Diagnosis of familial hypercholesterolemia in general practice using clinical diagnostic criteria or genetic testing as part of cascade genetic screening.

BACKGROUND: Too few familial hypercholesterolemia (FH) patients are diagnosed. The most cost-effective strategy to diagnose FH is to examine first-degree relatives of already diagnosed patients. This is referred to as cascade genetic screening. METHODS AND RESULTS: One thousand eight hundred and five first-degree relatives of index patients with molecularly defined FH consented to cascade genetic screening by the use of molecular genetic testing. Of these, 44.8% were mutation carriers and 55.2% were noncarriers. Only 44.2% of the mutation carriers were on lipid-lowering drugs at the time of genetic testing. Of these, only 9.4% had a value for total serum cholesterol below 5 mM. Among adult mutation carriers who were not on lipid-lowering treatment at the time of genetic testing, reductions in total serum cholesterol and low-density lipoprotein cholesterol of 18.4% (p < 0.0001) and 25.3% (p < 0.0001), respectively, were observed 6 months after genetic testing. It is assumed that this improvement in the lipid profile is due to a definite diagnosis obtained by molecular genetic testing. By using the results of genetic testing as the gold standard for diagnosis of FH, data from a questionnaire filled out by the relatives showed that the use of clinical criteria to diagnose FH in general practice had a sensitivity of 46.2% and a specificity of 88.0%. CONCLUSIONS: The use of clinical diagnostic criteria to diagnose FH in general practice identifies only approximately 50% of FH patients. Molecular genetic testing as part of cascade genetic screening is an efficient tool to diagnose patients, leading to significant improvement in the lipid profile. It should therefore be implemented in clinical medicine.

[Lipid profile in children and adolescents with familial hypercholesterolemia]. / Lipidprofil hos barn og ungdom med familiaer hyperkolesterolemi.

BACKGROUND: Previous reported serum lipid levels in children and adolescents with familial hypercholesterolemia are uncertain. Reasons are that the diagnosis may have been uncertain and that the reported lipid levels have been mainly from patients treated at tertiary referral centres. MATERIAL AND METHODS: The serum lipid levels in 434 children and adolescents (2-18 years) who had undergone molecular genetic testing for familial hypercholesterolemia as part of cascade genetic screening, were measured. RESULTS: 196/434 (45.2%) were heterozygous for the mutation in the LDL receptor gene that had been identified in the family, while 238/434 (54.8%) were not heterozygous. Those who were heterozygous had mean total serum cholesterol levels of 7.40 (+/- 1.41) mmol/L and LDL cholesterol of 5.60 (+/- 1.38) mmol/L. These values were 1.70 (p < 0.001) and 2.19 (p < 0.001) times higher than the corresponding values in those who were not heterozygous. A total serum cholesterol level of 5.5 mmol/L had a high sensitivity and specificity for the diagnosis of familial hypercholesterolemia. INTERPRETATION: Familial hypercholesterolemia should mainly be diagnosed by molecular genetic testing. If the underlying mutation cannot be identified a total serum cholesterol value of 5.5 mmol/L and an LDL cholesterol value of 3.5 mmol/L, should be used to diagnose children and adolescents.

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

A total of 119 different mutations in the low-density lipoprotein-receptor gene have so far been found to cause familial hypercholesterolemia (FH) among Norwegian patients. As of April 2003, 2390 patients from 959 unrelated families were provided with a molecular genetic diagnosis. Of these, 25.3% had xanthomas and 8.4% had xanthelasma. During the last 2-3 years, a systematic family-based program to identify close relatives of FH patients has been established. A total of 851 relatives of 188 index patients have undergone genetic testing. Four hundred seven people (47.9%) were affected, and 444 (52.1%) were unaffected. Only 41.5% of those affected were on lipid-lowering drugs, and only 6.1% had a value for total serum cholesterol below 193 mg/dL (5.0 mmol/L). A follow-up study was conducted in 146 of 407 affected relatives 6 months after genetic testing was performed. Of those already under treatment at the time of genetic testing, nonsignificant reductions of total serum cholesterol and low-density lipoprotein cholesterol of 3.2% and 7.1% were observed. Of those not under treatment who were aged 18 years and older, the corresponding reductions were 21.2% (p <.0001) and 30.0% (p <.0001), respectively. We conclude that molecular genetic methods represent a feasible and highly efficient tool in a family-based strategy to diagnose FH.

[A family-based strategy for diagnosing familial hypercholesterolemia]. / Slektsbasert strategi for diagnostikk av familiaer hyperkolesterolemi.

BACKGROUND: Patients with familial hypercholesterolaemia have increased risk of developing coronary heart disease. The most cost-effective way of diagnosing patients with familial hypercholesterolaemia is to perform genetic testing of close relatives of already diagnosed patients. MATERIAL AND METHODS: Probands with familial hypercholesterolaemia in whom the underlying mutation in the low-density lipoprotein receptor gene has been identified were informed that close relatives should also be tested. RESULTS: Blood samples were taken for molecular genetic testing from 851 first-degree relatives of patients with familial hypercholesterolaemia; 47.8 % tested positively and 52.2 % negatively. Among those with positive tests, only 41.5 % were on lipid-lowering drugs and only 6.1 % had a value for total serum cholesterol < 5 mmol/l. Six months after testing, 81.9 % were on lipid-lowering drugs, at which time a mean reduction in total serum cholesterol of 21.2 % (p < 0.0001) was observed in patients aged 18 and above who were not on treatment at the time of testing. INTERPRETATION: Molecular genetic testing for familial hypercholesterolaemia in a family-based strategy is a cost-effective way of diagnosing patients with this condition that leads to implementation of effective preventive measures.