Session III: workshops

1. Cardiovascular genetics

Facilitators:

Steve Humphries (CEO London IDEAS Genetics Knowledge Park)

Mabella Farrer (Genetics Nurse, London IDEAS Genetics Knowledge Park)

Devaki Nair (Consultant in Cardiovascular Lipids, Royal Free Hampstead NHS Trust)

Presentation

The presentation started with an outline of the London IDEAS project to evaluate cascade testing for Familial Hypercholesterolaemia (FH) and was rounded up with an account of two typical family stories in which identification of an initial proband had led to further identification of many other cases in the family.

The carrier rate for this autosomal dominant disorder suggests there should be about 100,000 cases in the UK. However, a recent survey of lipid centres found that only about 15,000 cases are known to them. In view of the very effective lipid-lowering treatment available it is important to identify the “missing” cases. Statins can result in at least a 5-fold reduction in mortality in the highest risk group (people aged between 19 and 30). It was stressed that the situation with respect to statin treatment is constantly changing as newer more powerful statins are brought into the market.

FH is caused by a failure to clear cholesterol from the blood. The principle genes involved are the LDL receptor and to a lesser extent Apolipoprotein B. A third gene, for a protease possibly involved in the recycling of the receptor, has also been identified.

In their 2003 White Paper on Genetics and the NHS, the government announced funding for a national pilot to find more FH patients. The FH cascade testing project will involve five lipid centres with a genetic nurse at each. The aim will be to contact all first degree relatives of FH patients and test their cholesterol levels. The nurses are key as without their support there is not time in the clinic to take family histories and offer pre-test counselling.

The outcomes of the project will include assessing the acceptability of cascade testing (previous studies suggest it is well received), as well as defining the costs in detail and establishing how many new patients are found per proband. The team will look at whether it is best to approach relatives through the proband, or directly by the study team. The best methods to find the “missing” probands will be explored (using GP notes vs . finding relatives of early-MI patients). The effectiveness of including DNA analysis to complement cholesterol measurements will also be assessed: finding a known mutation in a family provides an unequivocal method of determining carrier status, but at present a mutation is only found in 30 to 50% of cases, so new and cheaper methods will be tried.

Audience discussion

General

It was quickly established that many of the GPs present had FH cases under their care. They had generally been identified because of MI of a family member at a young age, typically early thirties. There are recommended clinical guidelines for identifying FH families and GPs would benefit from a wider dissemination of these, so that they know when to order a cholesterol test. A simple cut-off is that a cholesterol level of above 7.5mmol/L, which is roughly the 95th percentile in the UK, should be considered as of concern, although a family history is required to strengthen the diagnosis. It was pointed out that many people organise their own cholesterol testing.

Insurance is of concern to many people. A study has shown that some insurance companies are taking notice of successful FH treatment and lowering premiums accordingly. The view was widely expressed by the audience that insurance companies should behave with greater transparency. A member of the industry said that the principles were clear but the details were commercially sensitive.

The patient organisation HEARTUK can offer help and support to families with FH, for example with maintaining a low fat diet. The FH leaflet supplied in the conference pack is also available through London IDEAS for giving to patients.

Non-statin drug classes

The conflicting evidence on the use of HRT to reduce risk of heart disease was discussed. In general the most important thing for FH patients is to reduce cholesterol levels, although HRT is of benefit if there are severe menopausal problems. The new drug Ezetemibe blocks cholesterol absorption from the gut, a different mode of action to the statins. Adding this drug can be helpful particularly in cases with very high cholesterol, although so far it has not been shown by clinical trials to reduce heart disease. Although side effects are rare it is too new to have a proven long-term safety profile.

Children

It is usual to delay genetic testing until the late teens to allow fully informed consent but because of the early damage to blood vessels from high cholesterol and the effectiveness of statin treatment, this is not the best option in some families. Ten years ago guidelines were produced suggesting not testing below the age of ten. However, the seriousness of the disorder and the effectiveness of treatment has become clearer, and Dr Devi Nair, who runs the Royal Free Hospital lipid clinic, advised that testing at age five was more suitable. As this coincides with starting school it is possible to introduce lifestyle changes and avoid bad habits, such as eating crisps, which often start at school. Statins are not licensed for use below 18 years, but can be prescribed on a named patient basis, and are usually tolerated much better than the licensed resin drugs. It was noted that Dr Phil Lee at Great Ormond Street Hospital runs a large paediatric lipid clinic.

Prenatal testing

Prenatal testing would not normally be appropriate but in Britain there are currently 40 to 50 children who are homozygous for the mutant gene, sometimes as a result of consanguinity. Homozygosity carries a considerably raised risk of death. This emphasises the need for literature and information leaflets to be available in translation.

Useful links

British Heart Foundation website  www.bhf.org.uk

HEART UK website                 www.heartuk.org.uk

Mabella Farrer   email        m.farrer@ich.ucl.ac.uk