THE FAMILIAL CHYLOMICRONEMIA SYNDROME

https://doi.org/10.1016/S0889-8529(05)70025-6Get rights and content

The chylomicronemia syndrome is a disorder characterized by severe fasting hypertriglyceridemia and massive accumulations of chylomicrons in plasma that can lead to the development of eruptive xanthomas, lipemia retinalis, and pancreatitis. Genetic causes of the syndrome include familial deficiency of lipoprotein lipase (LPL), familial deficiency of apolipoprotein (apo) C-II, and familial inhibitor of LPL. In addition, in patients with familial forms of moderate hypertriglyceridemia, chylomicronemia may develop when other acquired causes of hypertriglyceridemia are present, such as diabetes mellitus, certain drug therapies, and alcohol intake problems.

Section snippets

CLINICAL FEATURES OF THE CHYLOMICRONEMIA SYNDROME

Patients with the familial chylomicronemia syndrome17, 118 often present early in childhood or adolescence with recurrent episodes of abdominal pain with or without pancreatitis frequently precipitated by the ingestion of a fatty meal. The pancreatitis is usually of acute onset and may be difficult to diagnose because both serum and urine amylase levels may seem normal owing to interference by the plasma lipids and circulating inhibitors of the lipase assay.35, 88, 135 In the presence of

LIPOPROTEIN LIPASE AND APOLIPOPROTEIN C-II

Lipoprotein lipase is a 55-kd glycoprotein located in the luminal surface of the capillary endothelium. It has a central role in lipoprotein metabolism by catalyzing the hydrolysis of the 1- and 3-ester bonds in triglycerides present in circulating chylomicrons and VLDL to monoglycerides, diglycerides, and free fatty acids. These substances can be used later for energy or stored in adipose tissue. In the process, triglyceride-rich lipoproteins are converted to smaller, denser chylomicron

LIPOPROTEIN LIPASE DEFICIENCY

Familial LPL deficiency, the most common underlying molecular defect leading to familial chylomicronemia syndrome, is a rare disorder inherited as an autosomal recessive trait. The frequency of LPL deficiency in the general population is about 1 per 1 million persons,13 although it may be higher in selected populations.9, 51 To date, several hundred patients with LPL deficiency have been described. In comparison with patients with deficiency of apoC-II, patients with LPL deficiency present at

APOLIPOPROTEIN C-II DEFICIENCY

ApoC-II deficiency is a rare genetic disorder inherited as an autosomal recessive trait. The syndrome is thought to be more rare than LPL deficiency, with only 14 kindreds with apoC-II deficiency described in the literature to date.17 The absence of apoC-II results in a functional deficiency of LPL. Thus, the clinical manifestations of this genetic disorder are similar to those in LPL deficiency and include eruptive xanthomas, hepatosplenomegaly, lipemia retinalis, and recurrent pancreatitis.

FAMILIAL LIPOPROTEIN LIPASE INHIBITOR

A family with chylomicronemia has been reported in which very low levels of postheparin plasma LPL activity are thought to be caused by the presence of a circulating plasma inhibitor of LPL.19 Unlike in classic patients with LPL or apoC-II deficiency, the chylomicronemia syndrome seems to be inherited as an autosomal dominant trait. Although postheparin plasma LPL activity is decreased, adipose tissue LPL activity is elevated, and plasma levels of functional apoC-II are normal. The patients

OTHER CAUSES OF CHYLOMICRONEMIA

Patients presenting with chylomicronemia not resulting from LPL or apoC-II deficiency represent a heterogeneous group. These patients were initially identified by Fredrickson and Lees49 as having a type V lipoprotein pattern with accumulations of both chylomicrons and VLDL. The majority of individuals with fasting plasma triglyceride concentrations above 2000 mg/dL have a common form of familial hypertriglyceridemia such as familial combined hyperlipidemia or familial hypertriglyceridemia in

TREATMENT

The goal of therapy in all patients is to reduce plasma triglycerides to levels less than 1000 to 2000 mg/dL, which will reverse all of the clinical manifestations of chylomicronemia syndrome. The treatment of patients with genetically inherited LPL and apoC-II deficiency primarily involves restriction of dietary fat to approximately 15% of total calories. The degree of fat restriction (10 to 15 g of fat daily) required to achieve an acceptable plasma triglyceride concentration may be variable.

References (146)

  • H.K. Das et al.

    The human apolipoprotein C-II gene sequence contains a novel chromosome 19-specific minisatellite in its third intron

    J Biol Chem

    (1987)
  • H.L. Dichek et al.

    Identification of two separate allelic mutations in the lipoprotein lipase gene of a patient with the familial hyperchylomicronemia syndrome

    J Biol Chem

    (1991)
  • M. Emi et al.

    Missense mutation (Gly→Glu188) of human lipoprotein lipase imparting functional deficiency

    J Biol Chem

    (1990)
  • J. Emmerich et al.

    Human lipoprotein lipase: Analysis of the catalytic triad by site-directed mutagenesis of Ser-132, Asp-156, and His-241

    J Biol Chem

    (1992)
  • F. Faustinella et al.

    Catalytic triad residue mutation (Asp156→Gly) causing familial lipoprotein lipase deficiency

    J Biol Chem

    (1991)
  • F. Faustinella et al.

    Structural and functional roles of highly conserved serines in human lipoprotein lipase

    J Biol Chem

    (1991)
  • R. Fellin et al.

    Familial lipoprotein lipase and apolipoprotein C-II deficiency: Lipoprotein and apoprotein analysis, adipose tissue and hepatic lipoprotein lipase levels in seven patients and their first degree relatives

    Atherosclerosis

    (1983)
  • FojoS.S. et al.

    An initiation codon mutation in the apoC-II gene (apoC-IIParis) of a patient with a deficiency of apolipoprotein C-II

    J Biol Chem

    (1989)
  • S.S. Fojo et al.

    The human preproapolipoprotein C-II gene: Complete nucleic acid sequence and genomic organization

    FEBS Lett

    (1987)
  • S.S. Fojo et al.

    The localization of the gene for apolipoprotein C-II to chromosome 19

    Biochem Biophys Res Commun

    (1984)
  • S.S. Fojo et al.

    A deletion mutation in the ApoC-II gene (ApoC-IINijmegen) of a patient with a deficiency of apolipoprotein C-II

    J Biol Chem

    (1988)
  • S.S. Fojo et al.

    Human preproapolipoprotein C-II: Analysis of major plasma isoforms

    J Biol Chem

    (1986)
  • GoldbergI.J. et al.

    Transient lipoprotein lipase deficiency with hyperchylomicronemia

    Am J Med Sci

    (1983)
  • T. Gotoda et al.

    Occurrence of multiple aberrantly spliced mRNAs upon a donor splice site mutation that causes familial lipoprotein lipase deficiency

    J Biol Chem

    (1991)
  • T. Gotoda et al.

    A newly identified null allelic mutation in the human lipoprotein lipase (LPL) gene of a compound heterozygote with familial LPL deficiency

    Biochim Biophys Acta

    (1992)
  • S. Haubenwallner et al.

    A novel missense mutation in the gene for lipoprotein lipase resulting in a highly conservative amino acid substitution (Asp180→Glu) causes familial chylomicronemia (type I hyperlipoproteinemia)

    Genomics

    (1993)
  • H.E. Henderson et al.

    A new mutation destroying disulphide bridging in the C-terminal domain of lipoprotein lipase

    Biochem Biophys Res Commun

    (1996)
  • H.E. Henderson et al.

    Structure-function relationships of lipoprotein lipase: Mutation analysis and mutagenesis of the loop region

    J Lipid Res

    (1993)
  • W.A. Hide et al.

    Structure and evolution of the lipase superfamily

    J Lipid Res

    (1992)
  • B. Holzl et al.

    Lipoprotein lipase deficiency due to a 3′ splice site mutation in intron 6 of the lipoprotein lipase gene

    J Lipid Res

    (1994)
  • A.J. Hoogewerf et al.

    Effect of chlorate on the sulfation of lipoprotein lipase and heparan sulfate proteoglycan: Sulfation of heparan sulfate proteoglycans affects lipoprotein lipase degradation

    J Biol Chem

    (1991)
  • K. Ishimura-Oka et al.

    A missense (Asp250→Asn) mutation in the lipoprotein lipase gene in two unrelated families with familial lipoprotein lipase deficiency

    J Lipid Res

    (1992)
  • P.H. Iverius et al.

    Lipoprotein lipase from bovine milk: Isolation procedure, chemical characterization, and molecular weight analysis

    J Biol Chem

    (1976)
  • P.H. Iverius et al.

    Preparation, characterization, and measurement of lipoprotein lipase

    Methods Enzymol

    (1986)
  • R.L. Jackson et al.

    Comparison of apolipoprotein C-II-deficient triacylglycerol-rich lipoproteins and trioleoylglycerol/phosphatidylcholine-stabilized particles as substrates for lipoprotein lipase

    Biochim Biophys Acta

    (1986)
  • J. Kobayashi et al.

    A heterozygous mutation (the codon for Ser447—a stop codon) in lipoprotein lipase contributes to a defect in lipid interface recognition in a case with type I hyperlipidemia

    Biochem Biophys Res Commun

    (1992)
  • A. Krapp et al.

    Structural features in lipoprotein lipase necessary for the mediation of lipoprotein uptake into cells

    J Lipid Res

    (1995)
  • J.C. LaRosa et al.

    A specific apoprotein activator for lipoprotein lipase

    Biochem Biophys Res Commun

    (1970)
  • Y. Ma et al.

    Two naturally occurring mutations at the first and second bases of codon aspartic acid 156 in the proposed catalytic triad of human lipoprotein lipase

    J Biol Chem

    (1992)
  • Y. Ma et al.

    High frequency of mutations in the human lipoprotein lipase gene in pregnancy-induced chylomicronemia: Possible association with apolipoprotein E2 isoform

    J Lipid Res

    (1994)
  • Y. Ma et al.

    A missense mutation (Asp250→Asn) in exon 6 of the human lipoprotein lipase gene causes chylomicronemia in patients of different ancestries

    Genomics

    (1992)
  • N. Matsuoka et al.

    Effects of apolipoprotein C-II (apoC-II) on the lipolysis of very low density lipoproteins from apoC-II deficient patients

    Metabolism

    (1981)
  • D. Ameis et al.

    Familial hyperchylomicronemia due to a single missense mutation in the lipoprotein lipase gene

    J Clin Invest

    (1991)
  • G. Baggio et al.

    Apolipoprotein C-II deficiency syndrome: Clinical features, lipoprotein characterization, lipase activity, and correction of hypertriglyceridemia after apolipoprotein C-II administration in two affected patients

    J Clin Invest

    (1986)
  • O.U. Beg et al.

    Lipoprotein lipaseBethesda: A single amino acid substitution (Ala-176―Thr) leads to abnormal heparin binding and loss of enzymic activity

    Proc Natl Acad Sci USA

    (1990)
  • C.M. Ben-Avram et al.

    Homology of lipoprotein lipase to pancreatic lipase

    Proc Natl Acad Sci USA

    (1986)
  • BenlianP. et al.

    Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene

    N Engl J Med

    (1996)
  • P. Benlian et al.

    Complete paternal isodisomy for chromosome 8 unmasked by lipoprotein lipase deficiency

    Am J Hum Genet

    (1996)
  • P. Benlian et al.

    A homozygous deletion of exon 9 in the lipoprotein lipase gene causes type I hyperlipoproteinemia [abstract]

    Arterioscler Thromb

    (1991)
  • J. Bergeron et al.

    Prevalence, geographical distribution and genealogical investigations of mutation 188 of lipoprotein lipase gene in the French Canadian population of Quebec

    Clin Genet

    (1992)

    • Cited by (0)

    Address reprint requests to Silvia Santamarina-Fojo, MD, PhD, Section of Molecular Biology, Molecular Disease Branch, National Heart, Lung, and Blood Institute, NIH, 10 Center Drive MSC 1666, Building 10, Room 7N115, Bethesda, MD 20892–1666

    *

    Section of Molecular Biology, Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

    View full text
    Copyright © 1998 W. B. Saunders Company. Published by Elsevier Inc. All rights reserved.