Autosomal recessive hypercholesterolaemia: normalization of plasma LDL cholesterol by ezetimibe in combination with statin treatment.
BACKGROUND
Severe hereditary hypercholesterolaemia is most frequently due to familial hypercholesterolaemia (FH), caused by mutations in the LDL receptor (LDLR) gene. However, a phenotype very similar to FH may also be caused by defects in other genes like the genes for apolipoprotein (apo) B-100 or autosomal recessive hypercholesterolaemia (ARH).


METHODS
An 8-year-old male of Lebanese origin was diagnosed with severe hypercholesterolaemia and extensive cutaneous and tendon xanthomas. Plasma LDL cholesterol before treatment was 17 mmol L(-1), whilst parents and both siblings had normal levels.


METHODS
Degradation of (125)I-labelled LDL in blood lymphocytes was reduced, but not abolished. Sequencing analysis of the LDLR and apoB-100 genes were negative, whilst a splice acceptor mutation in intron 1 (IVS 1 -1G>C) was detected in the ARH gene. The patient was homozygous for the mutation, whilst the parents were heterozygous. These findings were in agreement with a diagnosis of ARH.


METHODS
Monthly LDL apheresis and atorvastatin 120 mg daily reduced LDL cholesterol preapheresis level to 4.8 mmol L(-1). When ezetimibe was given 10 mg day(-1) in combination with rosuvastatin 80 mg day(-1), LDL cholesterol was further lowered to 1.6 mmol L(-1), which made apheresis unnecessary. Cutaneous and tendon xanthomas disappeared completely and the intima-media thickness of the common carotid arteries decreased. At age 23 he developed a small myocardial infarction.


CONCLUSIONS
ARH should be considered in cases of severe hypercholesterolaemia with a pattern of recessive inheritance. Combination therapy with high-dose statin and ezetimibe seems to be the treatment of choice in ARH and may reduce or eliminate the need for LDL apheresis treatment.
Department of Medicine and Care, Faculty of Health Sciences, Linköping University, Stockholm, Sweden. suzanne.lind@labmed.ki.se
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Lind
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Olsson
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Eriksson
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Rudling
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Eggertsen
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Angelin
D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage*; D001384:Azetidines / Q000008:administration & dosage*; D002648:Child; D008078:Cholesterol, LDL / Q000097:blood; D004338:Drug Combinations; D000069438:Ezetimibe; D005464:Fluorobenzenes / Q000008:administration & dosage*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D010375:Pedigree; D011743:Pyrimidines / Q000008:administration & dosage*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage*; D014973:Xanthomatosis / Q000188:drug therapy
D000924:Anticholesteremic Agents; D001384:Azetidines; D008078:Cholesterol, LDL; D004338:Drug Combinations; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D000069438:Ezetimibe