Hyperlipidemias: Charlton-Menys V

Charlton-Menys V, Durrington PN. · No affiliation provided · Clin Chem. · Pubmed #15681559 links to  free full text

This publication has no abstract.

Charlton-Menys V, Durrington PN. · Cardiovascular Research Group, School of Clinical & Laboratory Sciences, Core Technology Facility (3rd Floor), University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK. · Exp Physiol. · Pubmed #18165431 links to  free full text

Abstract: There has been a fascinating interplay between the discovery of some of the key enzymes, receptors and transporters in cholesterol biosynthesis and transfer and the development of drugs for the regulation of cholesterol metabolism. The discovery of the low-density lipoprotein (LDL) receptor led to the realization that circulating LDL cholesterol could be decreased when hepatic LDL receptor expression was stimulated by decreasing intrahepatic cholesterol levels. The first class of drugs which operate in this way were the bile-acid sequestrating agents, which, by interrupting the enterohepatic circulation of bile acids, deplete the liver of cholesterol used to replenish the pool of bile salts. Ezetimibe, which was developed to block cholesterol absorption from the intestine, led to the discovery of the Nieman-Pick C1-Like 1 sterol transporter channel. The statins, which have proved enormously successful in preventing cardiovascular disease, were discovered amongst fungal metabolites which inhibit hydroxyl methyl CoA reductase, the rate-limiting enzyme for hepatic cholesterol biosynthesis. Drugs which block enzymes at other stages of the cholesterol biosynthetic pathway, particularly the squalene synthase inhibitors, are entering the clinical phase of their development. Drugs which interfere with hepatic very low-density lipoprotein assembly in the liver, such as microsomal triglyceride transfer protein inhibitors and apolipoprotein B mRNA antisense oligonucleotides, are currently undergoing evaluation. Cholesteryl ester transfer protein (CETP) inhibitors, which decrease cholesteryl ester heteroexchange within the circulation, have undergone development to the point of clinical evaluation, and this will eventually settle the controversy about whether CETP is pro- or antiatherogenic.

Joy T, Cao H, Black G, Malik R, Charlton-Menys V, Hegele RA, Durrington PN. · Department of Vascular Biology and Medicine, Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada. · Orphanet J Rare Dis. · Pubmed #18154657 links to  free full text

Abstract: BACKGROUND: Alstrom syndrome (AS) is a rare autosomal recessive disease characterized by multiorgan dysfunction. The key features are childhood obesity, blindness due to congenital retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia. Thus, AS shares several features with the common metabolic syndrome, namely obesity, hyperinsulinemia, and hypertriglyceridemia. Mutations in the ALMS1 gene have been found to be causative for AS with a total of 79 disease-causing mutations having been described. CASE PRESENTATION: We describe the case of a 27-year old female from an English (Caucasian) kindred. She had been initially referred for hypertriglyceridemia, but demonstrated other features suggestive of AS, including blindness, obesity, type 2 diabetes, renal dysfunction, and hypertension. DNA analysis revealed that she is a compound heterozygote with two novel mutations in the ALMS1 gene - H3882Y and V424I. Examination of her family revealed that her phenotypically unaffected mother and younger sister also had heterozygous mutations in the ALMS1 gene. In addition to presenting these novel molecular findings for AS, we review the clinical and genetic features of AS in the context of our case. CONCLUSION: Two novel mutations in the ALMS1 gene causative for AS have been reported here, thereby increasing the number of reported mutations to 81 and providing a wider basis for mutational screening among affected individuals.

Beeharry D, Coupe B, Benbow EW, Morgan J, Kwok S, Charlton-Menys V, France M, Durrington PN. · University of Manchester, Division of Cardiovascular and Endocrine Science, Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13, UK. · Ann Rheum Dis. · Pubmed #16176995 links to  free full text

Abstract: BACKGROUND: Patients with heterozygous familial hypercholesterolaemia (HeFH) develop tendon xanthomata (TX), most commonly in their Achilles tendons. Even before tendons are chronically enlarged, tenosynovitis may occur and medical advice be sought. Untreated HeFH carries a high risk of premature coronary heart disease, which can be ameliorated by early diagnosis. OBJECTIVE: To determine the prevalence of episodes of Achilles tendon pain in HeFH before its diagnosis. METHODS: Patients with definite HeFH (Simon Broome criteria) attending a lipid clinic were identified. They completed a questionnaire asking about symptoms relating to their Achilles tendons. Unaffected spouses or cohabiting partners served as controls. RESULTS: 133 patients (47% men) and 87 controls (51% men) participated. TX had been recognised by the referring physicians in <5% of cases. However, 62 (46.6% (95% confidence interval (CI) 38.1 to 55.1)) patients had experienced one or more episodes of pain in one or both Achilles tendons lasting >3 days, whereas only 6 (6.9% (1.6 to 12.2)) controls had done so (difference p<0.001; likelihood ratio 6.75). Typically, in the patients with HeFH the pain lasted 4 days (median). It was described as severe or very severe in 24/62 (38.7% (30.4 to 47.0)) patients with HeFH, but never more than moderate in controls. 35 (26.3% (18.8 to 33.8)) patients with HeFH had consulted a doctor about Achilles tendon pain, but in no case had this led to a diagnosis of HeFH. None of the controls had consulted a doctor. CONCLUSIONS: Measurement of serum cholesterol in patients presenting with painful Achilles tendon could lead to early diagnosis of HeFH.