Haplotype analysis of the low density lipoprotein receptor (LDLR) gene was performed in Norwegian subjects heterozygous for familial hypercholesterolemia (FH). Southern blot analysis of genomic DNA, using an exon 18 specific probe and the restriction enzyme NcoI, showed that two out of 57 unrelated FH subjects had an abnormal 3.6 kb band. Further analyses revealed that this abnormal band was due to a 9.6 kb deletion that included exons 16 and 17. The 5' deletion breakpoint was after 245 bp of intron 15, and the 3' deletion breakpoint was in exon 18 after nucleotide 3390 of cDNA. Thus, both the membrane-spanning and cytoplasmatic domains of the receptor had been deleted. A polymerase chain reaction (PCR) method was developed to identify this deletion among other Norwegian FH subjects. As a result of this screening one additional subject was found out of 124 subjects screened. Thus, three out of 181 (1.7%) unrelated Norwegian FH subject possessed this deletion. The deletion was found on the same haplotype in the three unrelated subjects, suggesting a common mutagenic event. The deletion is identical to a deletion (FH-Helsinki) that is very common among Finnish FH subjects. However, it is not yet known whether the mutations evolved separately in the two countries.
BACKGROUND: Familial hypercholesterolemia leads to premature ischemic heart disease and is often caused by mutations in the gene for the low-density lipoprotein receptor. Mutations in the apolipoprotein B gene, which encodes a ligand for this receptor, may also result in this phenotype. METHODS: We studied the genotypes of 9255 women and men from the general population, 948 patients with ischemic heart disease, and 36 patients with familial hypercholesterolemia, all from Denmark, for three mutations in the apolipoprotein B gene: Arg3500Gln, Arg3531Cys, and Arg3500Trp. RESULTS: The prevalence of heterozygotes in the general population was 0.08 percent (95 percent confidence interval, 0.03 to 0.16 percent) for both the Arg3500Gln and the Arg3531Cys mutations, and 0.00 percent (95 percent confidence interval, 0.00 to 0.18 percent) for the Arg3500Trp mutation. Among carriers of the Arg3500Gln mutation, cholesterol levels were significantly higher than among noncarriers in the general population - by 100 mg per deciliter (2.6 mmol per liter) among carriers in the general population, 154 mg per deciliter (4.0 mmol per liter) among patients with ischemic heart disease, and 172 mg per deciliter (4.5 mmol per liter) among patients with familial hypercholesterolemia. Heterozygous carriers of the Arg3500Gln mutation were significantly more common among patients with ischemic heart disease (odds ratio, 7.0; 95 percent confidence interval, 2.2 to 22; P=0.003) and patients with familial hypercholesterolemia (odds ratio, 78; 95 percent confidence interval, 16 to 388; P=0.001) than in the general population. Heterzygous carriers of the Arg3531Cys mutation in the general population did not have higher-than-normal plasma cholesterol levels or an increased risk of ischemic heart disease (odds ratio; 1.4; 95 percent confidence interval, 0.2 to 11; P=0.54). CONCLUSIONS: The Arg3500Gln mutation in the apolipoprotein B gene, which is responsible for familial defective apolipoprotein B-100 and is present in approximately 1 in 1000 persons in Denmark, causes severe hypercholesterolemia and increases the risk of ischemic heart disease.
Comment In: N Engl J Med. 1998 Nov 26;339(22):1640-1; author reply 1641-29867529
Comment In: N Engl J Med. 1998 Nov 26;339(22):1641-29867530
We performed a screening of exon 9 of the low density lipoprotein receptor (LDLR) gene in 14 Danish families with familial hypercholesterolemia (FH) using the denaturing gradient gel electrophoresis (DGGE) technique. In one of the probands from these families an abnormal band pattern in the gradient gel was detected. Subsequent DGGE analysis of the family of this index patient revealed that the DGGE pattern cosegregated with the disease in this family. Sequencing of the exon showed a deletion of a C in codon 424 of the LDLR gene resulting in a frame shift with the introduction of a stop codon 5 codons further downstream. The mutation is referred to as FH-Odense. The predicted truncated receptor protein consists of the 428 amino terminal amino acids. Consequently, the cytosolic and membrane spanning parts of the mature LDL receptor, which normally secure the receptor in the plasma membrane, are missing. The FH-Odense mutation results in severe premature coronary atherosclerosis as shown by the clinical expression in 5 generations of the affected family.
Abnormal interaction between low density lipoprotein receptors (LDLR) and their ligands, apolipoprotein E and B, causes decreased catabolism of lipoproteins which carry these apolipoproteins (VLDL, IDL and/or LDL) and thereby increased plasma concentrations of these. In familial hypercholesterolemia (FH), abnormal interaction is due to mutations in the LDLR gene, and in type III hyperlipidemia due to mutations in the apo E gene. A few mutations in the apolipoprotein B (apo B) gene have been described, of which the apo B-3,500Arg-Gln seems by far the most frequent, that causes defective binding to normal LDLR. The metabolic disorder associated with these mutations has been named familial defective apolipoprotein B-100 (FDB). The frequency of the apo B-3,500Arg-Gln mutation is particularly high in Central Europe (Switzerland) with lower frequencies south of the Alpes, in Russia and in Scandinavia. We found an incidence of 1/1250 of the mutation in Denmark (III), employing a DNA based assay optimized to allow detection of the mutation in very small amounts of DNA (I). Since other mutations in the receptor binding domain of the apo B-100 have been described, we developed another DNA based assay, employing DGGE technique, to screen for other mutations in the region of amino acid 3,456 to 3,553 (II). However, no other mutations but the apo B-3,500Arg-Gln have so far been detected in Danish hypercholesterolemic patients. In a study of 5 Danish families with FDB (46 heterozygous FDB patients and 57 unaffected relatives) we found that FDB patients had significantly increased mean cholesterol and LDL cholesterol concentrations, but with a wide range of variation and with approximately 30% having cholesterol concentrations below the 95th percentile for the general population (IV). This was confirmed in a compilation of data on 205 FDB patients from the Netherlands, Germany and Denmark (V). In this study we also compared the biochemical and clinical features of FDB with those of 101 Danish FH patients in whome FDB had been ruled out. Our data support, that the LDL cholesterol elevation is less pronounced in FDB than in FH and that the age-specific prevalence of atherosclerotic cardiovascular disease (CVD) is lower in FDB than in FH. In the compiled study of 205 FDB heterozygotes (V), we found that age, gender and genetic variation in the LDLR gene explained a considerable part of the between-individual variation in total and LDL cholesterol. We conducted a prospective study of the lipid lowering effect of pravastatin and gemfibrozil in 30 Danish FDB patients (VI). Together with other, retrospective, studies, we conclude that the cholesterol lowering effect of HMG-coA-reductase inhibitors, anion binding resins and nicotinic acid is fully comparable to that observed when treating FH patients and type IIa hypercholesterolemic patients, without clinical signs of FH.
BACKGROUND: Awareness of genetic disease in the family may influence quality of life. The purpose of this study was to describe quality of life among nonaffected members of families with familial hypercholesterolaemia. All were aware of the risk for coronary heart disease. Their quality of life was compared with a reference group and with the patients with familial hypercholesterolaemia themselves. METHODS: Names of family members (n = 129) were given by the patients with familial hypercholesterolaemia. A randomly selected reference group (n = 1485) and patients with familial hypercholesterolaemia (n = 185) were included for comparison. They all completed the questionnaire Quality of Life Index, the Hospital Anxiety and Depression Scale, and the Mastery Scale measuring coping. Family members and patients with familial hypercholesterolaemia also completed a questionnaire on health and lipids. RESULTS: Family members were more satisfied with family life, mean 22.1 +/- 3.5 (SD), and psychological/spiritual life, 22.9 +/- 4.0, than the reference group, 21.4 +/- 4.3 and 21.1 +/- 4.8, respectively; this was particularly expressed among partners, P
The main aim of the study was to explore the extent to which familial hypercholesterolemia (FH) influences the life of the patients affected. The study employed a qualitative analysis of semi-structured interviews with 23 outpatients who were being treated following a diagnosis of heterozygous FH at a tertiary hospital in Göteborg, Sweden. Some interviewees reported concerns related to their medication and feelings of guilt when not complying with treatment recommendations. However, none of the respondents expressed sustained emotional distress or would have preferred to be ignorant of their diagnosis. Apart from being more observant about food intake, their awareness of FH did not appear to have had a substantial impact on their way of life. In fact, those who did not suffer from any other diseases generally regarded themselves as healthy. Discussing the genetic constitution with family members with whom they had close contact was natural, but informing distant family members was not.
The first patients with xanthomatosis and cardiovascular disease were described in end of the 18th century. From 1925 to 1938, the Norwegian pathologist Francis Harbitz (1867-1950) published several reports on sudden death and xanthomatosis. Harbitz called attention to certain peculiarities of the xanthomatosis. Microscopically he found that the so-called foam cells are more marked and more characteristic than in senile arteriosclerosis. Carl Müller's (1886-1983) attention was directed to this form of cardiovascular disease by the publications of Harbitz. Based on his own studies of 17 families in Oslo over a short period from 1936, he published his final report in 1939. He described hereditary heart disease due to xanthomatosis and hypercholesterolaemia to be fairly common. It was demonstrated to be a dominant trait in the families. Hypercholesterolaemia was present, most marked in connection with xanthoma tuberosus, but there was no definitive relationship between hypercholesterolaemia and xanthomatous deposits in the skin. The occurrence of heart disease in families should direct attention to this disorder. Carl Müller postulated that causal and prophylactic treatment might prove to be of value, but more than 50 years passed before this was possible in the disorder that is now called familial hypercholesterolaemia.