#144010
ICD+
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| HYPERCHOLESTEROLEMIA, AUTOSOMAL DOMINANT, TYPE B | ||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||
| APOLIPOPROTEIN B-100, FAMILIAL LIGAND-DEFECTIVE HYPERCHOLESTEROLEMIA, FAMILIAL, DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN B APOLIPOPROTEIN B-100, FAMILIAL DEFECTIVE | ||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that the phenotype is caused by mutation in the LDL receptor-binding domain of apolipoprotein B-100 (see 107730.0009 and 107730.0017). Higgins et al. (1975) described father and daughter with hypercholesterolemia which appeared to be due to an abnormality in LDL such that it did not interact properly with the receptor. The proband's leukocytes showed normal suppression of HMG CoA reductase activity when exposed to lipoprotein from sources other than the 2 patients. (Perhaps a letter designation can be used for the several forms of familial hypercholesterolemia. Roman numbers run the risk of confusion with the Fredrickson types of hyperlipoproteinemia.) The Ag system of lipoprotein types (see 107730) represents variation in the apoprotein of LDL and each LDL molecule may contain 2 identical protein subunits. Thus, the locus of this mutation might be the Ag locus (if the abnormal binding is due to a change in the protein of LDL). Goldstein (1987) stated that an abnormality in LDL was not confirmed in his or in a second laboratory. The putatively abnormal LDL tested normal in all of their culture systems and also tested normal when injected into animals. Myant et al. (1976) found that the putatively abnormal LDL behaved in a normal fashion in various in vivo and in vitro assays. Goldstein (1987) stated further that although no documented cases of hypercholesterolemia due to mutations in the apoB gene were known, he 'would not be surprised if such cases were discovered any time--now that cDNA probes for the apoB of LDL are widely available.' The prophecy was fulfilled by the demonstration of familial hypercholesterolemia due to defective apoB-100. Goldstein and Brown (1974) showed that the classic form of familial hypercholesterolemia (143890) results from defects in the cell surface receptor that removes LDL particles from plasma (LDLR; 606945). Innerarity et al. (1987) demonstrated the genetic heterogeneity of autosomal dominant hypercholesterolemia by reporting hypercholesterolemic patients with normal LDLR activity and defective apolipoprotein B-100 (APOB; 107730) that displayed low affinity for its receptor. This novel form of the disorder was called familial ligand-defective apolipoprotein B-100, or type B familial hypercholesterolemia, because mutations were identified in the APOB gene (e.g., 107730.0009). Classic FH and the ligand-defective form (type B) map to chromosomes 19 and 2, respectively. Hansen et al. (1997) attempted to identify determinants of phenotypic variation in patients heterozygous for familial defective apolipoprotein B in 205 patients: 73 from Germany, 87 from the Netherlands, and 45 from Denmark. In addition, they attempted to assess whether the clinical phenotype of familial defective apoB differs from that of familial hypercholesterolemia. Besides age, sex, and geographic origin, variation in the LDLR gene was found to be the most powerful determinant of variation in total cholesterol and LDL cholesterol levels. Polymorphic variation in the LDLR gene was associated with total cholesterol and LDL variation in women. The expected association of APOE genotypes with cholesterol concentrations was also seen. With regard to clinical expression, familial defective APOB patients had lower total cholesterol and LDL cholesterol levels and a lower prevalence of cardiovascular disease than did 101 Danish patients with familial hypercholesterolemia. | ||||||||||||||||||
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