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

• Autorzy: Kubalska J , Chmara M , Limon J , Wierzbicka A , Prokurat S , Szaplyko J , Kowalik A , Mierzewska H , Defesche J C , Pronicka E
• Języki publikacji: EN

Abstrakty

EN

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.

• Wydawca: -
• Czasopismo: Journal of Applied Genetics
• Rocznik: 2008
• Tom: 49
• Numer: 1
• Opis fizyczny: p.109-113,ref.

Twórcy

autor

Kubalska J

• Department of Metabolic Diseases, Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland
• Department of Genetics, Institute of Psychiatry and Neurology, Warszawa, Poland

autor

Chmara M

• Department of Biology and Genetics, Medical University of Gdańsk, Poland

autor

Limon J

• Department of Biology and Genetics, Medical University of Gdańsk, Poland

autor

Wierzbicka A

• Department of Laboratory Diagnostics

autor

Prokurat S

• Department of Nephrology, Transplantology and Hypertension, Children's Memorial Health Institute, Warszawa, Poland

autor

Szaplyko J

• Department of Laboratory Diagnostics

autor

Kowalik A

• Department of Metabolic Diseases, Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland

autor

Mierzewska H

• Department of Metabolic Diseases, Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland

autor

Defesche J C

• Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands

autor

Pronicka E

• Department of Metabolic Diseases, Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland

Bibliografia

• Bertolini S, Cassanelli S, Garuti R, Ghisellini M, Simone ML, Rolleri M, et al. 1999. Analysis of LDL receptor gene mutations in Italian patients with homozygous familial hypercholesterolemia. Arterioscler Thromb Vase Biol 19: 408-418.
• Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S, et al. 2000 Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype. Arterioscler Thromb Vase Biol 20: E41-E52.
• Couture P, Brun LD, Szots F, Lelievre M, Gaudet D, Despres JP, et al. 1998. Association of specific LDL receptor gene mutations with differential plasma lipoprotein response to simvastatin in young French Canadians with heterozygous familial hypercholesterolemia. Arterioscler Thromb Vase Biol 18: 1007-1012.
• Goldstein JL, Hobbs HH, Brown MS, 2001. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Valle D, Sly WS, eds. The metabolic and molecular bases of inherited disease. McGraw-Hill Medical Publishing Division, New York: 2863-2914.
• Gorski B, Kubalska J, Naruszewicz M, Lubinski J, 1998. LDL-R and Apo-B-100 gene mutations in Polish familial hypercholesterolemias. Hum Genet 102: 562-565.
• Hoeg JM, 1993. Homozygous familial hypercholesterolemia: a paradigm for phenotypic variation. Am J Cardiol 72: 11D-14D.
• Marais AD, Firth JC, Blom DJ, 2004. Homozygous familial hypercholesterolemia and its management. Semin Vase Med 4: 43-50.
• Moorjani S, Roy M, Torres A, Betard C, Gagne C, Lambert M, et al. 1993. Mutations of low-density-lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia. Lancet 341: 1303-1306.
• Schuster H, Rauh G, Muller S, Keller C, Wolfram G, Zollner N, 1992. Allele-specific and asymmetric polymerase chain reaction amplification in combination: a one step polymerase chain reaction protocol for rapid diagnosis of familial defective apolipoprotein B-100. Anal Biochem 204: 22-25.
• [WHO] World Health Organisation, 1999. Human Genetics Programme. Familial Hypercholesterolemia (FH); Report of a second WHO Consultation, Geneva.