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Journal of Applied Genetics 49(1), 2008, pp. 109-113

Clinical course of homozygous familial hypercholesterolemia during childhood: report on 4 unrelated patients with homozygous or compound heterozygous mutations in the LDLR gene

Jolanta Kubalska, Magdalena Chmara, Janusz Limon, Aldona Wierzbicka, Sylwester Prokurat, Janina Szaplyko, Agnieszka Kowalik, Hanna Mierzewska, Joep C. Defesche, Ewa Pronicka

Abstract: Natural history of the disease in 4 unrelated Polish children with homozygous familial hypercholesterolemia (FH) is described. Their phenotypic homozygosity was established by identification of known LDLR gene mutations on both alleles, respectively: p.G592E & p.G592E in Patient 1; p.G592E & p.C667Y in Patient 2; p.S177L & p.R350X in Patient 3; and p.G592E & deletion in the promoter region, exons 1 and 2 in Patient 4. Heterozygosity of the mutations was revealed in all patients' mothers and fathers (obligatory heterozygotes) and in 1 out of 4 siblings studied. FH was diagnosed at the age of 4 months to 9 years by cholesterol screening among family members of patients with early cardiovascular disease episodes. At the time of FH detection, the children were asymptomatic. Only in 2, some skin eruptions were found. Antihyperlipidemic therapy was started, including a lipid-lowering diet, cholestyramine, and HMG-CoA inhibitors if necessary. No cardiovascular symptoms appeared during the observation up to the age of 18, 20, 19, and 17 years, respectively. An increase in external carotid artery diameter was found in a patient at the age of 9 years, and LDL-apheresis was introduced in his therapy. We conclude that the analysis of LDLR gene mutations in the studied FH children made it possible to identify 4 presymptomatic FH homozygotes and to introduce early appropriate treatment. Multicenter analysis of such persons would finally determine if the early lipid-lowering procedures can significantly reduce the risk of premature cardiovascular disease in homozygous FH.

Key words: children, familial hypercholesterolemia, homozygotes, LDL-receptor gene mutations, LDLR gene.

Correspondence: E. Pronicka, Department of Metabolic Diseases, Endocrinology and Diabetology Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warszawa, Poland; e-mail:

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