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Prof Ari Zimran, who heads the Gaucher Clinic at the Shaare Zedek Medical Centre in Jerusalem addressed the audience of doctors, families with Gaucher disease and others during his visit to Bulgaria. This is a summary of his talk:
Gaucher disease is a storage disorder due to a deficiency of the enzyme glucocerebrosidase which normally degrades glucocerebroside (a fatty waste product).
Cells called macrophages normally use the enzyme to get rid of the waste product but instead the waste product remains stored which causes the cells to become enlarged. These cells are called Gaucher cells and are sited in the spleen, liver and bones.
However not all the disease manifestations are caused by the storage itself; some are probably caused by various substances which are excreted from these cells.
Mutations of the Gene
Over 200 mutations of the gene which lead to the deficiency have been discovered but we still have to learn what causes different manifestations of the disease within people with the same genetic mutations. Even brothers and sisters with the disease may vary in the severity of their disease. It is possible that other modifier genes or various environmental factors, such as infection or trauma may account for the variability in symptoms.
The most common mutation in Israel is N370S and when a patient is homozygous with this mutation (ie inherits two of this same mutation, one from each of his or her parents), this usually shows mild disease although not always.
If a patient inherits two different mutations called N370S and 84GG (one from each parent), this may show more severe disease. It is believed that if both parents pass on an 84GG mutation, this is incompatible with life and no such baby will be born. If two mutations of L444P are inherited, this usually leads to Type 3 disease although not always.
Some mutations of the gene are unique to individual groups or families. For instance D409H/D409H which causes calcification of the heart valves, occurs uniquely in Jenin Arabs, Japanese and Spanish patients.
Diagnosis of Gaucher disease must be made by an enzyme assay test to discover if the level of enzyme in the patient is low. This is carried out by a simple blood test. If the sample does not show a low level of the enzyme, the test should be repeated. If the level is still not low, then doctors should look for other diseases that could cause the symptoms.
Prof Zimran described the three types of Gaucher disease. He said that Types 1 and 3 can benefit from enzyme replacement therapy but babies born with Type 2 are too sick when born and cannot be helped by this form of treatment.
He stressed that if children are diagnosed with symptoms and are not treated, when they become teenagers their bones will become affected and damage will occur.
Prof Zimran described how Gaucher disease has been treated in the past, how it is treated in the present and how it will hopefully be treated in the future.
Management in the past has included:
Management in the Present includes:
Enzyme Replacement Therapy
Enzyme replacement therapy leads to spleen and liver reduction, and raised blood counts. Response in the bones is slower, for example it may take 42 months to reach normal levels in cortical thickness. As with bones, the effects on lung status are slow.
There used to be arguments regarding dosage levels: higher dose versus lower dose.
However if patients start on a high dose, the dose can be reduced as they improve. Alternatively if a patient starts on a low dose and does not improve, the dose can be raised to see if this makes a difference.
The main argument in Bulgaria, like Israel 10 years ago, is probably between low dose or no dose.
It is important for patients with symptoms to start treatment as soon as possible but the dose can be individ-ualised. Generally infusions are given once every two weeks regardless of the dose level although patients on a higher dose may have their infusion continue for longer than one hour.
Results from both dosage levels have been very successful. Possibly patients on a higher dose respond quicker but eventually they and those on a lower dose reach the same plateau, possibly after two years.
Prof Zimran said it was important that patients be seen at a specialist centre every six months for assessment. However most patients in Israel have infusions at home or at a local clinic.
About 3,200 people with Gaucher disease are on enzyme replacement therapy, the largest number being in the USA, Europe and Israel although there is a growing number in Japan, Egypt and China.
Gaucher disease appears equally in both men and women although because mild cases of bleeding show more in women than men due to menstruation and pregnancies, there are slightly more women than men patients in Israel.
Although there have been concerns over fertility in both boys and girls, there appears to be no problem especially if the patient is on enzyme replacement therapy. Prof Zimran said he knew of a few women with Gaucher disease in Israel who have seven or eight children.
There have been very few side effects caused by enzyme replacement therapy and usually these are mild allergic reaction in a small amount of patients.
Prof Zimran quoted Prof Grabowski's findings that 93% of patients who developed antibodies (as shown in blood tests) showed no manifestations and typically these antibodies vanished after 30 months.
Both ethical and social issues arise because enzyme replacement therapy is not available in all countries because of its high cost. However interest in Gaucher disease means more research is being carried out to establish new treatment modules.
Treatment in the Future
These last two are being researched but are not yet available.
People with Gaucher disease should eat a normal healthy diet. However adult patients should avoid smoking and heavy drinking although a glass of wine with dinner is okay.
Gaucher News Contents
Source: Gaucher News September 2001.
© Copyright Gaucher Association 2001