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The 1980s saw major advancements in the understanding of Gauchers disease, its symptoms and basic biochemistry, which enable the development of enzyme replacement therapy. While the majority of research was taking place in the USA, it was also in the Netherlands that such interest took a major turn. Dr Hans Aerts, Associate Professor at the Department of Biochemistry, University of Amsterdam was a key player in this research and spoke to members of the Gauchers Association on 9 October 1996 at the Royal Free Hospital, London, about his work and how Gauchers disease affects Dutch patients. A report by Sandy Maclachlan and Susan Lewis:
'Before 1980 not much scientific interest was shown in Gauchers disease in the Netherlands,' said Dr Aerts. 'But in 1981 my Department Head, Professor Joseph Tager, was visited by a Gauchers patient who was due to have his spleen removed and wished to offer it for research. This patient's initiative stimulated Prof Tager to start the biochemical research on Gauchers disease in Holland which was undertaken in close collaboration with other international researchers, the Dutch patient society and its Medical Scientific Advisory Board.
'In 1991 we began a clinical study of Gauchers patients in the Netherlands together with haematologist Prof Goudsmit,' said Dr Aerts. 'Our aim was to establish for individual patients the minimum effective dose that resulted in a good response.
'The participating patients were adults without rapidly progressive disease. They started on a very low dose and after 6 months were evaluated. If they had made no improvement on the basis of response criteria, their dose was doubled. If the improvement was moderate, the dose remained the same and if there was a complete improvement, the dose was halved again.
'The study revealed that some patients show a good response at low dose. However there was a marked difference in individual cases and it was not possible to tell who would do well beforehand.'
Dr Aerts felt that some patients needed more enzyme therapy, others less. He wondered whether dosage should not only be linked to a patient's weight in kilograms but whether also one should take into account other factors such as progressivity of disease, nature and extent of symptoms and body (skin) area. He asked: 'Why should a fat person get more than a thin person of the same height? Why should a child get less than an adult whose spleen or liver is no bigger?'
He pointed out that a lot of Ceredase infused into the body might not actually get to where it was required and there is still a need to look into the possibility of improved targeting.
Dr Aerts mentioned that in the Netherlands, relatively few children (under age 18) with symptomatic Gauchers disease are presently known. In most other countries such as the UK, a much larger percentage of sufferers are children. Dr Aerts could not give a reason for this fact.
Dr Aerts spoke about the different mutations of the gene for glucocere-brosidase, the enzyme deficient in Gauchers patients. The most prevalent genotype (the pair of genes which a patient has inherited from his or her parents) among affected Dutch Gauchers patients was 370/444. How-ever the genotype 370/370 is probably the most common. He has discovered five people who have the genotype 370/370 but show no symptoms.
He said that it has been calculated that about 500 people in the Netherlands theoretically have Gauchers disease but would never show symptoms.
He gave an example of one Dutch family where five children suffer symptoms from Gauchers disease. The mother was found to have the genotype 370/370 but has developed no symptoms despite the presence of the abnormal enzyme. She married a carrier of Gauchers disease with the 444 mutation and the combination 370/444 has shown in five of their nine children.
The Life of the Enzyme
In 1983 Dr Aerts prepared a thesis on the basic biochemistry of Gauchers disease and the enzyme, glucocere-brosidase. Working in close collaboration with the National Institutes of Health, USA, he began to investigate how the enzyme was made in the cells of the body, how it moved to where it was needed and how long it lived. Dr Aerts received the National Prize for Chemistry for his research.
'This enzyme is different from other lysosomal enzymes,' explained Dr Aerts. 'We know that it stays a relatively long time outside the lysosome, the part of the cell it has to reach to be effective. It is unstable and needs an activator protein for optimal activity and stability. We have also learned that in 95% of Type 1 Gauchers patients, the enzyme is produced in normal quantity but acts abnormally. Only in Types 2 and 3 are there low amounts of the enzyme. I believe there must be other factors which contribute to the disease such as another enzyme or an infection.'
In 1991 Dr Aerts discovered chitotriosidase, an enzyme produced by Gauchers cells in vast amounts. This has provided a further biochemical market to monitor the disease and its treatment, and is being used in many centres throughout Europe and the USA. Dr Aerts said this enzyme was elevated 100 to 5,000 times in Gauchers disease and was a valuable diagnostic tool.
In monitoring a good response to enzyme replacement therapy, this enzyme rapidly decreases but has not normalised in any of the Dutch patients. He said that about 5% of Gauchers patients were deficient in this enzyme activity.
The enzyme is thought to fight fungal infections so Gauchers patients might theoretically profit from the elevated enzyme levels.
Present research is focused on the discovery of other biochemical markers to monitor Gauchers cells, in particular their formation. Dr Aerts foresees that chitotriosidase and additional biochemical markers will play an important role in the future as guidelines for optimal therapy.
The meeting was chaired by Dr Pram Mistry, Consultant and Senior Lecturer at the Royal Free Hospital where he takes responsibility for patients attending the Gauchers Clinic there.
For more on Chitotriosidase, see also New Test for Disease Severity and Efficacy of Treatment and Diagnosis and Monitoring of Gauchers Disease at Great Ormond Street Hospital
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Source: Gauchers News February 1997.
© Copyright Gauchers Association 1997