperlipidemia
- Lipoprotein lipase deficiency
- Alpha and beta lipoproteins low
- Chylomicron removal defect
- Decreased plasma postheparin lipolytic activity (PHLA)
- Plasma lactescence
- Heterozygotes may show slight hyperlipemia and reduced PHLA
Inheritance
- Autosomal recessive
- multiple alleles and compounds

TEXT

A number sign (#) is used with this entry because type I hyperlipoproteinemia is caused by homozygous or compound heterozygous mutation in the lipoprotein lipase gene (LPL; 609708) on chromosome 8p21.


Clinical Features

Holt et al. (1939) first reported the familial occurrence of this syndrome. Boggs et al. (1957) described 3 affected sibs from a first-cousin mating. Massive hyperchylomicronemia occurs when the patient is on a normal diet and disappears completely in a few days on fat-free feeding. On a normal diet alpha and beta lipoproteins are low. A defect in removal of chylomicrons (fat induction) and of other triglyceride-rich lipoproteins (carbohydrate induction) is present. Decreased plasma postheparin lipolytic activity (PHLA) is demonstrated. Low tissue activity of lipoprotein lipase was suspected. The full-blown disease, manifested by attacks of abdominal pain, hepatosplenomegaly, eruptive xanthomas, and lactescence of the plasma, is a recessive. Heterozygotes may show slight hyperlipemia and reduced PHLA. Precocious atherosclerosis does not seem to be a feature.

Havel and Gordon (1960) first recognized deficiency of lipoprotein lipase (triacylglycerol acylhydrolase; EC 3.1.1.3) as the basic defect in type I hyperlipoproteinemia. The type I hyperlipoproteinemia phenotype can also result from deficiency of the activator of lipoprotein lipase, apolipoprotein C-II (Breckenridge et al., 1978)--see 207750. This condition was called fat-induced hypertriglyceridemia by Nevin and Slack (1968). Adipose tissue in heterozygotes shows intermediate levels of lipoprotein lipase.

Berger (1987) reported a case of variant lipoprotein lipase deficiency in which muscle lipoprotein lipase was essentially normal although the enzyme in adipose tissue was markedly reduced. Schreibman et al. (1973) studied a family with 2 clinically typical sibs whose lipoprotein lipase showed abnormal substrate specificity and kinetics. Hoeg et al. (1983) reported an extraordinary patient in whom the diagnosis was first made at the age of 75. Absolute abstinence from alcohol and a self-imposed low-fat diet may have been responsible for the long survival. Since childhood, he had had recurrent abdominal pain, nausea and vomiting, diagnosed as 'gall bladder attacks,' until age 48 when he was first hospitalized. During the next 15 years he had 1 to 3 episodes of abdominal pain per year necessitating hospitalization. These episodes were diagnosed as acute pancreatitis and were sometimes associated with an evanescent papular rash. Jaundice that developed rapidly at age 64 was found to be due to bile duct stenosis, which was surgically relieved. He had, at age 73, ischemic heart disease and a femoral bruit.

Eckel (1989) provided an extensive review of lipoprotein lipase. Auwerx et al. (1989) classified LPL deficiency at the protein level on the basis of the absence (class I) or presence of defective enzyme protein, and whether it binds (class II) or does not bind (class III) to heparin.

Slight to moderate hemolysis is often present in plasma from patients with primary LPL deficiency. Cantin et al. (1995) found that, while osmotic fragility was similar to that in control subjects, plasma prehemoglobin was significantly increased. Furthermore, an increase in plasma lysophosphatidylcholine concentration was found. This was thought to be due to an impairment in the reverse metabolic pathway converting lysophosphatidylcholine back to phosphatidylcholine. The findings, along with a positive correlation between plasma prehemoglobin and lysophosphatidylcholine levels, suggested that the hemolysis in LPL deficiency is mediated to some extent by the abnormally elevated concentration of lysophosphatidylcholine.

Feoli-Fonseca et al. (1998) reviewed the cases of 16 infants under 1 year of age who were found to have LPL deficiency; 7 presented with irritability, 2 with lower intestinal bleeding, 5 with pallor, anemia, or splenomegaly, and 2 with a family history or fortuitous discovery. All plasma samples were lactescent at presentation.

Kawashiri et al. (2005) reported a 22-year-old Japanese male with this mutation who had had no major pancreatic malformations, vascular complications, or severe glucose intolerance despite a 32-year clinical history of pancreatitis recurring more than 20 times. Based on the long-term observations of this patient, Kawashiri et al. (2005) proposed that LPL deficiency is not invariably associated with high mortality and that even with repeated episodes of acute pancreatitis, pancreatic function may be slow to decline.


Clinical Management

In the patients reviewed by Feoli-Fonseca et al. (1998), chylomicronemia responded rapidly to dietary fat restriction, and it was possible to maintain satisfactory metabolic control for a prolonged period of time. Only 1 adolescent girl had an episode of pancreatitis associated with the use of oral contraceptives. No persistent adverse effects on growth were seen. The development of pancreatitis indicates that estrogen therapy should be avoided in LPL-deficient patients.

Heaney et al. (1999) reported a dramatic response to antioxidant therapy (Antox, 1 tablet 4 times daily) in 3 patients with familial lipoprotein lipase deficiency complicated by frequent severe episodes of pancreatitis. Because these patients failed to respond to other dietary and pharmacologic measures, the authors concluded that antioxidant therapy may be an important advance in the management of this type of patient.

Triglycerides enter the plasma compartment from the liver in the form of very low density lipoprotein (VLDL) particles, and from dietary fat absorption in the intestine, in the form of chylomicrons. LPL activity is the primary mechanism by which plasma triglycerides are hydrolyzed, leading to subsequent efficient removal of triglyceride-rich lipoprotein remnants. In the absence of the LPL-dependent pathway, the removal of triglyceride-rich lipoproteins occurs through a less efficient LPL-independent pathway, resulting in massively elevated triglyceride levels. APOC3 (107720) is known to inhibit LPL (609708), although there is also evidence that APOC3 increases the level of plasma triglycerides through an LPL-independent mechanism. Gaudet et al. (2014) administered an inhibitor of APOC3 mRNA, called ISIS 304801, to treat 3 patients with familial chylomicronemia syndrome due to LPL deficiency and triglyceride levels ranging from 1,406 to 2,083 mg/dl (15.9-23.5 mM/l). After 13 weeks of study drug administration, plasma APOC3 levels were reduced by 71 to 90% and triglyceride levels by 56 to 86%. During the study, all patients had a triglyceride level of less than 500 mg/dl (5.7 mM/l) with treatment. Gaudet et al. (2014) concluded that these data supported the role of APOC3 as a key regulator of LPL-independent pathways of triglyceride metabolism.

Witztum et al. (2019) conducted a phase 3 double-blind randomized 52-week trial to evaluate the safety and effectiveness of antisense-mediated inhibition of hepatic APOC3 by volanesorsen in 66 patients with familial chylomicronemia syndrome. Most of the patients were homozygous or compound heterozygous for mutations in the LPL gene. The primary endpoint was the percentage change in fasting triglyceride levels from baseline to 3 months. Patients receiving volanesorsen had an 84% decrease from baseline in mean plasma apolipoprotein C-III levels at 3 months, whereas patients receiving placebo had a 6.1% increase from baseline (p less than 0.001). Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, whereas patients receiving placebo had an 18% increase (p less than 0.001). At 3 months, 77% of patients in the volanesorsen group, compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg/dl. Twenty of the 33 patients who received volanesorsen had injection site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000/microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000/microliter. No patient had platelet counts below 50,000/microliter after enhanced platelet monitoring began. Witztum et al. (2019) concluded that volanesorsen lowered triglyceride levels to less than 750 mg/dl in 77% of patients with familial chylomicronemia syndrome. Thrombocytopenia and injection site reactions were common adverse events.


Molecular Genetics

For a full discussion of the molecular genetics of lipoprotein lipase deficiency (type I hyperlipoproteinemia), see the entry for the LPL gene (609708).


REFERENCES

  1. Auwerx, J. H., Babirak, S. P., Fujimoto, W. Y., Iverius, P. H., Brunzell, J. D. Defective enzyme protein in lipoprotein lipase deficiency. Europ. J. Clin. Invest. 19: 433-437, 1989. [PubMed: 2511019, related citations] [Full Text]

  2. Berger, G. M. B. An incomplete form of familial lipoprotein lipase deficiency presenting with type I hyperlipoproteinemia. Am. J. Clin. Path. 88: 369-373, 1987. [PubMed: 3630977, related citations] [Full Text]

  3. Berger, H., Richter, A., Gilardi, A., Wagner, H. Essential familial hyperlipaemia in a 2-year-old child. Ann. Paediat. 199: 445-466, 1962.

  4. Boggs, J. D., Hsia, D. Y.-Y., Mais, R. F., Bigler, J. A. The genetic mechanism of idiopathic hyperlipemia. New Eng. J. Med. 257: 1101-1108, 1957. [PubMed: 13483896, related citations] [Full Text]

  5. Breckenridge, W. C., Little, A. C., Steiner, G., Chow, A., Poapst, M. Hypertriglyceridemia associated with deficiency of C-II apoprotein in plasma lipoproteins. New Eng. J. Med. 298: 1265-1273, 1978. [PubMed: 565877, related citations] [Full Text]

  6. Brunzell, J. D., Chait, A., Nikkila, E. A., Ehnholm, C., Huttunen, J. K., Steiner, G. Heterogeneity of primary lipoprotein lipase deficiency. Metabolism 29: 624-629, 1980. [PubMed: 7382827, related citations] [Full Text]

  7. Cantin, B., Boudriau, S., Bertrand, M., Brun, L.-D., Gagne, C., Rogers, P. A., Ven Murthy, M. R., Lupien, P.-J., Julien, P. Hemolysis in primary lipoprotein lipase deficiency. Metabolism 44: 652-658, 1995. [PubMed: 7752915, related citations] [Full Text]

  8. Eckel, R. H. Lipoprotein lipase: a multifunctional enzyme relevant to common metabolic diseases. New Eng. J. Med. 320: 1060-1068, 1989. Note: Erratum: New Eng. J. Med. 322: 477 only, 1990. [PubMed: 2648155, related citations] [Full Text]

  9. Emi, M., Wilson, D. E., Iverius, P.-H., Wu, L., Hata, A., Hegele, R., Williams, R. R., Lalouel, J.-M. Missense mutation (gly-to-glu188) of human lipoprotein lipase imparting functional deficiency. J. Biol. Chem. 265: 5910-5916, 1990. [PubMed: 1969408, related citations]

  10. Feoli-Fonseca, J. C., Levy, E., Godard, M., Lambert, M. Familial lipoprotein lipase deficiency in infancy: clinical, biochemical, and molecular study. J. Pediat. 133: 417-423, 1998. [PubMed: 9738727, related citations] [Full Text]

  11. Franklin, S. M. Splenomegaly with lipaemia. Proc. Roy. Soc. Med. 30: 711, 1937. [PubMed: 20915480, related citations]

  12. Fredrickson, D. S., Levy, R. I. Familial hyperlipoproteinemia.In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.) : The Metabolic Basis of Inherited Disease. (3rd ed.) New York: McGraw-Hill (pub.) 1972. Pp. 545-614.

  13. Gaudet, D., Brisson, D., Tremblay, K., Alexander, V. J., Singleton, W., Hughes, S. G., Geary, R. S., Baker, B. F., Graham, M. J., Crooke, R. M., Witztum, J. L. Targeting APOC3 in the familial chylomicronemia syndrome. New Eng. J. Med. 371: 2200-2206, 2014. [PubMed: 25470695, related citations] [Full Text]

  14. Havel, R. J., Gordon, R. S. Idiopathic hyperlipemia: metabolic studies in an affected family. J. Clin. Invest. 39: 1777-1790, 1960. [PubMed: 13712364, related citations] [Full Text]

  15. Heaney, A. P., Sharer, N., Rameh, B., Braganza, J. M., Durrington, P. N. Prevention of recurrent pancreatitis in familial lipoprotein lipase deficiency with high-dose antioxidant therapy. J. Clin. Endocr. Metab. 84: 1203-1205, 1999. [PubMed: 10199753, related citations] [Full Text]

  16. Henderson, H. E., Ma, Y., Hassan, M. F., Monsalve, M. V., Marais, A. D., Winkler, F., Gubernator, K., Peterson, J., Brunzell, J. D., Hayden, M. R. Amino acid substitution (ile194-to-thr) in exon 5 of the lipoprotein lipase gene causes lipoprotein lipase deficiency in three unrelated probands: support for a multicentric origin. J. Clin. Invest. 87: 2005-2011, 1991. [PubMed: 1674945, related citations] [Full Text]

  17. Hoeg, J. M., Osborne, J. C., Jr., Gregg, R. E., Brewer, H. B., Jr. Initial diagnosis of lipoprotein lipase deficiency in a 75-year-old man. Am. J. Med. 75: 889-892, 1983. [PubMed: 6638056, related citations] [Full Text]

  18. Holt, L. E., Jr., Aylward, F. X., Timbers, H. G. Idiopathic familial lipemia. Bull. Johns Hopkins Hosp. 64: 279-314, 1939.

  19. Kawashiri, M., Higashikata, T., Mizuno, M., Takata, M., Katsuda, S., Miwa, K., Nozue, T., Nohara, A., Inazu, A., Kobayashi, J., Koizumi, J., Mabuchi, H. 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. Endocr. Metab. 90: 6541-6544, 2005. [PubMed: 16174715, related citations] [Full Text]

  20. Nevin, N. C., Slack, J. Hyperlipidaemic xanthomatosis II: mode of inheritance in 55 families with essential hyperlipidaemia and xanthomatosis. J. Med. Genet. 5: 9-28, 1968. [PubMed: 5653873, related citations] [Full Text]

  21. Schreibman, P. H., Arons, D. L., Saudek, C. D., Arky, R. A. Abnormal lipoprotein lipase in familial exogenous hypertriglyceridemia. J. Clin. Invest. 52: 2074-2082, 1973.

  22. Sternowsky, H. J., Gaertner, U., Stahnkel, N., Kaukel, E. Juvenile familial hypertriglyceridemia and growth retardation: clinical and biochemical observations in three siblings. Europ. J. Pediat. 125: 59-70, 1977. [PubMed: 192555, related citations] [Full Text]

  23. Wessler, S., Avioli, L. A. Familial hyperlipoproteinemia. JAMA 207: 929-937, 1969. [PubMed: 5818258, related citations]

  24. Witztum, J. L., Gaudet, D., Freedman, S. D., Alexander, V. J., Digenio, A., Williams, K. R., Yang, Q., Hughes, S. G., Geary, R. S., Arca, M., Stroes, E. S. G., Bergeron, J., Soran, H., Civeira, F., Hemphill, L., Tsimikas, S., Blom, D. J., O'Dea, L., Bruckert, E. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. New Eng. J. Med. 381: 531-542, 2019. [PubMed: 31390500, related citations] [Full Text]


Ada Hamosh - updated : 05/19/2021
Ada Hamosh - updated : 1/12/2015
John A. Phillips, III - updated : 3/19/2007
John A. Phillips, III - updated : 4/13/2005
Marla J. F. O'Neill - updated : 2/4/2005
Victor A. McKusick - updated : 6/11/2004
John A. Phillips, III - updated : 9/30/2003
Victor A. McKusick - updated : 3/1/2002
Victor A. McKusick - updated : 12/27/2001
John A. Phillips, III - updated : 7/11/2001
Victor A. McKusick - updated : 4/5/2001
Victor A. McKusick - updated : 4/21/2000
Wilson H. Y. Lo - updated : 10/26/1999
John A. Phillips, III - updated : 10/7/1999
Victor A. McKusick - updated : 9/15/1999
Ada Hamosh - updated : 5/18/1999
Victor A. McKusick - updated : 2/4/1999
Victor A. McKusick - updated : 9/14/1998
Victor A. McKusick - updated : 9/1/1998
Victor A. McKusick - updated : 6/25/1998
Victor A. McKusick - updated : 12/31/1997
Jennifer P. Macke - updated : 5/30/1997
Victor A. McKusick - updated : 5/27/1997
Cynthia K. Ewing - updated : 10/8/1996
Moyra Smith - updated : 10/7/1996
Stylianos E. Antonarakis - updated : 7/3/1996
Creation Date:
Victor A. McKusick : 6/3/1986
alopez : 05/19/2021
carol : 05/30/2019
carol : 07/09/2016
alopez : 1/12/2015
terry : 3/15/2013
carol : 9/16/2010
terry : 6/3/2009
terry : 2/2/2009
carol : 3/19/2007
alopez : 11/15/2005
alopez : 11/15/2005
wwang : 5/11/2005
wwang : 4/13/2005
terry : 2/4/2005
tkritzer : 6/29/2004
terry : 6/11/2004
alopez : 3/17/2004
alopez : 9/30/2003
alopez : 9/30/2003
alopez : 10/21/2002
carol : 3/1/2002
terry : 3/1/2002
carol : 1/9/2002
mcapotos : 1/3/2002
terry : 12/27/2001
alopez : 7/11/2001
cwells : 4/12/2001
terry : 4/5/2001
mcapotos : 5/19/2000
mcapotos : 5/18/2000
terry : 4/21/2000
carol : 10/26/1999
mgross : 10/7/1999
carol : 9/30/1999
jlewis : 9/28/1999
terry : 9/15/1999
alopez : 5/24/1999
alopez : 5/24/1999
terry : 5/18/1999
carol : 2/7/1999
terry : 2/4/1999
dkim : 12/10/1998
carol : 9/16/1998
dkim : 9/14/1998
terry : 9/14/1998
carol : 9/2/1998
terry : 9/1/1998
alopez : 6/29/1998
terry : 6/25/1998
alopez : 2/9/1998
alopez : 1/28/1998
alopez : 1/28/1998
dholmes : 1/6/1998
terry : 11/10/1997
alopez : 8/1/1997
alopez : 7/24/1997
alopez : 7/24/1997
alopez : 7/8/1997
mark : 7/1/1997
mark : 6/16/1997
alopez : 6/11/1997
mark : 5/30/1997
mark : 5/30/1997
jenny : 5/30/1997
terry : 5/27/1997
jamie : 11/1/1996
terry : 10/28/1996
terry : 10/22/1996
mark : 10/7/1996
carol : 7/3/1996
terry : 7/1/1996
mark : 6/11/1996
terry : 5/13/1996
terry : 5/6/1996
mark : 5/2/1996
terry : 4/24/1996
mark : 1/27/1996
terry : 1/18/1996
mark : 9/22/1995
davew : 8/26/1994
carol : 5/16/1994
warfield : 3/16/1994
mimadm : 2/19/1994
carol : 11/30/1993

# 238600

HYPERLIPOPROTEINEMIA, TYPE I


Alternative titles; symbols

LIPOPROTEIN LIPASE DEFICIENCY
LPL DEFICIENCY
HYPERCHYLOMICRONEMIA, FAMILIAL
HYPERLIPEMIA, IDIOPATHIC, BURGER-GRUTZ TYPE
HYPERLIPEMIA, ESSENTIAL FAMILIAL
LIPASE D DEFICIENCY
LIPD DEFICIENCY
HYPERLIPOPROTEINEMIA, TYPE IA
CHYLOMICRONEMIA, FAMILIAL


Other entities represented in this entry:

HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 11, INCLUDED; HDLCQ11, INCLUDED

SNOMEDCT: 267435002, 275598004, 403827000;   ICD10CM: E78.3;   ICD9CM: 272.3;   ORPHA: 309015, 444490;   DO: 14118;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
8p21.3 Lipoprotein lipase deficiency 238600 Autosomal recessive 3 LPL 609708
8p21.3 [High density lipoprotein cholesterol level QTL 11] 238600 Autosomal recessive 3 LPL 609708

TEXT

A number sign (#) is used with this entry because type I hyperlipoproteinemia is caused by homozygous or compound heterozygous mutation in the lipoprotein lipase gene (LPL; 609708) on chromosome 8p21.


Clinical Features

Holt et al. (1939) first reported the familial occurrence of this syndrome. Boggs et al. (1957) described 3 affected sibs from a first-cousin mating. Massive hyperchylomicronemia occurs when the patient is on a normal diet and disappears completely in a few days on fat-free feeding. On a normal diet alpha and beta lipoproteins are low. A defect in removal of chylomicrons (fat induction) and of other triglyceride-rich lipoproteins (carbohydrate induction) is present. Decreased plasma postheparin lipolytic activity (PHLA) is demonstrated. Low tissue activity of lipoprotein lipase was suspected. The full-blown disease, manifested by attacks of abdominal pain, hepatosplenomegaly, eruptive xanthomas, and lactescence of the plasma, is a recessive. Heterozygotes may show slight hyperlipemia and reduced PHLA. Precocious atherosclerosis does not seem to be a feature.

Havel and Gordon (1960) first recognized deficiency of lipoprotein lipase (triacylglycerol acylhydrolase; EC 3.1.1.3) as the basic defect in type I hyperlipoproteinemia. The type I hyperlipoproteinemia phenotype can also result from deficiency of the activator of lipoprotein lipase, apolipoprotein C-II (Breckenridge et al., 1978)--see 207750. This condition was called fat-induced hypertriglyceridemia by Nevin and Slack (1968). Adipose tissue in heterozygotes shows intermediate levels of lipoprotein lipase.

Berger (1987) reported a case of variant lipoprotein lipase deficiency in which muscle lipoprotein lipase was essentially normal although the enzyme in adipose tissue was markedly reduced. Schreibman et al. (1973) studied a family with 2 clinically typical sibs whose lipoprotein lipase showed abnormal substrate specificity and kinetics. Hoeg et al. (1983) reported an extraordinary patient in whom the diagnosis was first made at the age of 75. Absolute abstinence from alcohol and a self-imposed low-fat diet may have been responsible for the long survival. Since childhood, he had had recurrent abdominal pain, nausea and vomiting, diagnosed as 'gall bladder attacks,' until age 48 when he was first hospitalized. During the next 15 years he had 1 to 3 episodes of abdominal pain per year necessitating hospitalization. These episodes were diagnosed as acute pancreatitis and were sometimes associated with an evanescent papular rash. Jaundice that developed rapidly at age 64 was found to be due to bile duct stenosis, which was surgically relieved. He had, at age 73, ischemic heart disease and a femoral bruit.

Eckel (1989) provided an extensive review of lipoprotein lipase. Auwerx et al. (1989) classified LPL deficiency at the protein level on the basis of the absence (class I) or presence of defective enzyme protein, and whether it binds (class II) or does not bind (class III) to heparin.

Slight to moderate hemolysis is often present in plasma from patients with primary LPL deficiency. Cantin et al. (1995) found that, while osmotic fragility was similar to that in control subjects, plasma prehemoglobin was significantly increased. Furthermore, an increase in plasma lysophosphatidylcholine concentration was found. This was thought to be due to an impairment in the reverse metabolic pathway converting lysophosphatidylcholine back to phosphatidylcholine. The findings, along with a positive correlation between plasma prehemoglobin and lysophosphatidylcholine levels, suggested that the hemolysis in LPL deficiency is mediated to some extent by the abnormally elevated concentration of lysophosphatidylcholine.

Feoli-Fonseca et al. (1998) reviewed the cases of 16 infants under 1 year of age who were found to have LPL deficiency; 7 presented with irritability, 2 with lower intestinal bleeding, 5 with pallor, anemia, or splenomegaly, and 2 with a family history or fortuitous discovery. All plasma samples were lactescent at presentation.

Kawashiri et al. (2005) reported a 22-year-old Japanese male with this mutation who had had no major pancreatic malformations, vascular complications, or severe glucose intolerance despite a 32-year clinical history of pancreatitis recurring more than 20 times. Based on the long-term observations of this patient, Kawashiri et al. (2005) proposed that LPL deficiency is not invariably associated with high mortality and that even with repeated episodes of acute pancreatitis, pancreatic function may be slow to decline.


Clinical Management

In the patients reviewed by Feoli-Fonseca et al. (1998), chylomicronemia responded rapidly to dietary fat restriction, and it was possible to maintain satisfactory metabolic control for a prolonged period of time. Only 1 adolescent girl had an episode of pancreatitis associated with the use of oral contraceptives. No persistent adverse effects on growth were seen. The development of pancreatitis indicates that estrogen therapy should be avoided in LPL-deficient patients.

Heaney et al. (1999) reported a dramatic response to antioxidant therapy (Antox, 1 tablet 4 times daily) in 3 patients with familial lipoprotein lipase deficiency complicated by frequent severe episodes of pancreatitis. Because these patients failed to respond to other dietary and pharmacologic measures, the authors concluded that antioxidant therapy may be an important advance in the management of this type of patient.

Triglycerides enter the plasma compartment from the liver in the form of very low density lipoprotein (VLDL) particles, and from dietary fat absorption in the intestine, in the form of chylomicrons. LPL activity is the primary mechanism by which plasma triglycerides are hydrolyzed, leading to subsequent efficient removal of triglyceride-rich lipoprotein remnants. In the absence of the LPL-dependent pathway, the removal of triglyceride-rich lipoproteins occurs through a less efficient LPL-independent pathway, resulting in massively elevated triglyceride levels. APOC3 (107720) is known to inhibit LPL (609708), although there is also evidence that APOC3 increases the level of plasma triglycerides through an LPL-independent mechanism. Gaudet et al. (2014) administered an inhibitor of APOC3 mRNA, called ISIS 304801, to treat 3 patients with familial chylomicronemia syndrome due to LPL deficiency and triglyceride levels ranging from 1,406 to 2,083 mg/dl (15.9-23.5 mM/l). After 13 weeks of study drug administration, plasma APOC3 levels were reduced by 71 to 90% and triglyceride levels by 56 to 86%. During the study, all patients had a triglyceride level of less than 500 mg/dl (5.7 mM/l) with treatment. Gaudet et al. (2014) concluded that these data supported the role of APOC3 as a key regulator of LPL-independent pathways of triglyceride metabolism.

Witztum et al. (2019) conducted a phase 3 double-blind randomized 52-week trial to evaluate the safety and effectiveness of antisense-mediated inhibition of hepatic APOC3 by volanesorsen in 66 patients with familial chylomicronemia syndrome. Most of the patients were homozygous or compound heterozygous for mutations in the LPL gene. The primary endpoint was the percentage change in fasting triglyceride levels from baseline to 3 months. Patients receiving volanesorsen had an 84% decrease from baseline in mean plasma apolipoprotein C-III levels at 3 months, whereas patients receiving placebo had a 6.1% increase from baseline (p less than 0.001). Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, whereas patients receiving placebo had an 18% increase (p less than 0.001). At 3 months, 77% of patients in the volanesorsen group, compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg/dl. Twenty of the 33 patients who received volanesorsen had injection site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000/microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000/microliter. No patient had platelet counts below 50,000/microliter after enhanced platelet monitoring began. Witztum et al. (2019) concluded that volanesorsen lowered triglyceride levels to less than 750 mg/dl in 77% of patients with familial chylomicronemia syndrome. Thrombocytopenia and injection site reactions were common adverse events.


Molecular Genetics

For a full discussion of the molecular genetics of lipoprotein lipase deficiency (type I hyperlipoproteinemia), see the entry for the LPL gene (609708).


See Also:

Berger et al. (1962); Brunzell et al. (1980); Emi et al. (1990); Franklin (1937); Fredrickson and Levy (1972); Henderson et al. (1991); Sternowsky et al. (1977); Wessler and Avioli (1969)

REFERENCES

  1. Auwerx, J. H., Babirak, S. P., Fujimoto, W. Y., Iverius, P. H., Brunzell, J. D. Defective enzyme protein in lipoprotein lipase deficiency. Europ. J. Clin. Invest. 19: 433-437, 1989. [PubMed: 2511019] [Full Text: https://doi.org/10.1111/j.1365-2362.1989.tb00255.x]

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Contributors:
Ada Hamosh - updated : 05/19/2021
Ada Hamosh - updated : 1/12/2015
John A. Phillips, III - updated : 3/19/2007
John A. Phillips, III - updated : 4/13/2005
Marla J. F. O'Neill - updated : 2/4/2005
Victor A. McKusick - updated : 6/11/2004
John A. Phillips, III - updated : 9/30/2003
Victor A. McKusick - updated : 3/1/2002
Victor A. McKusick - updated : 12/27/2001
John A. Phillips, III - updated : 7/11/2001
Victor A. McKusick - updated : 4/5/2001
Victor A. McKusick - updated : 4/21/2000
Wilson H. Y. Lo - updated : 10/26/1999
John A. Phillips, III - updated : 10/7/1999
Victor A. McKusick - updated : 9/15/1999
Ada Hamosh - updated : 5/18/1999
Victor A. McKusick - updated : 2/4/1999
Victor A. McKusick - updated : 9/14/1998
Victor A. McKusick - updated : 9/1/1998
Victor A. McKusick - updated : 6/25/1998
Victor A. McKusick - updated : 12/31/1997
Jennifer P. Macke - updated : 5/30/1997
Victor A. McKusick - updated : 5/27/1997
Cynthia K. Ewing - updated : 10/8/1996
Moyra Smith - updated : 10/7/1996
Stylianos E. Antonarakis - updated : 7/3/1996

Creation Date:
Victor A. McKusick : 6/3/1986

Edit History:
alopez : 05/19/2021
carol : 05/30/2019
carol : 07/09/2016
alopez : 1/12/2015
terry : 3/15/2013
carol : 9/16/2010
terry : 6/3/2009
terry : 2/2/2009
carol : 3/19/2007
alopez : 11/15/2005
alopez : 11/15/2005
wwang : 5/11/2005
wwang : 4/13/2005
terry : 2/4/2005
tkritzer : 6/29/2004
terry : 6/11/2004
alopez : 3/17/2004
alopez : 9/30/2003
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alopez : 10/21/2002
carol : 3/1/2002
terry : 3/1/2002
carol : 1/9/2002
mcapotos : 1/3/2002
terry : 12/27/2001
alopez : 7/11/2001
cwells : 4/12/2001
terry : 4/5/2001
mcapotos : 5/19/2000
mcapotos : 5/18/2000
terry : 4/21/2000
carol : 10/26/1999
mgross : 10/7/1999
carol : 9/30/1999
jlewis : 9/28/1999
terry : 9/15/1999
alopez : 5/24/1999
alopez : 5/24/1999
terry : 5/18/1999
carol : 2/7/1999
terry : 2/4/1999
dkim : 12/10/1998
carol : 9/16/1998
dkim : 9/14/1998
terry : 9/14/1998
carol : 9/2/1998
terry : 9/1/1998
alopez : 6/29/1998
terry : 6/25/1998
alopez : 2/9/1998
alopez : 1/28/1998
alopez : 1/28/1998
dholmes : 1/6/1998
terry : 11/10/1997
alopez : 8/1/1997
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mark : 7/1/1997
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alopez : 6/11/1997
mark : 5/30/1997
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jenny : 5/30/1997
terry : 5/27/1997
jamie : 11/1/1996
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mark : 10/7/1996
carol : 7/3/1996
terry : 7/1/1996
mark : 6/11/1996
terry : 5/13/1996
terry : 5/6/1996
mark : 5/2/1996
terry : 4/24/1996
mark : 1/27/1996
terry : 1/18/1996
mark : 9/22/1995
davew : 8/26/1994
carol : 5/16/1994
warfield : 3/16/1994
mimadm : 2/19/1994
carol : 11/30/1993