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Dr Jack Goldblatt, with over 20 years' experience of Gauchers disease in South Africa, America and Australia, spoke to members of the Gauchers Association on Sunday 21 April 1996. Dr Goldblatt, currently Genetic Services Director of Western Australia, appeared remarkably fresh despite having completed the 26 mile London marathon that morning in 3 hours 37 minutes.
'It is a doctor's duty to treat patients as individuals and to consider their needs over and above scientific debate'. These are the words that Jeremy Manuel remembered Dr Jack Goldblatt saying to leading practitioners and scientists in 1992 at a Symposium on Gauchers disease in Amsterdam. 'It was Dr Goldblatt voicing his concern and compassion for patients which I remember vividly', said Jeremy in his welcoming introduction.
Patients Knowledge Is Great
'I plan to give my views on Gauchers disease in an informal manner as I realise that the knowledge amongst patients and their families is very great', said Dr Goldblatt.
'I first saw patients with Gauchers disease in 1973 when I wrote my doctoral thesis on the condition. Then doctors could only treat the complications with eg splenectomies, hip replacements and blood transfusions which did not influence the underlying progressive metabolic abnormality. It was when I worked with Dr Bob Desnick at Mount Sinai Hospital, New York, in the early 80's that Dr Roscoe Brady's group at the NIH started reporting on the development of enzyme replacement therapy, to treat the underlying defect in the condition.
'Enzyme replacement therapy is now a reality and the good news is that Ceredase works but the dosage must be individualised. There are no set rules. In different individuals it works at different doses and when given at different frequencies. There are minimal reported side effects and nothing so far has shown up in terms of infectious risk with Ceredase, however on balance I would prefer enzyme obtained from recombinant DNA rather than human sources. However considering the relative risks in severely affected individuals, the results of not treating are a lot worse.
'I am not sure we will ever resolve what the ideal dose is for everybody in terms of the disease and response variability. Finding the right dosage would depend on how the patient responded but in the end, it will unfortunately often be an economic decision. The dose will inevitably be as low as possible but still be effective in that individual.
'Glucocerebrosidase is a housekeeping enzyme, which means that the body makes a consistent amount of it all the time, contrary to the situation with Gauchers disease where not enough is made or it is dysfunctional. The enzyme should remove unwanted lipids, the fatty tissue resulting from the breakdown of old blood cells, which otherwise accumulate. Ideally to mimic what should happen in the body, a patient should be on a low continuous dose but for most sufferers, the enzyme must clear the newly formed material plus any backlog abnormally stored over the pre-treatment period.
'All things being equal in terms of drug safety, cost and availability, I believe all patients should ideally be considered for treatment on diagnosis. According to the response to treatment, subsequently the dose and frequency could be cut and in this way complications could be avoided.
This would be preferable to waiting until severe symptoms arise as we cannot reverse all the complications once they occur. When body tissue is damaged, this often causes scarring and we can't reverse scars and restore normal tissue in this situation.
'Mild cases could be monitored every six months and if there is any deterioration, treatment could be started early. This way you could prevent complications occurring, rather than waiting for them to occur and then trying to reverse them.'
Dr Goldblatt said that in this situation, the minimal criteria when to ideally start treatment would be when a physician could feel an enlarged spleen or liver, the blood counts were low or there was any evidence of bone involvement.
'The answer is to monitor the patient and then decide what to do. It is therefore best to go to experts who are experienced with managing the condition and have seen other patients with Gauchers disease. They will be best able to objectively quantify disease severity and monitor responses to treatment.
'In 1996 it is due to the cost of treatment, shortage of placental derived enzyme and the theoretical risks of administering human derived products that all patients don't receive treatment early in the course of the disease. Treatment would certainly be cost effective if started early. However because of these facts, we have to start with those already severely affected.
'I see no reason why patients should not infuse themselves with enzyme at home after hospital training and ex-clusion of allergic reactions. After all diabetics give themselves injections and haemophiliacs self administer Factor VIII infusions at home.
The first patient to receive Ceredase in Australia was started when reports were available on only 12 patients on treatment in the whole world, from the original NIH study. Once one person received it, the news spread and a Government Committee for Enzyme Replacement Therapy was formed, to which I was appointed Chairman. Patients apply for therapy through their local politician and the Federal Health Department and the Committee make a decision as to suitability for therapy according to strict disease severity related criteria. We have 12 patients on treatment starting on an average of 30 units per kilogram of bodyweight every two weeks. There are about 50 Gauchers patients in Australia of whom 30 to 40 may need treatment. Overall about 18 million people live in Australia.
Variability in Symptoms
'In my experience of looking after about 200 families with Gauchers disease over the past 20 years, I have found great variations even with people carrying the same gene mutations. Jewish people of Ashkenazi descent tend to have milder disease than those in the general population. But having said that, even among sisters and brothers, there can be a great variation of symptoms. They may inherit the same Gauchers genes from their parents but because the other 100,000 genes they inherit may be different, even siblings might have different disease severity.
'I have a patient of 12 years who is severely affected and his 15 year sister is asymptomatic (has no symptoms) but they have the same gene mutations. The identical twins I know are also differently affected. This shows there must be other factors con-tributing to the disease severity of both a genetic and environmental nature.'
Dr Goldblatt said no one knew what exactly caused the severity of bone symptoms but he felt the major problem related to abnormal pressure dynamics in the bones from the stored material. He explained that the difference between bones and other organs where lipids (the fatty tissue which accumulates in Gauchers disease) go, is that the bones are rigid and cannot expand to accommodate the lipids. Other organs like the spleen and liver can enlarge but in the bones, space is limited and so this increased pressure squeezes the blood vessels cutting off the blood supply. For instance in the femur (the thigh bone), the blood is prevented from reaching the head (ball of the hip joint) and the bone begins to die. This may be the reason for the acute pain felt in bone crisis and also may be the reason why the bone structure deteriorates. Damage in the bones may also be caused by the Gaucher cells leaking and releasing damaging enzymes.
'Bones operated on by experienced orthopaedic surgeons tolerate proce-dures well if done during a quiescent phase (ie not during a bone crisis). When we reviewed Gauchers patients with hip replacements more than 10 years later, they were doing well. Hip replacements should only be con-sidered when the pain is unbearable and significantly compromising lifestyle or health. Preferably in 1996 the patient should have been on enzyme replacement therapy for a couple of years before bone surgery.
'It is early days to know if bones respond equally well on high or low doses. One problem is that it is difficult to judge the response of bones in the short term with most routinely available radiology techniques. Indeed it is possible to lose up to 50% of bone mineral and X-rays would still show bones having a normal appearance. Other measurements like bone densit-ometry and specialised MRI scans on the marrow need to be used to try and objectively monitor bone response.
'There is an argument that mild cases should wait for the recombinant enzyme', said Dr Goldblatt. It is theoretically purer than the placental enzyme and eventually there should be no shortage as one doesn't have to rely on donation of human tissue to obtain it. Other recombinant drugs have been found to be safe so in theory should recombinant glucocerebrosidase. The problem is that it is probably going to be just as costly because of the purification methods.
BMT and Splenectomy
'I see no reason for bone marrow transplants now that enzyme replacement therapy is available.
Taking the spleen out is generally not advisable but may be necessary under certain conditions. Paradoxically the spleen works better as it gets bigger but it also generates more stored material by removing younger and younger blood cells from the circulation. The spleen must however only be removed as a last resort after careful consideration in a specialist unit.
'Partial splenectomy is rarely used for Gauchers disease and must be done by an experienced surgeon. It would be theoretically worthwhile if blood counts return to normal and the potential store house for the abnormally accumulating lipids remained. However it is uncertain how quickly the residual spleen will grow large again if the patient does not receive enzyme replacement therapy, or how effectively it will continue to store the lipid, thus preventing accumulation in other tissues.'
A mother in the audience with an 18 month old daughter with Type 3 Gauchers disease, said that her child had recently undergone a partial splenectomy and was doing well. Her blood counts were now normal.
Dr Goldblatt said that four of the 12 patients receiving Ceredase in Australia were Type 3 and these included a set of identical twins. All were doing well and he was very optimistic about their future as thus far their neurological problems had not progressed on therapy.
Dr Goldblatt told the audience not to be scared to discuss with their doctors and nurses, aspects of their treatment, particularly if there were issues concerning them. 'You need to question aspects you are not happy with as it provides useful feedback to medical staff in terms of quality improvement,' he said. This brought a laugh from some members in the audience who plainly did not feel scared of dealing with their doctors.
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Source: Gauchers News September 1996
© Copyright Gauchers Association 1996