Hyperlipidemias: Norbury G

Humphries SE, Norbury G, Leigh S, Hadfield SG, Nair D. · Division of Cardiovascular Genetics, British Heart Foundation Laboratories, Department of Medicine, Royal Free and UCL Medical School, London, UK. · Curr Opin Lipidol. · Pubmed #18607183 No free full text.

Abstract: PURPOSE OF REVIEW: Familial hypercholesterolaemia is a common genetic disorder of lipid metabolism in which patients have a significantly elevated risk of early coronary heart disease, which can be substantially lowered by treatment with the statin class of drugs. In many countries in Europe, tracing of relatives using DNA information, once the family mutation has been identified, is being actively carried out. The present review examines the specificity and clinical utility of DNA testing in patients with familial hypercholesterolaemia. RECENT FINDINGS: Technological progress has improved the detection rate in patients with the strongest clinical suspicion of familial hypercholesterolaemia to more than 70-80%. Patients carrying a mutation have, on average, higher low-density lipoprotein cholesterol levels and greater risk of early coronary heart disease, and studies have reported the utility of DNA information in the identification of affected relatives. More than 1000 different molecular causes of familial hypercholesterolaemia are documented in the University College London database, and although more than 90% of these clearly cause familial hypercholesterolaemia, the remainder require careful interpretation. SUMMARY: DNA testing, as an adjunct to the measurement of plasma low-density lipoprotein cholesterol levels, has clinical utility in providing an unequivocal diagnosis in patients and in identifying affected relatives at an early age so that they can be offered lifestyle advice and appropriate lipid-lowering therapies. Researchers and DNA diagnostic laboratories need to interpret novel sequence changes with caution in order to avoid a false positive diagnosis.

Smith AJ, Ahmed F, Nair D, Whittall R, Wang D, Taylor A, Norbury G, Humphries SE. · Department of Medicine, Centre for Cardiovascular Genetics, University College London, London, UK. · Eur J Hum Genet. · Pubmed #17625505 links to  free full text

Abstract: A novel sequence change in repeat 3 of the promoter of the low-density lipoprotein receptor (LDLR) gene, -139C>G, has been identified in a patient with familial hypercholesterolemia (FH). LDLR -139G has been passed to one offspring who also shows an FH phenotype. Transient transfection studies using luciferase gene reporter assays revealed a considerable reduction (74+/-1.4% SEM) in reporter gene expression from the -139G variant sequence compared to the wild-type sequence, strongly suggesting that this change is the basis for FH in these patients. Analysis using electrophoretic mobility shift assay demonstrated the loss of Sp1 binding to the variant sequence in vitro, explaining the reduction of transcription.

Taylor A, Tabrah S, Wang D, Sozen M, Duxbury N, Whittall R, Humphries SE, Norbury G. · Regional Molecular Genetics Laboratory, Great Ormond Street Hospital for Children, Great Ormond Street, London, WC1N 3JH, UK. · Clin Genet. · Pubmed #17539906 No free full text.

Abstract: DNA analysis and mutation identification is useful for the diagnosis of familial hypercholesterolaemia (FH), particularly in the young and in other situations where clinical diagnosis may be difficult, and enables unambiguous identification of at-risk relatives. Mutation screening of the whole of the three FH-causing genes is costly and time consuming. We have tested the specificity and sensitivity of a recently developed multiplex amplification refractory mutation system assay of 11 low-density lipoprotein receptor gene (LDLR) mutations, one APOB (p.R3527Q) and one PCSK9 (p.D374Y) mutation in 400 patients attending 10 UK lipid clinics. The kit detected a mutation in 54 (14%) patients, and a complete screen of the LDLR gene using single-stranded conformation polymorphism/denaturing high performance liquid chromatography identified 59 different mutations (11 novel) in an additional 87 patients, for an overall detection rate of 35%. The kit correctly identified 38% of all detected mutations by the full screen, with no false-positive or false-negative results. In the patients with a clinical diagnosis of definite FH, the overall detection rate was higher (54/110 = 49%), with the kit detecting 52% of the full-screen mutations. Results can be obtained within a week of sample receipt, and the high detection rate and good specificity make this a useful initial DNA diagnostic test for UK patients.

Hendriksz CJ, Norbury G, Tabrah S, Taylor A, Humphries SE. · Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Pendlebury, Manchester M27 4HA, UK. · Acta Paediatr. · Pubmed #15046291 No free full text.

Abstract: A girl of Indian origin presented with unusual nodules on her hands, and total cholesterol was found to be > 25 mmol/L. The girl had "mild" P664L mutation and total cholesterol levels fell by 38% when she was on a diet and statin therapy. A further reduction of 26% in total cholesterol and 37% in low-density lipoprotein (LDL) was achieved by adding ezetimibe to the treatment. CONCLUSION: A case of homozygous hypercholesterolaemia is reported in order to highlight treatment options such as liver transplantation, LDL-aphaeresis and treatment with ezetimibe.