Genetic determinants of responsiveness to the HMG-CoA reductase inhibitor fluvastatin in patients with molecularly defined heterozygous familial hypercholesterolemia.

BACKGROUND: In familial hypercholesterolemia, plasma lipoproteins can be modulated by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, although the underlying response mechanisms are still unknown. METHODS AND RESULTS: A single-blind study with fluvastatin, an HMG-CoA reductase inhibitor, was conducted in 64 familial hypercholesterolemia patients who had defined apolipoprotein E (apo E) and apolipoprotein(a) [apo(a)] isoforms. Plasma lipids and lipoproteins were analyzed throughout the study. The patients were grouped according to low density lipoprotein (LDL) receptor genotype. After 4 weeks of treatment with 40 mg of fluvastatin, the mean decrease in plasma LDL cholesterol (LDL-C) in patients with the genetically characterized "Sephardic" and "Lithuanian" mutations was 16-18%, whereas in the other three groups, it was 25-30% (p < 0.005). High density lipoprotein cholesterol (HDL-C) levels increased in all groups. Multivariate analyses suggested that 41% of the LDL-C response can be explained by the LDL receptor mutation, body mass index, apo E3/E4 phenotype, apo(a) isoform LpS2, and baseline LDL-C levels, and 46% of the change in HDL-C is associated with age, sex, body mass index, baseline HDL-C, and the Sephardic mutation. CONCLUSIONS: Fluvastatin exhibits diverse and independent effects on plasma lipoproteins related to several constitutional, genetic, and familial factors. Information regarding these factors may provide better prediction of patients' clinical responses to fluvastatin.

Efficacy and safety of high dose fluvastatin in patients with familial hypercholesterolaemia.

The efficacy and safety of the HMG CoA reductase inhibitor fluvastatin have been evaluated in a double blind study in 52 patients with familial hypercholesterolaemia. A standard AHA Phase II lipid lowering diet was prescribed throughout the study. After 6 weeks of a single blind dosage stabilisation period, in which patients received fluvastatin 40 mg qPM, patients were randomly allocated to one of two double blind treatment groups: group A (n = 24) received fluvastatin 20 mg b.d. for 12 weeks and fluvastatin 20 mg AM + 40 mg PM for an additional 12 weeks; Group B (n = 28) received fluvastatin 40 mg qPM during the entire study. Safety and tolerability were evaluated by the analysis of biochemical and haematological parameters, and ophthalmological and physical examinations. Efficacy was analysed by the determination of plasma lipids, lipoproteins and apoproteins. Fluvastatin 40 mg/d was associated with up to a 27.4% decrease in LDL-C and a 9.6% increase in HDL-C concentrations. Increasing the dose of fluvastatin from 20 mg b.d. to 60 mg per day in Group A was associated with a 7.1% decrease in LDL-C, a 12.1% increase of HDL-C and a 12.8% decrease in the LDL-C/HDL-C ratio. In comparison with Group B (40 mg qPM) LDL-C, HDL-C and the LDL-C/HDL-C ratio in Group A (60 mg) differed by -8.9%, 6.6% and -12%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

A nonsense mutation in the LDL receptor gene leads to familial hypercholesterolemia in the Druze sect.

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the LDL receptor gene. Here we characterize an LDL receptor mutation that is associated with a distinct haplotype and causes FH in the Druze, a small Middle Eastern Islamic sect with a high degree of inbreeding. The mutation was found in FH families from two distinct Druze villages from the Golan Heights (northern Israel). It was not found neither in another Druze FH family residing in a different geographical area nor in eight Arab and four Jewish FH heterozygote index cases whose hypercholesterolemia cosegregates with an identical LDL receptor gene haplotype. The mutation, a single-base substitution, results in a termination codon in exon 4 of the LDL receptor gene that encodes for the fourth repeat of the binding domain of the mature receptor. It can be diagnosed by allele-specific oligonucleotide hybridization of PCR-amplified DNA from FH patients.

A common Lithuanian mutation causing familial hypercholesterolemia in Ashkenazi Jews.

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the low-density-lipoprotein (LDL) receptor. Here we characterize an LDL-receptor founder mutation that is associated with a distinct LDL-receptor haplotype and is responsible for FH in 35% of 71 Jewish-Ashkenazi FH families in Israel. Sixty four percent (16/25) of the Ashkenazi patients who carry this mutant allele were of Lithuanian origin. The mutation was not found in 47 non-Ashkenazi FH families. This mutation was prevalent (8/10 FH cases) in the Jewish community in South Africa, which originated mainly from Lithuania. The mutation, a 3-bp in-frame deletion that would result in the elimination of Gly197, has been previously designated FH-Piscataway. PCR amplification of a DNA fragment that includes the mutation in heterozygous individuals results in the formation of a heteroduplex that can be demonstrated by PAGE and used for molecular diagnosis.

The skull in chronic sarcoidosis.

A report of a 63 year old woman with giant osteolytic skull lesions simulating metastatic disease, and generalized cutaneous lesions is presented. Biopsy of a skin lesion revealed non-caseating granulomas compatible with sarcoidosis. The literature dealing with calvarial sarcoidosis is reviewed.