Professor Zimran Talks about Gauchers Disease while in London and Cambridge


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Professor Ari Zimran spoke at three venues during his visit to England in January 1998, apart from at the Reception in his honour at the House of Commons (see front page): the talks took place at the Middlesex Hospital, London (to the Israeli Medical Association); Addenbrooke's Hospital, Cambridge; and the Royal Free Hospital, London. This article highlights some of the important topics covered in his talks:

Fifteen years ago the first book on Gauchers disease was published by Desnick, Gatt and Grabowski celebrating 100 years since the disease was first described by Philippe Gaucher in 1812.

Significant advancements have occurred, both in the molecular biology and treatment of the disease, since that time and hence there was a need for a new comprehensive look at these developments.

Gauchers Clinic in Israel

I practise at the Shaare Zedek Medical Centre where the Gauchers Clinic opened in 1989. In December 1990 the first Gauchers patient had his first infusion of Ceredase.

We currently follow more than 300 Gauchers patients in our Clinic who also benefit from seeing consultants whose speciality is relevant to their symptoms such as paediatrics, orthopaedics.

Based on an estimated carrier rate among Ashkenazi Jews of 1 in 14 to 1 in 17, it is clear that there are many more Gauchers patients in Israel, who have not come to medical attention, probably reflecting the very mild nature of their disease. In these asymptomatic patients, the enzyme deficiency will not effect their health and they will probably not require treatment.

Treatment

Over a decade ago, a four year old boy Brian and his mother Robin Berman approached Dr Roscoe Brady at the National Institute of Health in Washington DC. Dr Bradyµs team had developed enzyme replacement therapy and Brian was the first patient to receive it.

The success led to the pivotal clinical trial at the NIH with results in the reduction in spleen volume by an average of 33% and in liver volume by 11% (average).

The results of efficacy (effectiveness) and safety led to FDA approval in April 1991. Yet the high cost of the drug precluded enzyme availability in many parts of the world.

Prof Ernest Beutler at the Scripps Institute in California suggested a much lower dose than Brian had been given but said that it should be infused more frequently.

The results in his patients were comparable.

In 1994 the recombinant enzyme (Cerezyme) was also approved by the FDA and the Israeli Ministry of Health. By 1997, 141 were receiving enzyme treatment in Israel.

We now start our patients on a regimen of 15 units of Cerezyme per kilogram of bodyweight (u/k/bw) every 2 weeks. If necessary we change this to 7.5 u/k/bw once a week. We raise this to 15 u/k/bw once a week in patients who show inadequate response.

Although there may be quicker improvements in the first 6-12 months if the patient is on high dose (based on the American clinical trial of Cerezyme wherein the dosage was 60u/k/bw every 2 weeks), I don't feel this difference is clinically significant and the results are the same thereafter.'

Prof Zimran was asked whether patients without symptoms should receive enzyme replacement therapy.

He replied that if there was severe disease in the family or the patient had a severe genotype, treatment should be considered. He stressed the need for expert opinion and said that every patient should be entitled to receive it.

Prof Zimran said that 15% of patients had developed antibodies to the drug on high dose and only 5% on low dose. But he went on to say that the only patient, among the ten participating in the initial clinical trial of Cerezyme in Israel, who had developed antibodies was in fact the one who had improved the most.

Enzyme replacement therapy has improved the health and quality of life of symptomatic patients and home infusions have been found to be a safe way of administering the drug. Enzyme therapy has reduced the number of bone crises and infarctions (bone damage) which may in part be due to the decreased need for splenectomy.

Type 3

This form has recently been subdivided into three clinically distinguishable forms:

IIIa Severe neurological involvement and minimal visceral (organ) involvement

IIIb Abnormal eye movement as the only neurological sign but severe visceral involvement.

IIIc Abnormal eye movement only and mild visceral involvement but with progressive calcification of the heart valves (most patients are Palestinian Arabs).

Jaw Involvement

In collaboration with Prof Fishman from Buffalo NY, we investigated dental aspects of 88 Gauchers patients: 25% showed evidence of Gauchers disease in their lower jaw bone (mandible) as seen in panoramic X-rays and some of the children had delayed growth of permanent teeth.

Screening

Prof Zimran spoke against screening among the general population, even among the Jewish Ashkenazi community. He said: 'If a family does not have a history of Gauchers in the family, there is no need for the test. As previously discussed, there are many Ashkenazi Jewish patients who will never show symptoms. I know of one case where a couple had an abortion because of screening which I feel was truly unjustified.'[

About 100 different mutations of the gene have already been discovered and there are probably even more. If a patient has mutations we know about, a prognosis can be made based on the mutations. For example, if someone has two copies of the 1226 mutation, they will probably not have severe disease. But if they have a copy of the mutation 84GG, their symptoms will be worse.'

Dr Zimran was asked where the 'mutations originated from. He said: 'There have been two theories to explain the high prevalence of Gauchers disease in Jews: one, a mutation arose many generations ago and was perpetuated thereafter in an inbred society (?founder effectµ). However even among the Jewish population, there are more than one mutation and in addition, Gauchers is one of several storage disorders among the Ashkenazi Jews.

'Therefore the second theory may be more plausible: that there is a selective advantage, meaning that there was an advantage in being a carrier (like in carriers of sickle cell anaemia, a disease found in the African population, which gives protection against malaria).'

Prof Zimran felt there could be such an advantage in Gauchers disease but so far the nature of it has not been elucidated. It had been thought that there might be an immunity to tuber-culosis, similar to the theory ascribed to explain the prevalence of Tay-Sachs disease among Jews, but research in Israel has failed to confirm this.

The Future

Hopes for the near future include improving the effectiveness of enzyme replacement therapy. Further into the future comes the hope of a successful development of gene transfer therapy.

When asked about bone marrow transplantation for Gauchers disease, Prof Zimran replied that the risk was too great compared to enzyme replacement therapy in Type 1. Yet it may be considered in certain patients with Type 3 who respond poorly to enzyme therapy.

We don't have to perform splenectomies any more and we hope that children will no longer be the victim of skeletal complications.'

Professor Zimran expressed his gratitude to the patients and patientsµ associations for their support in the past, and acknowledged their generosity even before there was an immediate reward for their efforts.n


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Source: Gauchers News July 1998

© Copyright Gauchers Association 1998