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The European Working Group on Gauchers Disease held a two day workshop in Trieste on 13-15 October 1994. Nearly 100 delegates attended, mainly doctors and researchers from Belgium, Czech Republic, France, Germany, Israel, Italy, Netherlands, Poland, Portugal, Spain, Sweden and the UK. Also attending were delegates from the patient associations in France, Israel, Italy, Netherlands, Sweden and the UK. This report is by Susan Lewis, Jeremy Manuel and Sandra Maclachlan who represented the UK Gauchers Association.
Professor Timothy Cox of Addenbrooke's Hospital, Cambridge together with his colleague, Dr Pram Mistry gave a number of lectures during the Workshop. Prof Cox chaired sessions on Therapy and Clinical Trials. He also spoke about Splenectomy in Gauchers Disease and Gene Therapy. Dr Mistry described the symptom diversity of the disease in a pair of identical twins and spoke about the important research he and Prof Cox have carried out into the tissue distribution and metabolism of Ceredase and Cerezyme, see Second Conference Report.
Macrophage Biology in Relation to Gauchers Disease
The workshop opened with a lecture by Dr R van Furth from the Netherlands about macrophages, the cells in the body which retain the fatty tissue glucocerebroside which causes the symptoms of Gauchers disease. He said 'Macrophages are crucial in Gauchers disease. They are the key as it is in these cells that the defect needs to be rectified.' A clinician who has carried out research into macrophage biology for the past 30 years, Dr van Furth said that in mice, 50% of macrophages are found in the liver, 10% in the spleen, 20% in the lungs and 5% in the skin. He explained how macrophages grew from monocytes which are carried from the bone marrow through the blood to the tissues in the liver, spleen etc. There are different types of macrophages and some help fight infection. Dr van Furth continued that normally macrophages die and disintegrate but it is not clear what happens to the Gauchers macrophages, and the waste material they contain (the fatty tissue glucocerebroside), when this happens.
Dr Scott Furbish, Associate Director of Genzyme Corporation, explained later that normal macrophages go to die in the lymph nodes, another part of the body. Gauchers macrophages don't go to the lymph nodes but remain in the spleen, liver or where they are located. Even if these macrophages do break up, the glucocerebroside which they contain remains where it is, probably to be taken up by other new macrophages.
It was evident from Dr van Furth's lecture that more research will need to be carried out into how macrophages work in relation to Gauchers disease.
Clinical Manifestation of Type 1 Gauchers Disease
Dr Ari Zimran of the Shaare Zedek Hospital, Jerusalem, spoke about the 250 Type 1 patients under his care. Their symptoms ranged enormously from very severe in children to asymptomatic (no symptoms ) in older people. Although he felt the variations were due to different mutations of the gene, other factors must come into account including environmental. 'An enlarged spleen is usually the first symptom' he said. Bone pain or bone crisis was also common even among the milder 370 genotype (gene mutation) and growth retardation was also evident in some patients.
Among 53 women of child bearing age, he had observed a relatively high incidence of miscarriages as well as increased Caesarian delivery although there was no greater incidence of infection after birth. Some patients had bone crises during pregnancy or after delivery. Delay of puberty was seen in nearly two-thirds and heavy menstrual bleeding was almost universal. Fertility was not affected.
In his study of 81 patients over the age of 6 years, more than half showed abnormal lung function tests although fewer than 10% were symptomatic. One symptom was airway obstruction.
The susceptibility to infection is increased amongst Gauchers patients. He found that both splenectomised patients (with their spleen surgically removed) and those with enlarged spleens tended to have frequent infections. Interestingly two children who had suffered from repeated infections stopped having bacterial infections after one year on Ceredase.
Bruising was another common symptom as well as increased pigmentation showing as brown or grey areas on the skin.
Although there had been speculation about the greater risk of certain cancers among Gauchers patients, he didn't feel there was an increased risk.
Dr Ayalah Abrahamov, also of the Shaare Zedek Hospital, spoke about another type of Gauchers, which she said could be described as Type 4. Here there was minimal signs of enlarged spleen or liver and no bone pains or fractures. However there was aggressive valvular sclerosis (heart disease). This had occurred in two Arab families, all the sufferers having the D409H/D409H mutation. She said that enzyme replacement therapy may prevent these symptoms.
Other doctors also spoke about unusual clinical presentations of Gauchers disease including Parkinsonian symptoms.
Neuronopathic Forms of Disease
Dr Anders Erikson of the County Hospital, Boden, Sweden began by saying that Gauchers disease is divided into three clinical types. Two of them (Types 2 and 3) have symptoms stemming from the central nervous system. Type 2 or infantile Gauchers disease is a severe rapidly progressive disease with its onset during the first 3 months of life. Death usually occurs at 9 months.
The largest group of patients assigned as Type 3 or juvenile Gauchers disease derives from north Sweden. He knew of 60 such cases. This group of patients have the same L444P mutation and stem from the same family tree. The symptoms from the nervous system varied considerably from horizontal gaze palsy only to progressive deterioration leading to early death. Dr Erikson said 'Both Type 1 and Type 3 comprise large variations of disease severity and prognosis and perhaps we should discuss another way of clinical typing in which we take the severity and speed of deterioration into account.'
Reports from Around Europe
Dr Martin Hrebicek of the 1st School of Medicine and General Faculty Hospital, Prague spoke about a survey of 27 patients in the Czech Republic and doctors from Portugal, Poland and Italy spoke about their own countries' experiences and results.
Gene Mutations and Other Factors
Prof Mia Horowitz from the Tel Aviv University, Israel, said that 38 mutations of the Gauchers gene for glucocerebrosidase had been discovered but she argued that there must be other factors which cause the disease to vary within these mutations. She gave an example of two brothers who had a rare Gauchers mutation. One brother had died of the disease, the other had very mild disease.
The basic cause of Gauchers disease was the gene for glucocerebrosidase but there must be other factors: another modified gene or genes and/or environmental factors.
She also described another enzyme saposin C which was involved in ridding the body of the fatty tissue, glucocerebroside, which accumulates in Gauchers patients. She said the body needs saposin C to activate the enzyme glucocerebrosidase. She described two mutations of the enzyme saposin C which might prevent glucocerebrosidase working.
Dr A M Vaccaro of the Istituto Superiore Sanita, Rome, Italy also described the function of saposin C. She said that Gauchers disease is caused by a defect of either the enzyme glucocerebrosidase or saposin C, a small protein also required to break down the fatty tissue in the spleen, liver, bone marrow etc. Saposin C is able to do this provided that acidic phospholipids are also present.
Dr Ari Zimran said that the genotype 370/370 was milder in all definitions than other mutations of the disease. He also said that careful DNA testing was needed to differentiate between mild and more severe mutations. However much remains to be discovered, such as the importance of biological/environmental triggers which may explain the enormous variability seen within each genotype.
Different mutations found in Italy, Portugal, France, Greece, Netherlands and Portugal were also highlighted.
Additional Parameters in Diagnosis and Monitoring Disease
Dr J E Mansson of the Department of Paediatrics, Boden, Sweden, spoke about the importance of having suitable parameters to monitor the optimal dosage of enzyme replacement therapy. He said: 'Measurement of the concentration of glucosyceramide in red blood cells seems to be a sensitive parameter to monitor the dosage of enzyme replacement therapy for Norrbottnian Type 3 Gauchers disease'
Dr Hans Aerts of the EC Slater Institute, University of Amsterdam, Holland, spoke about the discovery of high levels of an enzyme called chitotriosidase released by Gauchers cells into blood. He described other markers for the disease which were not very clear. In contrast chitotriosidase showed an increase of 100 to 2,000 times the normal in patients with Gauchers disease. In patients with no symptoms, there was no significant increase. However 5% of Gauchers patients were deficient in this enzyme. He said that this enzyme level was higher in Type 1 than Types 2 or 3.
He had discovered that in spleen tissues of Gauchers sufferers, there was a very high count. After splenectomy, there was a rapid decrease in the blood. He said 'A more than hundred-fold elevated plasma chitotriosidase activity is a character-istic feature, constituting a diagnostic marker. Since the excessive plasma chitotriosidase most likely originates from storage cells, changes in enzyme level may be a useful indication for progression of the disease and efficacy of therapeutic intervention.'
Preliminary evidence had shown that there was a clear decrease of chitotriosidase in patients receiving Ceredase at an overall dose of 50 units a kilogram a month infused three times a week. However the counts varied between patients receiving the same dose. It was found that when a higher dose was introduced, the reduction was faster. As yet there had been no normalisation in any patient.
Dr R G Poll of University Hospital Leiden, the Netherlands, said 'The most important orthopaedic problems are: spinal abnormalities, aseptic bone necrosis, especially of the head of the femur and humerus, pseudo-osteomyelitis, osteomyelitis and pathological fractures. Aseptic bone necrosis and osteomyelitis are the most crippling conditions. Radiologically demonstrable characteristic skeletal abnormalities are deformation of the long bones, patchy sclerosis of the bone and major secondary arthrosis of the hip, knee and shoulder due to aseptic bone necrosis.
Orthopaedic treatment concerns treatment of bone pain, fracture treatment, joint replacement and spine decompression with or without internal spine stabilisation. Special problems in the operative treatment of skeletal and joint disorders are a higher rate of infection, loosening of artificial joints and haemorrhage. He said that treatment of bone symptoms should be on the conservative side.
Dr Poll spoke about 33 patients in Holland of whom 31 had co-operated in his study. Their average age was 40 and they had complained of bone involvement for an average of 21 years. 75% had complained of bone and joint pain. 50% had suffered aseptic bone necrosis, 40% in the hip, 12% in the knee and 6% in the shoulder. 17% had received an artificial joint replacement, mostly in the hips. 22% had suffered from pseudo-osteomyelitis and 12% from osteomyelitis. Patients had complained of pain and limitation of movement.
Dr Poll went on to speak about the benefits of MRI scans. In one patient, although necrosis in the hip had shown on MRI, the hip had appeared normal on an X-ray. Two years later, the necrosis could be seen on X-ray.
He concluded that due to Ceredase, the characteristic orthopaedic lesions of Gauchers disease may possibly one day be something of the past. More information was needed about the ability of Ceredase to infiltrate the bone marrow but he felt that operative treatment was safer if the patient was receiving Ceredase.
Dr Bruno Bembi spoke about using bisphosphonates treatment in patients with bone problems. He had carried out a trial with a small group of patients using the drug intravenously and by pill. The bone density of one patient had increased and he felt that after one year there were some good results.
Dr Zimran said that he felt that this treatment would only help one or two patients out of a dozen. Another doctor pointed out the need for physiotherapy saying it was important lifelong as well as during crises.
Efficacy of Low Dose Enzyme Replacement
Dr Carla Hollak of the Academic Medical Centre, Amsterdam talked about 23 patients in Holland (12 of whom had had their spleen removed previously). They were studied to determine the lowest effective dose of Ceredase for every individual patient. They were given 1.15 units per kg of body weight three times a week (15 units/kg per month). Every 6 months, the response was assessed according to hematological (blood) response and organ (liver and spleen) volume reduction and classified as no, moderate or good response. Subsequently dosages were adjusted by doubling, maintenance or reduction respectively. At the first assessment, 16 out of 23 patients had a moderate or good response while seven patients had no response. Doses were then adjusted accordingly. After 18 months, sustained improvement was found in all patients.
Dr Hollak ended 'Very low initial doses of Ceredase, when administered frequently, are in most cases effective in the treatment of Type 1 Gauchers disease. Neither the presence or absence of a spleen nor the severity of the disease can fully account for the variability in response to treatment, emphasizing the need for individual dosing.'
Dr Ari Zimran spoke about his patients in Israel. Because the high dose regimen is unaffordable, patients have learned to cope with frequent infusions and have shown an improvement in all hematological parameters and in organ reduction comparable to results reported on the original high dose protocol.
'Our current experience encompasses 49 patients with moderate to severe Gauchers disease who have completed 6 to 36 months of treatment. No sub-set of patients responded in a unique way, implying that there is apparently no correlation with age, sex, prior splenectomy, genotype or general phenotypic expression on the extent of response to therapy. Conversely, although several patients with a previous history of chronic bone pain, crises and/or necrosis of large joints, noticed an amelioration of intensity or frequency of pain, radiological evid-ence of bone improvement was not seen within the time of our follow-up.
'In the clinical trial of the new recombinant form of the enzyme, Cerezyme, we compared the low-dose regimen on two frequencies of administration, three times a week and once a fortnight, using five pairs of matched patients.
'Our results, albeit in a small sample, show that Cerezyme is safe and its efficacy in the low dose regimen is comparable to that of Ceredase. Since there were no statistically significant differences between the pairs or between the groups, our intention is to enrol all new patients eligible for treatment, on the low dose/low frequency Cerezyme protocol thereby combining effective therapy with unimpaired quality of life at a savings of hundreds of thousands of dollars a year per patient.'
Dr Pilar Giraldo of Hospital Miguel Servet, Spain, spoke about 4 patients on Ceredase. She reiterated what Dr Zimran said about low dose, high frequency infusions. Our limited experience with a low dose regime is positive; nevertheless, one case, unresponsive to this regime, improved when the dose was increased.
High Dose, Low Frequency Therapy
Dr M Beck, Childrens Hospital, University of Mainz spoke about 8 patients being treated with Ceredase in Germany. All had started on a dose of 50-60 units per kg body weight every 2 weeks. After blood and organ improvement, the dose was reduced to 25-30 units per kg. He said that liver and/or spleen volume had decreased in all cases from 50% to 95%. During the course of therapy (18 to 24 months) no radiographic signs of skeletal improvement had been seen. He concluded that further clinical studies are necessary to evaluate the effect of Ceredase on skeletal changes.
Dr Billette de Villemeur of Hospital Necker Enfants Malades, Paris had experience of 53 patients on Ceredase receiving a two hour infusion of 60 units per kg every 2 weeks. Increasing vitality was a first striking effect noticeable after one month. Bruises had disappeared and bone crises were dramatically decreased after three months. Enlarged spleen and/or livers noticeably reduced after three months and decreased slowly afterwards. Platelets increased rapidly in most patients (including splenectomised patients) but slowly in patients with huge spleens. Haemo-globin level increased in all patients. Few radiological bone improvement was noticed on X-ray after 18 months .
Dr de Villemeur said 'Our results confirm the efficacy of Ceredase at 60 units per kg every 2 weeks in severe Type 1 but it did not help Type 2 patients. As long as the treatment is of placental origin, it shall be reserved for severe Gauchers disease. Recombinant treatment will allow us to extend treatment to less severe cases and therefore prevent bone destruction and other severe evolutions.
Source: Gauchers News February 1995
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