Autosomal recessive hypercholesterolaemia: long-term follow up and response to treatment


      Autosomal recessive hypercholesterolaemia (ARH) is caused by mutations in ARH on chromosome 1p35–36, encoding a putative adaptor protein. Mutations in the gene prevent normal internalisation of the low density lipoprotein (LDL) receptor by cultured lymphocytes and monocyte-derived macrophages, but not skin fibroblasts. This newly identified disorder is characterised by severe hypercholesterolaemia, large tendon, tuberous and planar xanthomas and premature atherosclerosis.
      We describe long-term (9–23 years) follow up and response to treatment of eight subjects with ARH from four families (Turkish/Lebanese, Indian-Asian, English and Italian). The clinical phenotype of ARH is similar to that of classical homozygous familial hypercholesterolaemia (FH) caused by mutations in the LDL-receptor gene but is more variable, less severe and is more responsive to lipid-lowering therapy with bile acid sequestrants and/or HMG–CoA reductase inhibitors. The latter reduced total serum cholesterol by up to 60% and the former by 20–35%. The cardiovascular complications of premature atherosclerosis seem to be delayed in some individuals and the involvement of the aortic root and valve are rarer in comparison with homozygous FH.


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        • Khachadurian A.K.
        • Uthman S.M.
        Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients.
        Nutr. Metab. 1973; 15: 132-140
        • Harada-Shiba M.
        • Tajima S.
        • Yokoyama S.
        • et al.
        Siblings with normal LDL-receptor activity and severe hypercholesterolemia.
        Arterioscler. Thromb. 1992; 12: 1071-1078
        • Zuliani G.
        • Arca M.
        • Signore A.
        • et al.
        Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia.
        Arterioscler. Thromb. Vasc. Biol. 1999; 19: 802-809
        • Norman D.
        • Sun X.M.
        • Bourbon M.
        • Knight B.L.
        • Naoumova R.P.
        • Soutar A.K.
        Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia.
        J. Clin. Invest. 1999; 104: 619-628
        • Eden E.R.
        • Naoumova R.P.
        • Burden J.J.
        • McCarthy M.I.
        • Soutar A.K.
        Use of homozygosity mapping to identify a region on chromosome 1 bearing a defective gene that causes autosomal recessive homozygous hypercholesterolemia in two unrelated families.
        Am. J. Hum. Genet. 2001; 68: 653-660
        • Garcia C.K.
        • Wilund K.
        • Arca M.
        • et al.
        Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL-receptor adaptor protein.
        Science. 2001; 292: 1394-1398
        • Forman-Kay J.D.
        • Pawson T.
        Diversity in protein recognition by PTB domains.
        Curr. Opin. Struct. Biol. 1999; 9: 690-695
        • Eden E.R.
        • Patel D.D.
        • Sun X.M.
        • et al.
        Restoration of LDL-receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1.
        J. Clin. Invest. 2002; 110: 1695-1702
        • Cohen J.C.
        • Kimmel M.
        • Polanski A.
        • Hobbs H.H.
        Molecular mechanisms of autosomal recessive hypercholesterolemia.
        Curr. Opin. Lipidol. 2003; 14: 121-127
        • Harada-Shiba M.
        • Takagi A.
        • Miyamoto Y.
        • et al.
        Clinical features and genetic analysis of autosomal recessive hypercholesterolemia.
        J. Clin. Endocrinol. Metab. 2003; 88: 2541-2547
        • Soutar A.K.
        • Naoumova R.P.
        • Traub L.M.
        Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia.
        Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1963-1970
        • Zuliani G.
        • Vigna G.B.
        • Corsini A.
        • Maioli M.
        • Romagnoni F.
        • Fellin R.
        Severe hypercholesterolaemia: unusual inheritance in an Italian pedigree.
        Eur. J. Clin. Invest. 1995; 25: 322-331
        • Schmidt H.H.
        • Stuhrmann M.
        • Shamburek R.
        • et al.
        Delayed low density lipoprotein (LDL) catabolism despite a functional intact LDL-apolipoprotein B particle and LDL-receptor in a subject with clinical homozygous familial hypercholesterolemia.
        J. Clin. Endocrinol. Metab. 1998; 83: 2167-2174
        • Ciccarese M.
        • Pacifico A.
        • Tonolo G.
        • et al.
        A new locus for autosomal recessive hypercholesterolemia maps to human chromosome 15q25-q26.
        Am. J. Hum. Genet. 2000; 66: 453-460
        • Arca M.
        • Zuliani G.
        • Wilund K.
        • et al.
        Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis.
        Lancet. 2002; 359: 841-847
        • Barbagallo C.M.
        • Emmanuele G.
        • Cefalu A.B.
        • et al.
        Autosomal recessive hypercholesterolemia in a Sicilian kindred harboring the 432insA mutation of the ARH gene.
        Atherosclerosis. 2003; 166: 395-400
        • Al Kateb H.
        • Bahring S.
        • Hoffmann K.
        • et al.
        Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.
        Circ. Res. 2002; 90: 951-958
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin. Chem. 1972; 18: 499-502
        • Rallidis L.
        • Nihoyannopoulos P.
        • Thompson G.R.
        Aortic stenosis in homozygous familial hypercholesterolaemia.
        Heart. 1996; 76: 84-85
      1. Thompson GR. A Handbook of hyperlipidaemia. 2nd ed. London: Current Sciences Ltd.; 1994.

        • Rallidis L.
        • Naoumova R.P.
        • Thompson G.R.
        • Nihoyannopoulos P.
        Extent and severity of atherosclerotic involvement of the aortic valve and root in familial hypercholesterolaemia.
        Heart. 1998; 80: 583-590
      2. Goldstein J, Hobbs H, Brown M. Familial hypercholesterolemia. In: Valle D, Scriver CR, Beaudet A, Sly WS, Childs B, Kinzler KW, Volgestein B, editors. The metabolic and molecular bases of inherited disease. 8th ed., vol. 2, New York: McGraw Hill; 2001. p. 2863–913.

        • Marais A.D.
        • Naoumova R.P.
        • Firth J.C.
        • Penny C.
        • Neuwirth C.K.
        • Thompson G.R.
        Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial hypercholesterolemia.
        J. Lipid Res. 1997; 38: 2071-2078
        • Bilheimer D.W.
        • Grundy S.M.
        • Brown M.S.
        • Goldstein J.L.
        Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes.
        Proc. Natl. Acad. Sci. U.S.A. 1983; 80: 4124-4128
        • Spengel F.A.
        • Jadhav A.
        • Duffield R.G.
        • Wood C.B.
        • Thompson G.R.
        Superiority of partial ileal bypass over cholestyramine reducing cholesterol in familial hypercholesterolaemia.
        Lancet. 1981; 2: 768-770
        • Naoumova R.P.
        • Dunn S.
        • Rallidis L.
        • et al.
        Prolonged inhibition of cholesterol synthesis explains the efficacy of atorvastatin.
        J. Lipid Res. 1997; 38: 1496-1500