An Overview of Neuronopathic Gaucher Disease

Neuronopathic Gaucher's News Contents
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Dr Ashok Vellodi, who is in charge of the Gaucher Clinic at Great Ormond Steet Children's Hospital, opened the conference with an over view of Neuronopathic Gaucher disease.

Neuronopathic Gaucher disease (NGD) can be defined as the presence of neurological features in a person who has Gaucher disease for which there is no other obvious cause.

There are two broad types of NGD, Type 2 (acute) and Type 3 (non-acute or chronic). The pathogenesis (cause of development) of NGD is unclear. Sufferers have a lower residual enzyme and there is increased glucosylceramide, a substance that builds up in the brain, as well as an increase in psychosine, another substance.

Sufferers of Type 1 Gaucher disease may have just enough enzyme to break down glucosylceramide in the brain, whereas Type 2 and 3 sufferers do not and therefore storage takes place in the central nervous system. Gaucher cells can be seen surrounding the blood vessels in the brain. However, whether there is direct storage of glucosylceramide in the nerve cells remains debatable.

Different Mutations

The effect of different genetic mutations also needs to be considered. There is some correlation between the genotype (the mutated genes inherited from both parents) and the phenotype (clinical features). For example, the L444P mutation, when inherited from both parents, confers a high risk of NGD. On the other hand, the N370S mutation is thought to protect against NGD. However, some sufferers with the mutations L444P/L444P do not have any clinical evidence of NGD.

A founder effect may also be seen in some areas. This refers to a small population directly descended from one or two families. The descendants of such families all live within a small geographical area and intermarriage is common. This results in a high incidence of the disease, with affected family members usually having similar clinical features. Such a founder effect has been seen in the Norbotten region of Sweden, the Jenin Arabs and the Mappila Muslims of Kerala in South India.

As of October 1998, there are 89 Type 3 patients out of 1735 Gaucher disease patients on the International Registry. The sex incidence of Type 3 patients is equal, 85% of them having the gene mutation L444P/L444P and the mean age at diagnosis being 3.8 years.

There are four sub-groups of Type 3 Gaucher Disease: A, B, C and the Norbottnian variant. Such a classification is probably no longer valid. It may be more correct to say that there is a spectrum, with some patient having predominantly neurological problems, and some having mainly visceral problems, eg in the spleen, liver and bone marrow.

Of particular interest, however, is the group referred to as Type 3C. This was first described in 1995 in Israel and Spain. These patients have an eye movement abnormality and heart valve calcification. They are only mildly affected neurologically and have the gene mutation D409H/D409H.

NGD should be suspected when there is early onset of aggressive visceral disease, falling IQ scores or a 'high-risk' genotype. It is often very difficult to identify someone who has Type 3 Gaucher disease merely by looking at them. Careful assessment is therefore essential. A patient who is suspected of having NGD has to have a thorough clinical assessment, eye movement studies, audiology and neuropsychometric tests, and imaging. In this way, some patients who were originally diagnosed with Type 1 have been re-diagnosed as having Type 3 Gaucher disease.

Clinical examination should include an assessment of cognitive function, looking for movement disorders and assessment of brainstem function. Early brainstem dysfunction is a clinical hallmark of early NGD. Eye movement and audiology studies were not discussed in detail as they were the subjects of other specialists' talks.

It is important that all children have regular tests of their cognitive function to identify deterioration. It is also important that these tests are slightly delayed as most children who first come to the attention of a doctor are initially very ill. The children may also perform these tests very slowly because of their eye movement abnormality. This may result in misleadingly low scores.

Imaging using MRI and CT scanning is frequently used. More recently, SPECT (Single Photon Emission Computed Tomography) has been used, specifically looking at blood flow in the brain. This has been used in other countries as well. This has shown, in a number of children, abnormalities of blood flow to the basal ganglia, an area of the brain that is specifically concerned with movement and posture. This may be of importance because certain movement disorders such as Parkinson's disease Tourette's syndrome are more common in Gaucher disease.

Special Educational Needs

Children with NGD have Special Educational Needs (SEN). It is very important that these children are statemented and that those involved in their education are fully informed about the disease and its implications on the children's ability to access the national curriculum.

Regular network meetings with doctors, teachers, physiotherapists, occupational therapists and others are essential to ensure regular communication about the childµs progression and problems. These may include eye movement, auditory processing, speech apraxia (where the child has difficulty in articulating words when there is no obvious problem with the mouth or hearing) and co-ordination. These problems will mean that these children will have problems coping with crowds, physical safety, processing sounds in busy playgrounds and classrooms.


The treatment for Type 2 Gaucher disease is only supportive.

For Type 3 sufferers, splenectomy may be necessary in some children, if the spleen is so large that it is actually compromising breathing or feeding. A partial splenectomy is preferable to a total splenectomy since it is well known that the neurological features accelerate after a total splenectomy.

In the past bone marrow transplantation was used. However, currently for Type 3 the treatment of choice is enzyme replacement therapy. Today children in the UK receive 120 units per kilogram of bodyweight fortnightly, by agreement between the two Gaucher Centres for children at Great Ormond Street Hospital and the Royal Manchester Children's Hospital. This dose should not be reduced.

Clearly, enzyme replacement therapy is effective in treating the visceral disease in these children. Some effect on the central nervous system has also been seen such as an improvement in ataxia (unsteadiness) fit control and improved IQ scores in some patients. However myoclonic epilepsy and movement disorders do not seem to improve.

The future for NGD is to try to find ways of improving delivery of enzyme replacement therapy to the central nervous system. Dr Roscoe Brady's team at the National Institutes of Health in the US has performed some interesting experiments in rats, using direct delivery of enzyme to the brain. They showed that enzyme was directly taken up by the nerve cells. They plan to carry out similar studies in Type 2 patients.

Substrate deprivation (balance) therapy and gene therapy are also promising areas.

In conclusion, NGD can be very difficult to diagnose and there is clearly a spectrum of disease rather than well-defined subgroups. The treatment of choice is enzyme replacement therapy. However, careful follow up is mandatory at a few specialist centres using well-defined protocols.

Neuronopathic Gaucher's News Contents
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Source: Gaucher's News February 2000. © Copyright Gauchers Association 2000