Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands.

BACKGROUND: Familial hypercholesterolaemia is a common lipid disorder that predisposes for premature cardiovascular disease (CVD). We set up a screening programme in the Netherlands in 1994 to: establish the feasibility of active family screening supported by DNA diagnostics; assess whether or not active identification of these patients with familial hypercholesterolaemia would lead to more cholesterol-lowering treatment; and compare diagnosis by DNA analysis with that by cholesterol measurement. METHODS: Both DNA analysis and measurement of cholesterol concentrations were used to screen families in which a functional mutation in the LDL-receptor gene had been detected. FINDINGS: In the first 5 years, 5442 relatives of 237 people with familial hypercholesterolaemia were screened; 2039 individuals were identified as heterozygous by LDL-receptor gene mutation analysis. At the time of examination, 667 of these adults with familial hypercholesterolaemia (39%) received some form of lipid-lowering treatment; 1 year later, this percentage had increased to 93%. In addition, laboratory analysis showed that for carriers as well as non-carriers 18% would have been misdiagnosed by cholesterol measurement alone, with sex-specific and age-specific 90th percentiles of the general Dutch population as diagnostic criteria. INTERPRETATION: Targeted family screening with DNA analysis proved to be highly effective in identifying patients with hypercholesterolaemia. Most of the identified patients sought treatment and were successfully started on cholesterol-lowering treatment to lower the risk of premature CVD. Our findings could have wider relevance for the screening of other prevalent genetic disorders in the population at large.

The molecular basis of familial hypercholesterolemia in The Netherlands.

Mutations in the low-density lipoprotein (LDL) receptor gene are responsible for familial hypercholesterolemia (FH). At present, more than 600 mutations in this gene are known to underlie FH. However, the array of mutations varies considerably in different populations. Therefore, the delineation of essentially all LDL-receptor gene mutations in a population is a prerequisite for the implementation of nation-wide genetic testing for FH. In the Netherlands, mutation analysis by denaturing gradient gel electrophoresis and sequencing in 1641 clinically diagnosed FH patients resulted in the characterization of 159 different LDL-receptor gene defects. The nine most common mutations were responsible for 66.5% of our FH index cases. Of these, four mutations occurred with relatively high frequencies in specific parts of the Netherlands. The remaining mutations were only encountered in single FH patients, comprising 22.2% of the patient cohort analyzed. Subsequent genetic testing of relatives of the index cases within the national FH screening program resulted in the identification of 5,531 FH patients in total. The analysis for LDL-receptor mutations is a continuing effort to update the LDL-receptor mutation catalogue. Subsequently, with the newly generated index cases, the screening program can be extended and continued to identify and treat FH patients as early as possible and reduce cardiovascular morbidity and mortality in these patients at high risk.

[Tracing of patients with familial hypercholesterolemia in the Netherlands]. / Opsporing van patiënten met familiaire hypercholesterolemie in Nederland.

OBJECTIVE: To inventory the possibilities of tracing relatives of patients with familial hypercholesterolaemia (FH) by means of family tree research and DNA diagnostics. DESIGN: Descriptive. METHOD: 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. RESULTS: 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. In the non-carrier group, 14.6% had a serum LDL cholesterol level > P95. CONCLUSION: Tracing FH patients is feasible in practice and leads to detection of as yet untreated patients.

[Liver rupture in a newborn infant; diagnosis, treatment and prognosis]. / Leverruptuur bij pasgeborenen; diagnostiek, behandeling en prognose.

Between August 1989 and August 1992 four neonates with rupture of the liver were admitted to the Neonatal Intensive Care Unit of the Sophia Children's Hospital in Rotterdam, the Netherlands. Two neonates were born after breech delivery, two after caesarean section because of foetal distress. All four patients had Apgar scores < 5 after 1 minute and of < 8 after 5 minutes and required artificial ventilation for a prolonged period. All infants collapsed within 6 hours after birth. Surgical treatment was not considered because of the poor clinical condition. All patients were treated conservatively. Clinical signs were: rapid onset pallor, hypotension, tachycardia and abdominal distension. Ultrasonography of the abdomen confirmed the clinical diagnosis of rupture of the liver. Despite rapid diagnosis and maximal non-surgical treatment mortality was 75%. Surgical intervention is indicated in neonatal liver rupture with significant intra-abdominal bleeding.

[Application of non-glycoside inotropic agents in newborn infants]. / Het gebruik van niet glycoside inotropica bij de pasgeborene.

Non glycoside inotropic agents are regularly used in the treatment of critically ill neonates. There are reasons to believe that the neonate reacts differently to these inotropic agents because of differences in physiology and maturation. In this paper the oxygen consumption and oxygen transport, heart failure in the newborn, effects of non glycoside inotropic agents in general and the doses of the commonly used inotropic agents (dopamine, dobutamine and isoproterenol) will be discussed. Finally a review of the literature and a therapeutic advise on the use of inotropic agents in the neonate is presented.