Diagnostic test for rare genetic condition | Action Medical Research

Touching Lives - June 2007

Diagnostic test for rare genetic condition

The effects of Von Hippel-Lindau (VHL) vary depending on where in the body the growths have developed, but they can cause a range of complications including headaches, blurred vision or blindness, unsteadiness, pain and even cancer.VHL is estimated to affect more than 200,000 people globally, around 2,000 of whom are in the UK.

This variation in symptoms renders diagnosis difficult, yet early recognition of the syndrome and timely action can help prevent serious, often fatal, complications. Before the development of the genetic test, doctors were unable to tell parents if their children had inherited the condition unless the characteristic cysts and tumours had started to occur. Patients and at-risk relatives were given regular screening tests to detect the complications, but this was expensive and time consuming, and non-sufferers spent years undergoing unnecessary, nervewracking testing, while those who had inherited the gene had no idea of how severe their symptoms might become.

The first step in developing a conclusive test was to identify where the faulty gene responsible for VHL lay. In 1991, an Action Medical Research grant was awarded to a team led by Professor Eamonn Maher at Cambridge University. In 1993, working in collaboration with US scientists and with support from other funding bodies, the breakthrough came — the gene for VHL was identified.

Then, with further Action Medical Research funding, Professor Maher, now based at the University of Birmingham, and his team tackled the challenge of developing an accurate diagnostic test for the condition.They studied 142 families with VHL to find out what different mutations occurred.They also performed a range of tests on affected patients and their relatives to see if the variability in clinical symptoms was related to the type of mutation.The team identified a whole range of VHL gene mutations, and used this data to develop methods for accurate genetic testing for the condition. They also identified genetic factors which predicted the likely severity of some of the clinical complications.

The genetic tests mean that once the faulty gene is identified in a patient, doctors can immediately set up regular screening sessions so the cysts and tumours that are likely to ensue can be picked up as early as possible.This way, if a complication does arise, action can be taken before the problem becomes more serious or life-threatening. Genetic testing can also give a prediction of the likely severity of some of the complications.

Action Medical Research has a long history of supporting genetic research, having helped to identify the genes for an inherited form of cleft lip and palate and the hereditary skin condition incontinentia pigmenti. In the 1970s the Charity also contributed to the building of the Institute of Medical Genetics in Glasgow, which is now one of the centres providing genetic testing for VHL.

The knowledge gained from studying this disease may have even wider benefits, particularly for cancer sufferers. A normal VHL gene is now known to produce a tumour suppressor protein which, when it functions, stops uncontrolled growth of cells which lead to tumours. Errors in the VHL gene are now also known to be associated with more common, non-inherited cancers, and with funding from Cancer Research UK, Professor Maher is investigating the implications of the VHL findings for cancerous conditions.

Providing answers for families

Tracey Fox-Stillwell is all too familiar with the process of genetic testing for VHL. Her husband, Allen, was diagnosed with the condition in 2001, having inherited it from his mother, and since then three of the couple’s four daughters have been confirmed as carrying the VHL gene.

Tracey explains, “Allen was diagnosed with the condition after having a brain tumour removed. Since then he has had a second tumour removed from his brain and been treated for growths on his retina and kidneys. At present he has four further brain tumours, three on his spine and multiple tumours on his kidneys.”

Despite the constraints that the condition places on Allen — he’s apprehensive about driving at night or with the family in the car, and suffers constant vertigo which often makes him ill — he remains positive. He continues to work full time as a self employed engineer, fitting in regular appointments with neurologists, urologists and ophthalmologists who monitor his condition.

Aware of the hereditary nature of VHL, the couple decided to have their daughters genetically tested to see whether the gene had been passed on to them.Tracey explains,”We chose the option of genetic testing for the family, as opposed to annual screening tests, because they give a straightforward answer. It would be far more stressful going to each screening appointment knowing you could be about receive bad news.”

Their tests were carried out at the University of Birmingham under the care of Professor Maher, beginning with their eldest daughter, eleven-year-old Tantara, in 2003. She tested positive. A year later her nine-year-old sister, Ella, was also confirmed as carrying the gene, as was the couple’s youngest daughter Freya, aged four, in 2006.The test showed that Ella’s twin sister, Mia, does not carry the gene. Although Ella and Freya are yet to show signs of the disease,Tantara is now active with VHL and already has 14 retinal tumours, for which she is receiving treatment.

Tracey says, “It was a big shock to be told that three of our daughters had the gene, but we were counselled before the tests and I think, in a way, we almost expected the results.We felt it was better to know — at least now the girls can grow up coming to terms with it from an early age, rather than being hit with it in their teens.

Tracey continues,”The girls all took the news that they had VHL very well.They can only go by Allen’s attitude towards the condition and he is so positive about the future that they are too.”

Following Tantara’s diagnosis, the family set up a charity to raise money for more research into the condition.Tracey believes it helps the girls to see their friends and relations fundraising hard in the hope of finding a future cure.

Tracey believes the genetic testing has been a vital progression for families affected by VHL. “The test will save lives. Living with VHL relies on the early detection and treatment of growths, and knowing for sure that you’ve got the gene means that doctors can immediately offer the right medical care, rather than on a cautionary basis. Allen says,”We’re lucky — we don’t have to wait for appointments and scans like other patients who do not even know what is wrong.” TL

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