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Neuronopathic Gaucher disease continues to be a challenge despite the advances made, explained Dr Ashok Vellodi at the opening of the Type 3 Gaucher Disease European Family Conference on 26 November 2004. Dr Vellodi, who is pictured below, runs the paediatric Gaucher Centre at Great Ormond Street Hospital in London. This is an abstract of his talk:
Gaucher Disease was first described in 1882 by Dr Philippe Gaucher in France but it was almost 40 years later in 1921 when Dr Rusca described the neuronal involvement in Gaucher Disease. Dr P O Hillborg wrote about the Norrbottnian form of Type 3 found in northern Sweden in 1959.
In 1965 Dr Roscoe Brady and colleagues discovered the enzyme responsible for the disease and the gene was cloned in 1985.
Enzyme replacement therapy was first successfully used in 1990 and in 1994 Dr Frances Platt and her colleagues showed that a drug named NB-DNJ inhibited the synthesis of glycosphingolipids of which glucocerebrosidase is one.
Symptoms in the nrain
Dr Vellodi explained that there are two forms of neuronopathic Gaucher Disease: Type 2 (acute) and Type 3 (chronic). However there is a continuum of symptoms which runs between Type 2 and Type 3 and an intermediate state exists between the two types. He said that patients who develop neurological problems have a lower residual enzyme activity and cannot break down the waste material of glucosylceramide or glucocerebroside which accumulates in the brain.
There is also accumulation of another substance called glucosylsphingosine in the brain and this may be toxic to nerve cells. Patients with neurono-pathic Gaucher Disease have higher levels of this substance in the brain than patients with Type I disease.
Dr Vellodi referred to Dr Futerman's work on the role of calcium.
He said that it has been shown that the brain is in fact involved in all forms of Gaucher Disease but that severe changes, for example neuronal loss, are seen only in the neuronopathic forms. Some Type 3 patients show mainly visceral symptoms (physical symptoms in the body but little neurological symptoms) whilst others show predominantly neurological symptoms.
Groups of patients with Type 3 Gaucher Disease have been found in localised areas in Sweden, an Arab population in Israel and the West Bank and in South India (Mappila Muslims of Malabar). A subdivision of Type 3 into Types A, B and C and the Norrbottnian variant has been suggested but this is probably artificial. The only group that appears to be distinct is that having two copies of the D409H mutation reported from Israel and Spain.
Dr Vellodi described symptoms similar to those of Parkinson's disease which occurs in a few patients, even those with Type 1 disease, which are often difficult to treat. He spoke about progressive myoclonic epilepsy which was also difficult to treat. In both situations there may be a relationship between the patient's genetic mutations and the symptoms though prediction is as yet not possible.
Genetics
If a patient inherits at least one genetic mutation of N370S, this protects against neuronopathic Gaucher Disease but high risk genotypes (genetic mutations) are L444P/L444P, D409H/D409H and L444P/D409H. Genetic mutations with Rec in their names are more likely to be associated with Type 2 Gaucher Disease and if a child inherits two of these, this will cause fatality.
Other symptoms
It should not be forgotten that patients also have significant visceral (physical) involvement. Lung disease is common and lymph node collections have also been observed even on high dose enzyme therapy.
Treatment
Bone marrow transplantation and enzyme replacement therapy were discussed. In particular, Dr Vellodi explained that recent neuropsycho-metric tests at Great Ormond Street Hospital clearly showed tremendous individual variation in response to treatment and the possible reasons were discussed. Zavesca (also known as OGT 918) is now being used in a clinical trial on children with Type 3 Gaucher Disease to discover if the drug can alleviate their neurological symptoms. The trial is under way at two centres (one at Great Ormond Street Hospital and the other at the NIH in the USA). Thirty children are participating and the trial will be completed by the beginning of 2006.
Challenges
The two main challenges are why neurological involvement is seen only in certain patients and how we can treat patients more effectively than we have been doing. There have been some important discoveries at the basic cellular level that have improved our understanding of the mechanisms involved and we have also been able to delineate the clinical profiles more carefully. All this means that we now have more to offer patients than before.
However, we should not under-estimate the challenges that remain. Dr Vellodi stressed that it was important to understand the blood-brain barrier and further research should be undertaken to find out if certain other genes have an influence on the disease. It would be helpful to create an animal model and to understand how the enzyme actually works in the body.
Neuronopathic Gaucher's News
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Source: Gauchers News May 2005.
Copyright © Gauchers
Association 2005.