Zuliani et al. (1995) described a Sardinian family in which the probands had a severe form of hypercholesterolemia with the clinical features of familial hypercholesterolemia (FH; 143890) homozygotes, including severely elevated plasma low density lipoprotein (LDL) cholesterol, tuberous ... Zuliani et al. (1995) described a Sardinian family in which the probands had a severe form of hypercholesterolemia with the clinical features of familial hypercholesterolemia (FH; 143890) homozygotes, including severely elevated plasma low density lipoprotein (LDL) cholesterol, tuberous and tendon xanthomata, and premature atherosclerosis. However, LDL receptor (LDLR; 606945) activity measured in skin fibroblasts was normal, as was LDL binding ability. Haplotype segregation analysis excluded involvement of the LDLR and apolipoprotein B (APOB; 107730) genes in the pathogenesis of the disorder. Consanguinity, absence of vertical transmission, and bimodal distribution of plasma cholesterol levels in the kindred were consistent with autosomal recessive inheritance. Sitosterolemia (210250) and pseudohomozygous hyperlipidemia (see 144250) were ruled out. Zuliani et al. (1999) identified a second Sardinian kindred with similar characteristics. The probands showed severe hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective apoB, sitosterolemia, and cholesteryl ester storage disease (278000) were excluded by in vitro studies. By LDL turnover studies, the authors found a marked reduction in the fractional catabolic rate and a significant increase in the production rate of LDL apoB in the probands compared with normolipidemic controls. The probands also showed a significant reduction in hepatic LDL uptake, similar to that observed in the FH homozygote studied in parallel. A reduced uptake of LDL by the kidney and spleen was also observed in all patients. These findings suggested that this recessive form of hypercholesterolemia is due to a marked reduction of in vivo LDL catabolism. This appeared to be caused by a selective reduction in hepatic LDL uptake. Zuliani et al. (1999) proposed that in this new lipid disorder, a recessive defect causes a selective impairment of LDLR function in the liver. In a note added in proof, Zuliani et al. (1999) stated that 4 'new' Sardinian families with the characteristics of familial recessive hypercholesterolemia had been identified. In all probands, the LDLR activities in fibroblasts as well as the binding ability of LDL to the LDLR were normal. Schmidt et al. (1998) identified a 38-year-old male patient with the clinical expression of homozygous familial hypercholesterolemia presenting as severe coronary artery disease, tendon and skin xanthomas, arcus lipoides, and joint pain. They concluded that the disorder was autosomal recessive. Serum concentrations of cholesterol responded well to diet and statins. There was no evidence of an abnormal LDL-APOB particle, which was isolated from the patient by use of the U937 proliferation assay as a functional test of the LDL binding capacity. APOB-3500 and APOB-3531 defects were ruled out by PCR, and there was no evidence for a defect within the LDLR by skin fibroblast analysis, linkage analysis, SSCP, and Southern blot screening across the entire LDLR gene. The in vivo kinetics of radioiodinated LDL-APOB were evaluated in the proband and 3 normal controls. The LDL-APOB isolated from the patient showed normal catabolism, confirming an intact LDL particle. In contrast, the fractional catabolic rate of autologous LDL in the subject and normal controls revealed remarkably delayed catabolism of the patient's LDL. The elevation of LDL cholesterol in the patient resulted from an increased production rate with 22.8 mg/kg per day vs 12.7 to 15.7 mg/kg per day. The authors concluded that there is another catabolic defect beyond the APOB and LDLR genes causing familial hypercholesterolemia. Norman et al. (1999) identified apparently recessive familial hypercholesterolemia (FH) in 2 kindreds, one of Turkish origin and the other of Asian-Indian origin. The index patient of the Turkish family had a longstanding presumptive diagnosis of homozygous FH based on a raised plasma cholesterol concentration, the presence of extensive cutaneous xanthomata in the webs of her fingers and creases of her hands, and tendon xanthomata from an early age, as well as supravalvular aortic stenosis and premature coronary heart disease. The clinical characteristics of this woman were described in detail by Rallidis et al. (1996). A sib and a double first cousin were also affected. The affected individuals were the offspring of a first-cousin marriage in each case. All 4 parents were apparently unaffected. In the Asian-Indian family, 2 sisters were affected. The parents of this family were also reported to be first cousins, but no additional members of the family were available for study. Cells from the patients in these families exhibited no measurable degradation of LDL in culture. Extensive analysis of DNA and mRNA revealed no defect in the LDL receptor gene, and alleles of the LDLR and apolipoprotein B (APOB; 107730) genes did not cosegregate with hypercholesterolemia in these families. Fluorescence-activated cell sorting (FACS) analysis of binding and uptake of fluorescent LDL or anti-LDLR antibodies showed that LDL receptors were on the cell surface and bound LDL normally, but failed to be internalized, suggesting that some component of endocytosis through clathrin-coated pits was defective. Internalization of the transferrin receptor (190010) occurred normally, suggesting that the defective gene product may interact specifically with the LDL receptor internalization signal. Norman et al. (1999) concluded that identification of the defective gene would aid genetic diagnosis of other hypercholesterolemic patients and elucidate the mechanism by which LDL receptors are internalized, thus suggesting perhaps more appropriate methods of treatment then those currently used for FH patients with known genetic defects.
Analysis of the gene defect in large cohorts of patients with a diagnosis of heterozygous FH provided evidence that inherited defects in genes other than those encoding LDLR and APOB can cause the hypercholesterolemia typical of FH. In ... Analysis of the gene defect in large cohorts of patients with a diagnosis of heterozygous FH provided evidence that inherited defects in genes other than those encoding LDLR and APOB can cause the hypercholesterolemia typical of FH. In several of these cohorts, exhaustive analysis of the LDLR gene failed to reveal a defect in about 15% of the patients, and in 2 such studies a family with a sufficiently large pedigree was available to determine that an allele of these genes did not segregate with hypercholesterolemia, suggesting that their defect lay elsewhere (Sun et al., 1997; Haddad et al., 1999). In families with autosomal recessive hypercholesterolemia, Garcia et al. (2001) identified mutations in the ARH gene (see 605747.0001-605747.0006). In a Syrian family with autosomal recessive hypercholesterolemia, Al-Kateb et al. (2002) found evidence for an interaction between loci on 1p36.1-p35 and 13q22-q32 (see cholesterol-lowering factor, 604595). They identified an intron 1 acceptor splice site mutation in the ARH gene (605747.0007) in this family. In 2 affected sibs from a nonconsanguineous Mexican family with autosomal recessive hypercholesterolemia, Canizales-Quinteros et al. (2005) identified homozygosity for a donor splice site mutation in intron 4 of the ARH gene (605747.0008), resulting in a mutant protein with an altered phosphotyrosine-binding (PTB) domain. Both parents and an unaffected sister were heterozygous for the mutation.