1. Autosomal recessive hypercholesterolemia in a kindred of Syrian ancestry.
- Author
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Martinsen, Morten Hostrup, Klausen, Ib Christian, Tybjaerg-Hansen, Anne, and Hedegaard, Berit Storgaard
- Subjects
ANTILIPEMIC agents ,COMBINATION drug therapy ,CONFERENCES & conventions ,HYPERCHOLESTEREMIA ,LOW density lipoproteins ,GENETIC mutation ,GENETIC testing ,STATINS (Cardiovascular agents) ,PRAVASTATIN ,TREATMENT effectiveness ,EZETIMIBE ,ATORVASTATIN ,CHOLESTYRAMINE ,JUVENILE xanthogranuloma - Abstract
Autosomal recessive hypercholesterolemia is a rare genetic disorder due to homozygosity or compound heterozygosity for mutations in the low-density lipoprotein receptor adapter protein 1 gene (LDLRAP1), resulting in elevated low-density lipoprotein cholesterol (LDL-C) levels, large xanthomas, and increased cardiovascular risk. Here, we describe a Danish family of Syrian ancestry carrying a frameshift mutation in LDLRAP1, previously only described in Sardinia and Sicily in Italy and in Spain. In 2 children homozygous for this mutation, we evaluate the effect of long-term lipid-lowering treatment with atorvastatin as monotherapy or in combination with ezetimibe. At referral to the lipid clinic at Viborg Regional Hospital, 3 of 4 children had LDL-C levels of 468, 538, and 371 mg/dL, respectively, with 1 child already showing cutaneous xanthomas at 10 years of age. For comparison, the fourth child and the parents had LDL-C levels of 85, 116, and 124 mg/dL. Genetic testing revealed that all 3 children with severely elevated LDL-C were homozygous for a rare frameshift mutation in LDLRAP1, p.His144GlnfsTer27 (c.431dupA), whereas the fourth child and both parents were heterozygous for this mutation. Lipid-lowering treatment was started in the 2 oldest children (at 10 and 7 years of age). Atorvastatin (40 mg/d) combined with ezetimibe (10 mg/d) reduced LDL-C by 75% in the first child and resulted in near-complete regression of xanthomas. In the second child, atorvastatin (40 mg/d) as monotherapy reduced LDL-C by 61%. Both regimens were superior to treatment with pravastatin as monotherapy (20 mg/d) and to pravastatin in combination with cholestyramine (2 g twice daily). High-intensity statin therapy alone or in combination with ezetimibe resulted in marked reductions in LDL-C in 2 children homozygous for a rare frameshift mutation in LDLRAP 1 and lead to regression of large xanthomas. • First documented case of autosomal recessive hypercholesterolemia from a low-density lipoprotein receptor adapter protein 1 gene mutation in Denmark. • Regression of large xanthoma after intensive lipid-lowering treatment. • Atorvastatin with ezetimibe yields great biochemical response. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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