Opsporing van patiënten met familiaire hypercholesterolemie in Nederland

To inventory the possibilities of tracing relatives of patients with familial hypercholesterolaemia (FH) by means of family tree research and DNA diagnostics. Descriptive. Blood from patients with the clinical diagnosis of 'FH' was sent, through one of the lipid outpatient clinics in the country, to the Foundation for Tracing Hereditary Hypercholesterolaemia (StOEH) for DNA examination, to characterize the genetic defect. If a mutation was diagnosed in this index patient, he was invited by telephone by a StOEH staff member to have DNA testing done in relatives (especially those of the first degree). The data were stored in a data base. The analysis concerns the patients approached in 1994-1997, as well as those in whom the serum concentration of LDL cholesterol was also determined in 1993-1995. A total of 3013 persons were approached and examined: 146 index patients and 2867 relatives. The DNA diagnosis of 'FH' was made in 1067 relatives (37.2%), 585 (54.8%) women and 482 (45.2%) men. Of these, 21.2% were younger than 20 years, 37.0% 20-39 years, 26.6% 40-59 years and 15.2% > or = 60 years; 44.1% reported being known with a raised cholesterol level, 29.4% were treated with cholesterol-reducing drugs and 6.1% were suffering from a cardiovascular disease. Of the 990 persons in whom the serum LDL cholesterol level was determined, 325 (32.8%) were carriers of a mutation in the LDL receptor gene. 21.2% Of them had a LDL cholesterol level P95. Tracing FH patients is feasible in practice and leads to detection of as yet untreated patient

Two years after molecular diagnosis of familial hypercholesterolemia: Majority on cholesterol-lowering treatment but a minority reaches treatment goal

Background: The risk of premature cardiovascular disease in patients with familial hypercholesterolemia (FH) can be profoundly reduced by cholesterol-lowering therapy, and current guidelines for FH advocate ambitious low-density lipoprotein cholesterol (LDL-C) goals. In the present study, we determined whether these goals are reflected in current clinical practice once FH has been diagnosed. Methodology/Principal Findings: In 2008, we sent questionnaires to all subjects (aged 18-65 years) who were molecularly diagnosed with FH in the year 2006 through the screening program in the Netherlands. Of these 1062 subjects, 781 completed the questionnaire (46% males; mean age: 42±12 years; mean LDL-C at molecular diagnosis (baseline): 4.1±1.3 mmol/L). The number of persons that used cholesterol-lowering therapy increased from 397 (51%) at baseline to 636 (81%) after diagnosis. Mean treated LDL-C levels decreased significantly to 3.2±1.1 mmol/L two years after diagnosis. Only 22% achieved the LDL-C target level of ≤2.5 mmol/L. Conclusions/Significance: The proportion of patients using cholesterol-lowering medication was significantly increased after FH diagnosis through

Founder mutations in the Netherlands: geographical distribution of the most prevalent mutations in the low-density lipoprotein receptor and apolipoprotein B genes

Background In the Netherlands, a screening programme was set up in 1994 in order to identify all patients with familial hypercholesterolaemia (FH). After 15 years of screening, we evaluated the geographical distribution, possible founder effects and clinical phenotype of the 12 most prevalent FH gene mutations. Methods Patients who carried one of the 12 most prevalent mutations, index cases and those identified between 1994 and 2009 through the screening programme and whose postal code was known were included in the study. Low-density lipoprotein cholesterol (LDL-C) levels at the time of screening were retrieved. The prevalence of identified patients in each postal code area was calculated and visualised in different maps. Results A total of 10,889 patients were included in the study. Mean untreated LDL-C levels ranged from 4.4 to 6.4 mmol/l. For almost all mutations, a region of high prevalence could be observed. In total, 51 homozygous patients were identified in the Netherlands, of which 13 true homozygous for one of the 12 most prevalent mutations. The majority of them were living in high-prevalence areas for that specific mutation. Conclusions Phenotypes with regard to LDL-C levels varied between the 12 most prevalent FH mutations. For most of these mutations, a founder effect was observed. Our observations can have implications with regard to the efficiency of molecular screening and physician's perception of FH and to the understanding of the prevalence and distribution of homozygous patients in the Netherland

Subjects with Molecularly Defined Familial Hypercholesterolemia or Familial Defective apoB-100 Are Not Being Adequately Treated

To study whether subjects with a molecular genetic diagnosis of familial hypercholesterolemia (FH) or familial defective apoB-100 (FDB) are being adequately treated.A questionnaire regarding medical history was sent to 2611 subjects who had been provided with a molecular genetic diagnosis of FH or FDB, and a blood sample was obtained for lipid measurements.956 (36.6%) of the 2611 subjects participated. The mean age for starting lipid-lowering therapy was 33.4 (±12.1) years. Among those below 18 years of age, only 20.4% were on lipid-lowering drugs, whereas 89.1% of those aged 18 and above were on lipid-lowering drugs. The mean levels of total serum cholesterol and LDL-cholesterol were 5.7 (±1.5) mmol/l and 3.9 (±1.3) mmol/l, respectively. Among those who were on lipid-lowering drugs, 29.0% and 12.2% had levels of LDL cholesterol below 3.0 mmol/l and 2.6 mmol/l, respectively. Only 47.3% of the 956 subjects were considered as being adequately treated largely due to a failure to titrate their drug regimens. From the use of cholesterol-years score, lipid-lowering therapy must start before the age of 20 in order to prevent the subjects from contracting premature coronary heart disease.The majority of FH/FDB subjects are being diagnosed late in life and are not being adequately treated. In order to prevent them from contracting premature coronary heart disease, it is key that levels of LDL cholesterol are normalized from a young age and that sufficient doses of lipid-lowering drugs are being used

Would raising the total cholesterol diagnostic cut-off from 7.5 mmol/L to 9.3 mmol/L improve detection rate of patients with monogenic familial hypercholesterolaemia?

A previous report suggested that 88% of individuals in the general population with total cholesterol (TC)>9.3mmol/L have familial hypercholesterolaemia (FH). We tested this hypothesis in a cohort of 4896 UK civil servants, mean (SD) age 44 (±6) years, using next generation sequencing to achieve a comprehensive genetic diagnosis. 25 (0.5%) participants (mean age 49.2 years) had baseline TC>9.3mmol/L, and overall we found an FH-causing mutation in the LDLR gene in seven (28%) subjects. The detection rate increased to 39% by excluding eight participants with triglyceride levels over 2.3mmol/L, and reached 75% in those with TC>10.4mmol/L. By extrapolation, the detection rate would be ~25% by including all participants with TC>8.6mmol/L (2.5 standard deviations from the mean). Based on the 1/500 FH frequency, 30% of all FH-cases in this cohort would be missed using the 9.3mmol/L cut-off. Given that an overall detection rate of 25% is considered economically acceptable, these data suggest that a diagnostic TC cut-off of 8.6mmol/L, rather than 9.3mmol/L would be clinically useful for FH in the general population

The sense and nonsense of direct-to-consumer genetic testing for cardiovascular disease

Expectations are high that increasing knowledge of the genetic basis of cardiovascular disease will eventually lead to personalised medicine—to preventive and therapeutic interventions that are targeted to at-risk individuals on the basis of their genetic profiles. Most cardiovascular diseases are caused by a complex interplay of many genetic variants interacting with many non-genetic risk factors such as diet, exercise, smoking and alcohol consumption. Since several years, genetic susceptibility testing for cardiovascular diseases is being offered via the internet directly to consumers. We discuss five reasons why these tests are not useful, namely: (1) the predictive ability is still limited; (2) the risk models used by the companies are based on assumptions that have not been verified; (3) the predicted risks keep changing when new variants are discovered and added to the test; (4) the tests do not consider non-genetic factors in the prediction of cardiovascular disease risk; and (5) the test results will not change recommendations of preventive interventions. Predictive genetic testing for multifactorial forms of cardiovascular disease clearly lacks benefits for the public. Prevention of disease should therefore remain focused on family history and on non-genetic risk factors as diet and physical activity that can have the strongest impact on disease risk, regardless of genetic susceptibility

COLOR CODED TISSUE CHARACTERIZATION BY 40 MHZ INTRAVASCULAR ULTRASOUND RELIABLY IDENTIFIES PLAQUE COMPOSITION COMPARISON WITH 64 SLICE COMPUTED TOMOGRAPHY

In The Netherlands, cascade screening to identify patients with familial hypercholesterolaemia (FH) has been introduced in 1994; a nationwide screening programme is currently ongoing to detect all - approximately 40 000 - carriers by molecular screening. Active identification by DNA testing has social implications such as difficulties in obtaining life and disability insurance. In The Netherlands, insurance companies are restricted in the use of genetic information of their clients by the Medical Examination Act (1998). Within the scope of this specific law, the Foundation for the Identification of Persons with Inherited Hypercholesterolaemia, the patient support association, representatives of the medical profession as well as insurers designed guidelines for risk assessment of mortality and morbidity of FH carriers. Risk assessment should be based on phenotype, that is, lipoprotein profile and the presence of classical cardiovascular risk, instead of the LDL receptor gene mutation. Applicants with FH should be accepted at normal rates if LDL-c levels are <4.0 mmol/l, in the absence of additional risk factors. After implementation of these guidelines, the number of complaints about insurance contracts has decreased markedl

Cascade testing in Familial Hypercholesterolaemia: how should family members be contacted?

Cascade testing or screening provides an important mechanism for identifying people at risk of a genetic condition. For some autosomal dominant conditions, such as Familial Hpercholesterolaemia (FH), identifying relatives allows for significant health-affecting interventions to be administered, which can extend a person’s life expectancy significantly. However, cascade screening is not without ethical implications. In this paper, we examine one ethically contentious aspect of cascade screening programmes, namely the alternative methods by which relatives of a proband can be contacted. Should the proband be responsible for contacting his or her family members, or should the screening programme contact family members directly? We argue that direct contact is an ethically justifiable method of contact tracing in cascade screening for FH. Not only has this method of contact already been utilised without adverse effects, an examination of the ethical arguments against it shows these are unsubstantiated. We describe several criteria which, if met, will allow an appropriate balance to be struck between maximising the efficiency of family tracing and respecting the interests of probands and their relatives. Keywords Cascade genetic screening; cascade testing; confidentiality; autonomy; genetics; ethics; guidelines; familial hypercholesterolaemi