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Hyperapobetalipoproteinemia(FCHL)

MedGen UID:
6965
Concept ID:
C0020474
Disease or Syndrome
Synonyms: FCHL; Hyperlipidemia, familial combined
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Familial combined hyperlipidemia (238040008); Familial multiple lipoprotein-type hyperlipidemia (299465007)
 
Gene (location): LPL (8p21.3)
OMIM®: 144250
HPO: HP:0008158

Disease characteristics

Excerpted from the GeneReview: APOE p.Leu167del-Related Lipid Disorders
APOE p.Leu167del is a rare genetic variant described in 38 cases in the literature with a range of clinical phenotypes. Three phenotypes can be associated with the APOE p.Leu167del variant: Inherited lipemic splenomegaly (also known as sea-blue histiocytosis) characterized by hypertriglyceridemia and splenomegaly. Variable manifestations include thrombocytopenia, liver function abnormalities, and cardiovascular disease. Autosomal dominant hypercholesterolemia (ADH) characterized by markedly elevated LDL cholesterol levels that leads to premature morbidity and mortality from atherosclerotic cardiovascular disease (ASCVD). Familial combined hyperlipidemia (FCHL) characterized by variable elevations of total cholesterol, triglycerides, or LDL cholesterol and a high risk of premature ASCVD. It has been suggested that the phenotype associated with the APOE p.Leu167del variant may depend on multiple factors, including sex, APOE genotype, control of hyperlipidemia, gene-gene interactions, gene-environment interactions, or perhaps epigenetic and other non-Mendelian effects. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  GeneReview Scope  |  Diagnosis  |  Clinical Characteristics  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Nicole Greyshock  |  John R Guyton  |  Siby Sebastian, et. al.   view full author information

Additional description

From OMIM
Goldstein et al. (1973) gave the designation 'familial combined hyperlipidemia' to the most common genetic form of hyperlipidemia identified in a study of survivors of myocardial infarction. Affected persons characteristically showed elevation of both cholesterol and triglycerides in the blood. The combined disorder was shown to be distinct from familial hypercholesterolemia (143890) and from familial hypertriglyceridemia (145750) for the following reasons: (1) lipid distributions in relatives were unique; (2) unlike familial hypercholesterolemia, children of affected persons did not express hypercholesterolemia; and (3) informative matings suggested that variable expression of a single gene rather than segregation for 2 separate genes was responsible. This disorder leads to elevated levels of VLDL, LDL, or both in plasma. From time to time the pattern can change in a given person. Unlike familial hypercholesterolemia, hyperlipidemia appears in only 10 to 20% of patients in childhood, usually in the form of hypertriglyceridemia. Xanthomas are rare. Increased production of VLDL may be a common underlying metabolic characteristic in this disorder, which may be heterogeneous. The disorder may be 5 times as frequent as familial hypercholesterolemia, occurring in 1% of the U.S. population. Using elevation of VLDL, of LDL, or of both as the phenotype in family studies, Goldstein et al. (1973) and Brunzell et al. (1983) concluded that familial combined hyperlipidemia is an autosomal dominant with high penetrance. Homozygotes can show severe hypertriglyceridemia (Chait and Brunzell, 1983). Brunzell et al. (1976) estimated that 10% of premature coronary artery disease is caused by FCHL.  http://www.omim.org/entry/144250

Clinical features

Familial hypercholesterolemia
MedGen UID:
5688
Concept ID:
C0020445
Disease or Syndrome
Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. Xanthomas (patches of yellowish cholesterol buildup) may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. In FH, the more common cardiovascular disease is coronary artery disease (CAD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Untreated men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years. An estimated 70%-95% of FH results from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9). FH is the most common inherited cardiovascular disease, with a prevalence of 1:200-250. FH likely accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years. In contrast, homozygous FH (HoFH) results from biallelic (homozygous or compound heterozygous) pathogenic variants in one of these known genes (APOB, LDLR, PCSK9). Most individuals with HoFH experience severe CAD by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.
Myocardial infarction
MedGen UID:
10150
Concept ID:
C0027051
Disease or Syndrome
Gross necrosis of the myocardium, as a result of interruption of the blood supply to the area, as in coronary thrombosis.
Increased circulating very-low-density lipoprotein levels
MedGen UID:
867364
Concept ID:
C4021729
Finding
An increase in the amount of very-low-density lipoprotein cholesterol in the blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHyperapobetalipoproteinemia

Conditions with this feature

Sitosterolemia
MedGen UID:
87466
Concept ID:
C0342907
Congenital Abnormality
Sitosterolemia is characterized by: Tendon xanthomas or tuberous (i.e., planar) xanthomas that can occur in childhood and in unusual locations (heels, knees, elbows and buttocks); Premature atherosclerosis which can lead to angina, aortic valve involvement, myocardial infarction, and sudden death; Hemolytic anemia, abnormally shaped erythrocytes (stomatocytes), and large platelets (macrothrombocytopenia). On occasion, the abnormal hematologic findings may be the initial presentation. The phenotypic spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis and the fact that clinical findings in infants are likely to be highly dependent on diet.

Professional guidelines

PubMed

Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, Stalenhoef AF; Endocrine society.
J Clin Endocrinol Metab 2012 Sep;97(9):2969-89. doi: 10.1210/jc.2011-3213. PMID: 22962670Free PMC Article

Recent clinical studies

Etiology

Perron P, Brisson D, Santuré M, Blackburn P, Bergeron J, Vohl MC, Després JP, Gaudet D
J Endocrinol Invest 2007 Jul-Aug;30(7):551-7. doi: 10.1007/BF03346348. PMID: 17848837
Ryomoto KI, Suzuki M, Kanazawa A, Hasegawa M, Kimura Y, Yamamura T, Harano Y
Am J Hypertens 2000 Jun;13(6 Pt 1):617-24. PMID: 10912744
Vohl MC, Lepage P, Gaudet D, Brewer CG, Bétard C, Perron P, Houde G, Cellier C, Faith JM, Després JP, Morgan K, Hudson TJ
J Lipid Res 2000 Jun;41(6):945-52. PMID: 10828087
Hattori Y, Suzuki M, Tsushima M, Yoshida M, Tokunaga Y, Wang Y, Zhao D, Takeuchi M, Hara Y, Ryomoto KI, Ikebuchi M, Kishioka H, Mannami T, Baba S, Harano Y
Atherosclerosis 1998 Jun;138(2):289-99. PMID: 9690912
Nuotio IO, Raitakari OT, Porkka KV, Räsänen L, Moilanen T, Viikari JS
Arterioscler Thromb Vasc Biol 1997 May;17(5):820-5. PMID: 9157943

Diagnosis

Ryomoto KI, Suzuki M, Kanazawa A, Hasegawa M, Kimura Y, Yamamura T, Harano Y
Am J Hypertens 2000 Jun;13(6 Pt 1):617-24. PMID: 10912744
Vohl MC, Lepage P, Gaudet D, Brewer CG, Bétard C, Perron P, Houde G, Cellier C, Faith JM, Després JP, Morgan K, Hudson TJ
J Lipid Res 2000 Jun;41(6):945-52. PMID: 10828087
Hattori Y, Suzuki M, Tsushima M, Yoshida M, Tokunaga Y, Wang Y, Zhao D, Takeuchi M, Hara Y, Ryomoto KI, Ikebuchi M, Kishioka H, Mannami T, Baba S, Harano Y
Atherosclerosis 1998 Jun;138(2):289-99. PMID: 9690912
Kwiterovich PO Jr, Coresh J, Bachorik PS
Am J Cardiol 1993 Mar 15;71(8):631-9. PMID: 8447257
Sniderman A, Cianflone K, Kwiterovich PO Jr, Hutchinson T, Barre P, Prichard S
Atherosclerosis 1987 Jun;65(3):257-64. PMID: 3619989

Therapy

Kwiterovich PO Jr
Nutr Metab Cardiovasc Dis 2001 Oct;11 Suppl 5:30-4. PMID: 12063773
Nuotio IO, Raitakari OT, Porkka KV, Räsänen L, Moilanen T, Viikari JS
Arterioscler Thromb Vasc Biol 1997 May;17(5):820-5. PMID: 9157943
Superko HR
Can J Cardiol 1995 May;11 Suppl C:4C-8C. PMID: 7750049
Solakivi T, Salo MK, Puska P, Nikkari T
Atherosclerosis 1988 Jul;72(1):55-61. PMID: 3214459
Lussier-Cacan S, Cantin M, Roy CC, Sniderman AD, Nestruck AC, Davignon J
Clin Invest Med 1986;9(2):94-9. PMID: 3731582

Prognosis

Gazi IF, Filippatos TD, Tsimihodimos V, Saougos VG, Liberopoulos EN, Mikhailidis DP, Tselepis AD, Elisaf M
Lipids 2006 Jul;41(7):647-54. PMID: 17069348
Ryomoto KI, Suzuki M, Kanazawa A, Hasegawa M, Kimura Y, Yamamura T, Harano Y
Am J Hypertens 2000 Jun;13(6 Pt 1):617-24. PMID: 10912744
Wetsel RA, Kildsgaard J, Zsigmond E, Liao W, Chan L
J Biol Chem 1999 Jul 2;274(27):19429-33. PMID: 10383458
Juo SH, Beaty TH, Kwiterovich PO Jr
Arterioscler Thromb Vasc Biol 1997 Nov;17(11):2729-36. PMID: 9409249
Sniderman A, Teng B, Genest J, Cianflone K, Wacholder S, Kwiterovich P Jr
Am J Cardiol 1985 Feb 1;55(4):291-5. PMID: 3969864

Clinical prediction guides

Kildsgaard J, Zsigmond E, Chan L, Wetsel RA
Mol Immunol 1999 Sep-Oct;36(13-14):869-76. PMID: 10698341
Wetsel RA, Kildsgaard J, Zsigmond E, Liao W, Chan L
J Biol Chem 1999 Jul 2;274(27):19429-33. PMID: 10383458
Hattori Y, Suzuki M, Tsushima M, Yoshida M, Tokunaga Y, Wang Y, Zhao D, Takeuchi M, Hara Y, Ryomoto KI, Ikebuchi M, Kishioka H, Mannami T, Baba S, Harano Y
Atherosclerosis 1998 Jun;138(2):289-99. PMID: 9690912
Juo SH, Beaty TH, Kwiterovich PO Jr
Arterioscler Thromb Vasc Biol 1997 Nov;17(11):2729-36. PMID: 9409249
Sniderman A, Teng B, Genest J, Cianflone K, Wacholder S, Kwiterovich P Jr
Am J Cardiol 1985 Feb 1;55(4):291-5. PMID: 3969864

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