Autosomal recessive hypercholesterolemia in a kindred of Syrian ancestry
Autor: | Berit Storgaard Hedegaard, Ib Christian Klausen, Anne Tybjærg-Hansen, Morten Hostrup Martinsen |
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Rok vydání: | 2020 |
Předmět: |
medicine.medical_specialty
Nutrition and Dietetics business.industry Endocrinology Diabetes and Metabolism Atorvastatin Genetic disorder 030204 cardiovascular system & hematology Xanthoma Compound heterozygosity medicine.disease Gastroenterology Frameshift mutation 03 medical and health sciences 0302 clinical medicine Ezetimibe Autosomal Recessive Hypercholesterolemia Internal medicine Internal Medicine medicine lipids (amino acids peptides and proteins) 030212 general & internal medicine Cardiology and Cardiovascular Medicine business Pravastatin medicine.drug |
Zdroj: | Journal of Clinical Lipidology. 14:419-424 |
ISSN: | 1933-2874 |
Popis: | 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 LDLRAP1 and lead to regression of large xanthomas. |
Databáze: | OpenAIRE |
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