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Neuronopathic Gaucher Disease
Dr Ashok Vellodi has wide experience in lysosomal disorders. He looks after 16 children with Gauchers disease at Great Ormond Street Hospital for Children where he is a full-time Paediatric Consultant. He is a specialist in bone marrow transplantation for children affected by severe lysosomal diseases. He works closely with Professor Bryan Winchester and his laboratory at the Institute of Child Health where research into the DNA of Gauchers disease and other similar diseases takes place. The following is a summary of Dr Vellodi's talk at the Association's Third Conference in February 1997.
'Children are not small adults,' explained Dr Vellodi. 'Certain aspects need to be addressed in paediatric centres and one of these is the frequency of infusions. Children do not stand up well to very frequent infusions and needle phobia is more common, the more often the exposure to infusions.
The time taken up with treatment also affects busy parents and it eats into the children's school and educational needs. Home infusion carried out by parents is therefore much better for the whole family.
Growth and development are other important aspects of childhood. Children tend to have more aggressive disease and enzyme replacement therapy needs to take this into account. Children often have to travel great distances and therefore there should be at least two paediatric centres focusing on Gauchers disease.
Paediatric Workshop 1996
Towards the end of 1996, a workshop for paediatricians on Gauchers disease was held. Questionnaires were completed in respect of 25 children. Fifteen had Type 1, 8 had Type 3 and two were "not known". The following points were discussed:
Out of the 25 children, 21 presented with enlarged spleens and livers, 13 were bed-ridden or lethargic, 10 suffered with bone pain, 6 with fractures, 5 with bruising and one was a sibling of a known patient.
Initial assessment for a child is not much different from that of an adult,' said Dr Vellodi. 'Clinical assessment involves examination of the child for growth and development, size of liver and spleen and eye movements. Laboratory assessment consists of blood and other tests being carried out and radiological review includes X-ray and other imaging techniques.
Not all scans are suitable for children. X-rays remain important and MRI scans are also suitable and widely used. Scans involving nuclear medicine may not be appropriate for children.
CT scanning is not advisable because of radiation risks although 12% of the children reviewed have undergone this test. 25% of the children had bone densitometry readings.
It is important that all children should start enzyme replacement therapy to obtain peak bone mass so that they are not susceptible to fractures and can grow normally.
The majority of the 25 children reviewed (65%) received enzyme replacement therapy at a schedule of 60 units per kilogram of body weight every two weeks, while the remaining 35% received varying doses and frequency. There is no consensus yet about the best regime or protocol but hopefully one will be reached soon. It is important to take into account compliance and needle phobia as well as response to treatment.
Quality of life is as important for children as it is for adults although it is harder to assess. There is a need for a standardised protocol which is suitable for children. We need proper data collection and analysis to help us and this should be centralised at a few centres.
Of the 25 children we reviewed, eight had Type 3 disease. This is quite a significant number. How do we define neurological Gauchers disease? We carry out enzyme assay tests to diagnose Gauchers disease and then look for the presence of neurological features. We also make sure that there is no other obvious cause.
Type 2 is an acute neurological disease and Type 3 is the non-acute, chronic form. There is low residual enzyme activity in these forms of the disease and increased glucocere-broside, the fatty tissue which accumulates in different parts of the body.
Outside the brain, most glucocere-broside originates from the breakdown of blood cells. Inside the brain there is another source of this fatty tissue called gaglioside.
Children with neurological disease do not have enough enzyme to cope with this accumulation. There are also increased levels of a chemical called psychosine which is currently being studied and the role of cytokines, which are inflammatory mediators, is also under scrutiny.
As the disease progresses, the number of Gaucher cells increase and these changes are worse in Type 2. People have found that there are some structural differences between Type 2 and Type 3 but we are not sure of their significance.
Although there is some correlation amongst patients between the genotype (gene mutations) and the course of the disease (phenotype), there remains considerable variation in symptoms, even among families.
However if the genotype of a patient is N370S plus another, this will indicate Type 1 disease with no neurological symptoms. If the mutations are L444P/L444P, the disease will be severe and tends to be neurological but not in all cases.
Type 2 Gauchers Disease
The onset of this fatal form of the disease is in the first few months of life. A squint develops with fisting of the hands. There is retroflexion of the neck and early loss of skills. Death occurs in the first 1-2 years and there is enlargement of the liver and spleen.
The management of Type 2 is supportive only. I do not think enzyme replacement therapy or any other specific treatment should be given.
Type 3 Gauchers Disease
There are four sub-types of Type 3 Gauchers disease: A, B, C and the Norbottnian variant.
Type 3A: Onset begins in children and young adults. They tend to suffer from seizures, gaze palsy (abnormal eye movement), ataxia (losing balance) and spasticity (stiffness). They also suffer developmental regression.
Type 3B: Onset is in childhood and the children suffer from aggressive systemic disease (eg enlarged liver and spleen). They also suffer from gaze palsy and cognitive impairment (difficulty in comprehension and understanding).
Type 3C: This form of disease has recently been described in Arab patients. They suffer from abnormal eye movements but no other neurological involvement. They also have heart valve calcification and have a specific gene mutation (D409H).
Norbottnian variant: Sufferers from this form of Type 3 come from a particular region in Sweden where they have a single gene mutation L444P which originates from one family many generations ago. However there is intrafamilial variation, with some members in the same family having Type 1 disease with no neurological symptoms. Neurological symptoms for this form of Type 3 are ataxia and spasticity, gaze palsy and seizures with EEG abnormalities. The condition deteriorates after splenectomy.
Pulmonary (lung) disease does not respond well to enzyme replacement therapy. The enzyme ACE (angiotensin converting enzyme) tends to measure pulmonary disease. In a patient receiving Ceredase for 7 months at 60 units per kilogram of bodyweight every two weeks, there was no change in the pulmonary disease or the ACE level. But when the dose was raised to 100 units every two weeks, the ACE came down dramatically accompanied by improvement in the lung disease.
All Type 3 patients have abnormal eye movements. This is an early diagnostic sign and can be picked up by specialist equipment in a non-invasive test.'
Dr Vellodi demonstrated through slides how a curtain was rotated around a seated child. The child's eyes slowly followed the pattern in the curtain as far as it could. In a normal child, the eyes would quickly turn back to follow the pattern through another semi-circle. However in a Type 3 child, the eyes could not make this quick movement .
Dr Vellodi pointed out that this may be the only sign of neurological disease and no other signs may appear in the future. 'I believe all children should be checked for this symptom. Out of the eight Type 3 children diagnosed, only one was clinically suspected beforehand but six have abnormal eye movement.
We have early evidence that the way a patient responds to certain questions correlates with disease within the brain. A consistent pattern appears to be emerging.' Dr Vellodi also described a hearing test which might help diagnose the disease.
Management of Type 3
Dr Vellodi described three forms of treatment for Type 3 Gauchers disease which have been used. He said:
Splenectomy: When indicated part or all of the spleen may have to be removed. The risk of removing the whole spleen is that the patient can develop an overwhelming infection and neurological and skeletal disease may progress faster. In children I prefer partial splenectomy but this is a much riskier operation. All splenec-tomised patients should have a Pneu-movax injection and take prophylactic (preventative) antibiotics for life.
Bone marrow transplantation: This is an effective but risky procedure. How-ever it does seem to prevent neuro-logical progression. There is some evidence that after bone marrow trans-plantation, eye movements subside.
Enzyme replacement therapy: High doses of enzyme replacement therapy are required in Type 3 patients. In Sweden patients are now started with 100 u/kg/bw every two weeks. We start with 60 u/kg/bw every two weeks. No one knows what the optimum dose is but the dose should not be reduced. We do not know if this will help neuro-logical symptoms but it is effective in treating the spleen, liver and bones.
Concluding on Type 3, he said:
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Source: Gaucher's News June 1997. © Copyright Gauchers Association 1997.