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Professor Timothy Cox is responsible for a large group of Gauchers disease patients at Addenbrooke's Hospital, Cambridge. Professor of Medicine at Cambridge University, he has a special interest in inherited disorders of the metabolism and is Vice-Chairman of the European Working Group on Gaucher Disease. He has worked on Gauchers disease for several years and was the first speaker at the Gauchers Association's Third Conference. During his introduction, Jeremy Manuel thanked Professor Cox for ensuring that special funding from central government had been allocated to the care of Gauchers disease.
We are delighted - and relieved - that the Government has recognised the needs of Gauchers patients in granting special funding,' replied Prof Cox. 'I believe this will help to improve the care of patients. We plan to have a telephone helpline manned throughout the working week which will provide assistance on day-to-day issues concerning Gauchers disease.
For the first time at Addenbrooke's Hospital we will also have nursing support and additional X-ray and orthopaedic expertise so that we can specifically review some of the complications which arise. Bone disease experts will regularly meet to discuss specific cases and their progress. Until now, we have had very little means to fulfil these services to our patients.
There will also be an anonymous national register of patients held by the Department of Health which will detail how patients are progressing and we hope this will pick up early warning signs of any clinical deterioration.
It is intended there be a National Panel of experts from different centres which will meet regularly to discuss consensus issues and whose aim it will be to speak with one voice.
The question as to whether Ceredase and Cerezyme should be funded centrally is also under review and I believe will also be an important national issue for the Association.'
A Cellular Condition
Prof Cox then outlined some of the aspects of Gauchers disease which will need to be considered in the future: 'The disease was recognised over 115 years ago by a French doctor, Philippe Gaucher, when he identified distinctive cells in a spleen but he wrongly thought they represented a malignant condition resembling leukaemia.
I first looked after a patient with the disease in 1976. This young man had his spleen removed in 1985 because he was bleeding: the spleen was enormous. Since the operation, he has progressed very well; he and his sister live in Spain and both receive treatment with Ceredase.
What is interesting is that these enlarged cells in the spleen, which contain the accumulated material, glucocerebroside, only account for a fraction of the total weight of the enlarged organ. It is water and the effects of inflammation which makes up the bulk of the extra weight and volume. An average spleen weighs 0.12 kilograms, in a Gauchers patient it may weigh up to 3-4 kilograms - or even more. A normal liver weighs 1.5 kilograms, an enlarged Gauchers liver may weigh from 3-5 kilograms. In Gauchers disease, the amount of total glucocerebroside in these tissues amounts to only a few tens of grams - so it must be doing something bad, just by being there!
We have known for 30 years that the disease is caused by a deficiency in the enzyme, glucocerebrosidase, which allows the accumulation of the substance, glucocerebroside, in the spleen, liver and other parts of the body. This material stays in certain cells called macrophages and these enlarge so that inside they look as if there are areas of sand - under the microscope that is!
These macrophage cells which occur in everyone, originate in the bone marrow and travel to every part of the body including the spleen, liver, lung etc. They are very important because they destroy material that is foreign to the body and are part of our defence (immune) response.
During an infection they are responsible for releasing chemicals called cytokines that give you a fever so that you lie down to rest. They also take part in responses to inflammation and they remodel and repair scar tissue and growing bone.
If there is insufficient enzyme produced in the macrophages of the liver, spleen and bone, then accum-ulation of the fatty material occurs. The macrophages get 'indigestion' and become activated in an attempt to overcome their build-up problem; in some way damage results.
It is the aim of our laboratory - and others - to find out how and in what way the macrophages become activated to become Gauchers cells.
Unlike Type 1 disease, in Types 2 and 3, accumulation to varying extent occurs in the brain and in Type 2 is fatal within a couple of years of life.
Damage to the spleen, liver and bones is also due to the death and scarring of tissue close to Gauchers cells within these organs of the body. Again we are not sure exactly how these effects are brought about but local actions of the Gauchers cells must be responsible for the injury.
Difference in Twins
The gene, which is the blueprint for the enzyme, was cloned in the 1980's by Prof Mia Horowitz and mutations in it were found to be responsible for Gauchers disease. It was discovered that inheritance of two copies of the gene mutation N370S causes Type 1 Gauchers disease whilst usually two copies of L444P causes the more severe Types 2 and 3. However there is significant variation of disease among those patients harbouring the same mutant genes.
One example of this is a pair of identical twins who have lived very similar lives. One is unaffected with normal blood counts, the affected twin had to have her spleen removed some years ago. Hereditary defects are necessary but not sufficient to produce the symptoms of the condition. Environmental or other factors, such as viral or other infections, must also be relevant and somehow trigger off the disease.
Very, very, rarely, patients have developed multiple myeloma, a condition in the bone marrow and a form of cancer, which may be caused by the prolonged presence of Gauchers cells in the marrow space. Perhaps something is made by the Gauchers cells which irritates neighbouring cells so that they go through a phase of uncontrolled growth,' speculated Prof Cox. 'We have investigated various substances which are known to be secreted by activated macrophages. Many of these chemicals are called Interleukins and Chemokines now generally termed Cytokines. For example, Interleukin 6 causes fever and co-ordinates the body's response to infection. It also has a specific growth-promoting effect on multiple myeloma.
We measured blood samples from 22 Gauchers patients for the presence of cytokine mediators for inflam-matory response. There was a marked increase in Interleukins 6 and 10. Interleukin 6 is also known to have an effect on the skeleton. The values were higher in patients with evidence of non-malignant cell growth that resembles myeloma (but almost never becomes serious) and in those with X-ray evidence of bone disease.
Our findings are backed up by studies in mice that have been made experimentally deficient in Interleukin 6. Incredibly, these animals don't get osteoporosis (thinning of the bone) when an artificial menopause is induced.
Interleukin 10 may also prevent bone repair. So in Gauchers disease, there may be a need to stop the activity of these substances. In other areas where they influence disease, the pharmaceutical industry has already begun to develop drugs that do this.
Understanding the Gauchers Cell
In our laboratory at Addenbrooke's, a new PhD student, Mary Teresa Moran, and Dr Paul Schofield are now working with me on on a more systematic project to characterise the Gauchers cell. The Gauchers Association and the Medical Research Council (MRC) are supporting this research; we are very grateful for this and knowing all the efforts and hope invested in us, this spurs us on.
This project may give a clue as to why some patients have severe disease and indicate better means of relief. The research is coming on extremely well and I hope to report more to you on this at a later date.
Gauchers disease causes bone deformity and some bones don't have the right shape, for instance the femur at the knees which are often flask-shaped. Some bone may die, for instance in the hip and shoulder, and this can cause immense pain. Holes then occur in the bones and these, as well as generalised bone thinning may cause fractures after very slight injuries. Demineralisation takes place. The specialised macrophages or osteoclasts in the bone eat the bone and takes it away but often not enough bone is replaced. Enzyme replacement therapy can stop bone damage but it cannot cure the main problem of bone death once it has occurred.
Bisphosphonates for Bones
The bisphosphonate group of drugs has been used for the treatment of osteoporosis and a medical article published in 1991 describes very precisely for the first time how one of these drugs, pamidronate, helped two Gauchers patients who had very thin bones. Their bone density increased on receiving the drug. This research was carried out by Dr Jonathan Reeve who is now working at Cambridge in the MRC Bone Research Unit.
A new bisphosphonate agent, alendronate, has a thousand times greater potency. It is less toxic and is pretty safe. It has been shown to improve fracture rates in people with osteoporosis by arresting bone thinning and improving bone density. It has a direct effect on osteoclasts and some Gauchers patients are receiving the treatment. The drug is licensed at present for use in osteoporosis whatever the cause.
Other even better tolerated bisphosphonates are coming on stream.
Three trials for gene therapy for Gauchers disease are underway although it may take 5-10 years before it comes into effect in the Clinic. There is no real news of immediate practical value but all experiments have been found to be safe so far - an important point for the future.
Mothers and Babies
When we think of the future for Gauchers disease, we also think of children,' said Prof Cox. 'Inheritance plays its part and in certain people at risk, it may be necessary to consider the possibility of future children being affected.
The fertility of some Gauchers women with active disease may be lower and Ceredase has certainly helped several women to conceive and carry babies to term. Up to one quarter of women deteriorate during pregnancy but most get through it without ill effects and have healthy babies. There are of course important issues at delivery when extra bleeding may need special measures.
Ceredase should probably be stopped during pregnancy although five women, under the care of Dr Ari Zimran, receiving Ceredase during pregnancy in Israel showed no ill effects at all. Dr Zimran has a very large experience of Gauchers disease and its effects on women's health. His published findings are very encouraging as well as informative. For more details on this subject, see Obstetric and Gynaecological Aspects in Women by Dr Ari Zimran.
The future clearly offers much promise for Gauchers patients and their families,' concluded Prof Cox. 'I wish all of you good luck as you plan for it.'
A paper describing this work entitled 'Pro-inflammatory cytokines and the pathogenesis of Gauchers disease: increased release of interleukin-6 and interleukin-10 was published in the Quarterly Journal of Medicine 1997: 90:19-25. The paper acknowledges the support given to the research team by the Gauchers Association.
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Source: Gauchers News June 1997
© Copyright Gauchers Association 1997