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Prof Gregory Grabowski, Director of Human Genetics at Cincinatti Children's Hospital and previously Director of the Comprehensive Gaucher Disease Clinic at Mount Sinai Hospital New York, spoke at a symposium on Gauchers disease held on 21 February 1993 in Manchester to local doctors and Association members. Prof Grabowski also spoke to doctors in London the next day. The following is a summary of his talks reported by David Lewis.
Prof Grabowski said that Gauchers disease was an hereditary deficiency of an enzyme called glucocerebrosidase. The condition is found worldwide and the only group not known to have any patients is the Australian Aborigine. Prof Grabowski's patients include a full blooded Inca and a Cherokee Indian.
'All surviving patients have some of the enzyme. If it were totally missing, you would accumulate 15 kilos (30 lbs) a year of Gaucher cells in your body. The cells accumulate in the organs and bone marrow.' he said. 'The residual enzyme is sufficient for 95% of the body's needs.' he added.
Reviewing the symptoms of Type 1 Gauchers disease (the most common form), he said there were extreme variations between patients. 'There is no good understanding why there is this variation - even between siblings.' He gave an example of three young brothers. All had Gauchers but the oldest and youngest showed signs of advanced disease including very enlarged stomachs. The middle brother, although having the disease, seemed normal in appearance.
Examples of his own patients
Prof Grabowski gave examples and showed slides of his own patients. He said his oldest living patient was 104 who was diagnosed at the age of 98.
He explained how misdiagnosis was still quite common. He had seen patients diagnosed as having had bone infection where no bone infection actually occurred. A bone crisis can look very much like a bone infection.
Whenever he takes on a new patient, he requires a full set of body X-rays for comparison purposes. Then if the patient gets ill in a few years time, and a new X-ray shows, for example, a hole in a bone, he can compare and see whether this is new (and therefore might require orthopaedic surgery) or it is old (and therefore possibly not the cause of new pain or other symptoms at all).
Prof Grabowski then posed the question: 'Do other symptoms get worse if you take out the spleen?' 'We try to leave it in for as long as possible; especially in children as their symptoms can get worse. In all cases of partial splenectomy, the spleen has regrown to its original size.' he said. 'However if patients have a very low platelet count or are in a life threatening situation, the spleen has to be removed.
'Bones get thin, they lose calcium and become weak. Areas of missing calcium are found in dead bone. The marrow dies and bones can break. The hip is the most commonly involved joint, and hip replacements may be needed in 25% of adult patients. When the bone dies, pressure builds up and a painful bone crisis can occur. However you don't need bone crises to get bone deterioration and pain may continue on a more chronic basis.'
He said that only rarely was there significant liver disfunction in Gauchers patients. He then added 'Some severe liver and spleen effected patients never get bone disease.' On the other hand, one of his patients was in a wheelchair with severe bone involvement but did not have enlarged organs.
Prof Grabowski explained that three different mutations commonly cause the disease. These are N370S (1226), N84GG and L444P (1448). He has reviewed 161 patients and looked for a quantitative assessment of clinical involvement. He looked at age at onset of the disease, spleen and liver volume, age at splenectomy and bone involvement. He then related these to type of mutation. His conclusion was that N370S/N370S was often mild disease; and that N370S plus any other was usually severe and should therefore receive early treatment. He said you should prevent bone disease, not deal with it after it occurred.
These above two groups of mutations comprise 70% of the whole population and 92% of the Ashkenazi Jewish population.
Prof Grabowski then reviewed the results of patients who have been treated with Ceredase. He said that in a group of 70 patients:
He explained that most of his patients had started at the full dose of 60 units per kilo every 2 weeks with the dose being halved every 6 months. Some are now on a dose of 3.5 units or 7 units per kilo every 2 weeks. He said there was a noticeable slow down in effectiveness as the dose fell to the range 3.5 to 15 units per kilo. However above this, the dosage did not seem to be significant and no difference in improvement between patients on 60 units or 30 units per kilo was found.
He said that Ceredase was clearly effective at several doses and at several frequencies but there was not enough data to conclude that one or other method was more clinically or cost effective. It was necessary to keep an open mind as to how high or frequent doses should be but very few patients did not respond to treatment. He said it was not known whether bone treatment needed more than spleen.
Prof Grabowski also reported that good results were emerging from treatment with the recombinant enzyme.
He expressed the need to find cheap tests to discover how effective the take up of the enzyme was.
A question was asked as to whether any women had had a child after receiving Ceredase treatment. Prof Grabowski said that currently several women were pregnant who had either received treatment and stopped prior to pregnancy or were still receiving treatment while pregnant. None of these women had completed their pregnancy at the time of his talk.
Dr David Evans, who recently retired as Consultant Haematologist at the Royal Manchester Children's Hospital, also spoke at the symposium and repeated the excellent talk he gave at the Association's Conference last November (reported in Gauchers Medical News February 1993). He said that not many people had Gauchers disease in the North West of England and that 13 Gauchers patients had been identified at the hospital during the last 27 years. Now tests to diagnose Gauchers did not need liver or bone marrow biopsies but only blood tests.
Dr Alan Cooper, Principal Bio-chemist at the Willink Biochemical Genetics Unit, explained that his laboratory was able to test for three mutations of Gauchers disease: 1226, 84GG and 1448 and 11 Gauchers patients had been tested so far. He said that his laboratory had previously been involved in screening for Tay Sachs, another hereditary disorder found more frequently among the Ashkenazi Jewish population.
They had taken samples from the Tay Sachs studies of 93 individuals and DNA tested them for Gauchers mutations. Eight carriers of Gauchers disease had been found in the sample which indicated an incidence rate of 1 in 11 carriers in the Ashkenazi Jewish population. (This carrier rate confirms the findings of Professor Beutler in California).
Dr Cooper explained the complicated process of extracting the DNA material from blood samples and testing it for the three mutations. Dr Cooper ended his talk by saying that he would not recommend pre-natal diagnosis for Type 1 Gauchers disease.
Source: Gauchers News September 1993
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