Advertisement

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

      Abstract

      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.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • 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