Conference Reports - 1999
July 2-4, 1999
Naarden, the Netherlands
Preface: Pompe’s disease: From diagnosis to treatment
In 1932 the Dutch pathologist J.C. Pompe discovered a disease which caused a baby to die from heart enlargement. This discovery was the actual beginning of the process which will lead to the finding of a therapy for Pompe’s disease. This therapy is now within reasonable expectations.
The process from diagnosis to therapy involves various stages. Actors playing a role in these stages are doctors, researchers and industries. Patient organisations are an emerging partner in the process which they can substantially accelerate. For many patients suffering from as yet incurable diseases, it is a race against time, in which genetic technology offers new tools.
The crucial partners in the process from diagnosis to treatment were invited by patient organisations from several countries to join their forces on the First Conference of the International Pompe Association. This meeting took place in Naarden, the Netherlands, from 2-4 July 1999 and both doctors, researchers, industries and patients actively took part in this exciting conference.
In this report all partners present the results of their tremendous commitment to help people with Pompe’s disease and their families to cope with the disease and to find an effective treatment. A joint commitment which has made a therapy for Pompe’s disease a realistic prospective.
The researchers will show how Enzyme Replacement Therapy (ERT) in Pompe’s disease (or acid-maltase deficiency) has reached the phase of testing in affected humans. As early diagnosis of the disease becomes even more important in the scope of a possible therapy, work in this area will be discussed as well. In addition, the results of the work into gene therapy are reported, which has great potential for an effective treatment in the future.
The involved partners from the industry are committed to bring Enzyme Replacement Therapy to the market as soon as possible. In this report they give insight in the process of enzyme production and of market approval.
For patients and their families the principal issue is how to act in the uncertain situation which has arisen: on the one hand there is hope and happiness because a drug might influence their disease positively and on the other hand there are still a lot of unanswered questions with regard to the effect of the drug and the time schedule for availability of the treatment. Patient representatives will stress the importance of information, support, and ethical debate.
The final part of the conference and this report is reserved for a very joyful event: In order to share experiences and to increase the influence of patients (for example towards politicians), national patient associations have founded an International Pompe Association (IPA).
IPA will become the representative body for people with Pompe’s disease and their families all around the world. Its mission and objectives are described in this report. Moreover, information can be found on the IPA Internet site (www.worldpompe.org).
As chairmen of the IPA we are very proud and thankful to hand over to you the summarised results of the extensive work to which doctors, researchers, industries and patient associations have committed themselves over the last decades.
Facing the new decade, we trust that an effective treatment for Pompe’s disease will be available soon.
Ysbrand S. Poortman
I. Historical Perspective and the Way to Therapy
Pompe´s disease in historical perspective and the way to therapy
Dr. A.J.J. Reuser, Erasmus University Rotterdam, and Dr. A.T. van der Ploeg, Sophia’s Children Hospital Rotterdam (the Netherlands)
II. Diagnosis and Clinical Variability of Pompe’s Disease
Clinical variability in Pompe’s disease
Dr. M.B.C. Loonen, Rotterdam (the Netherlands)
Epidemiological studies in glycogen storage diseases type II
Dr. M.G.E.M. Ausems, University Medical Centre Utrecht (the Netherlands)
Early detection and diagnosis of Pompe
Prof. Dr. J.J. Hopwood, Women’s & Children’s Hospital Adelaide (Australia)
III. State of the Art of Research in Enzyme Replacement Therapy
A transgenic approach to enzyme replacement therapy in Pompe patient
Mr. A. Curtis, MBA, Genzyme Corp. (USA), et al.
Treatment Strategies for Glycogen Storage Disease Type II
Dr. Amalfitano, Duke University Medical Centre (USA)
The challenges of rhGAA manufacture
Dr. B. Devlin, Synpac (NC), Inc. (USA)
IV. Patient Initiative and Ethics
From patient initiative to treatment
Ms. M. Schoneveld van der Linde, MA, VSN (the Netherlands)
Knowledge is power
Dr. K. O’Donnell, AGSD (UK)
How to do good and to prevent harm?
Dr. H.J.M.A. van den Boer – van den Berg,
Academic Hospital Rotterdam (the Netherlands)
Forming a national Pompe group: our experience
Ms. M. House, AMDA (USA)
The International Pompe Association; position, objectives, policy and activities
Mr. Y. Poortman, VSN (the Netherlands)
V. Policy of the International Pompe Association
The sponsors of the conference and this report are
- Pharming/Genzyme LLC
- Synpac (North Carolina) Inc.
- Vereniging Spierziekten Nederland
Towards a therapy for Pompe’s disease
Report of the First meeting of the International Pompe Association
2-4 July 1999
Naarden, the Netherlands
- Vereniging Spierziekten Nederland
Baarn, the Netherlands
- S. Hekkelman
- H. van Veenendaal, M.Sc.
- Vereniging Spierziekten Nederland
- International Pompe Association
Dr. A.J.J. Reuser
Associate Professor of Cell Biology
Erasmus University Rotterdam Rotterdam
Dr. A.T. van der Ploeg
Department of Clinical Genetics, Sophia Children’s Hospital The Netherlands
The first time that I (dr. Reuser, ed.) heard of Pompe’s disease was back in 1973, when I was interviewed for a PhD training position in the Department of Cell Biology and Genetics of the Erasmus University Rotterdam. A little later, I became aware of a similar position on the same subject in the Department of Biochemistry of the University of Amsterdam. To me, an ignorant young student, it seemed that Pompe’s disease was one of the better-known metabolic diseases that received wide scientific attention. Nothing was less true. Even to date it takes great effort to publish articles on Pompe’s disease in trendy, high ranking, scientific journals. Albeit, thanks to the patients and scientists who were persistent in their efforts to “raise the awareness” about the disease and decipher the clinical, pathological, and molecular details, the world of patients, the world of science, the world of treating physicians and the world of industry and financing have learned about this disease. Their activities have merged, and at present we are engaged together in clinical trials of enzyme replacement therapy.
Accumulation of glycogen
The course has taken its time. Pompe’s disease was named after the Dutch pathologist Dr J.C. Pompe who presented in 1932 the case of a 7-month-old infant who had died of idiopathic hypertrophy of the heart. In addition to the cardiac problems, the infant had generalised muscle weakness. The crucial observation was that the symptoms were associated with massive accumulation of glycogen within vacuoles in virtually all tissues. In the listing of different glycogen storage diseases, made by Cori and Cori, Pompe’s disease was ranked as number two and named “glycogen storage disease type II” (GSDII). In 1955, Professor Christian DeDuve made history with his discovery of a new intra-cellular compartment that he called “lysosome”.
Lysosomes contain hydrolytic enzymes which are needed for the degradation of a wide variety of biological compounds. Eight years later, Professor H.G. Hers discovered that the glycogen accumulation in GSDII was caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase. This first finding of an inherited lysosomal enzyme deficiency has led to the concept of “lysosomal storage diseases” and, indirectly, to the enzymatic definition of many other lysosomal storage disorders in the following years. The assay of alpha-glucosidase activity became a diagnostic tool. Since maltose is a convenient substrate in this assay, Pompe´s disease acquired “acid maltase deficiency” as a third name. It did not take long to discover acid maltase deficiency in patients with skeletal muscle weakness, in the absence of cardiac involvement. These patients were reported to have childhood, juvenile or adult forms of Pompe’s disease. The years from 1980 until approximately 1990 were marked by studies on the biosynthesis and structure of acid alpha-glucosidase, culminating in the cloning of the acid alpha-glucosidase gene between 1986 and 1990.
At present, the GSDII mutation database is filled with close to sixty different mutations in the acid alpha-glucosidase gene. The clinical phenotype of patients is primarily determined by the nature of these mutations and the combination in which they occur. DNA analysis has become an important diagnostic and prognostic tool next to the assay of enzyme activity. It is the only reliable instrument for carrier detection.
Enzyme replacement therapy
Enzyme Replacement Therapy, the most exciting new development in the field, originates from the mid-sixties. Already then, it was attempted to remove the lysosomal glycogen from the patient’s tissues by intravenous administration of the missing enzyme. The rationale behind this type of treatment is that tissues and cells in these tissues take up biological compounds, and that these compounds are then transported to the lysosomes. These early clinical trials were unsuccessful. It was impossible to obtain acid alpha-glucosidase in sufficient quantity and of safe and efficient quality. The development of biotechnology has changed that situation dramatically. Human recombinant acid alpha-glucosidase can now be produced on a large scale. Scientists at this meeting (First Conference of the International Pompe Association, ed.) have explored the possibilities of enzyme production in the milk of transgenic animals and in Chinese hamster ovary cells, and thereby received strong technological and financial support from industrial partners. It is through their combined input that enzyme replacement therapy has found its way from the laboratory to the clinic.
We can only speak for the situation we are in with our clinical trial in the Sophia Children’s Hospital in Rotterdam, and thereby quote a recent press release issued by our invaluable partner Pharming Group N.V. of Leiden: “The phase II clinical trial with human alpha-glucosidase for Pompe’s disease is on track. Professor Hans Büller, director of the Sophia Children’s Hospital in Rotterdam…and principal investigator of the trial Dr Ans van der Ploeg…expressed their optimism about the trial. All infants enrolled in the trial are alive…and are doing relatively well.
The trial is well underway to meet its objectives…Pharming expects to initiate Phase II pivotal trials…in Europe and the USA” (end of citation)
We would like to end this short historic perspective with highlighting the role of the patients, patient organisations and charities that have kept the “process” alive. Our research team at the Department of Clinical Genetics of the Erasmus University Rotterdam and the Sophia Children’s Hospital has experienced tremendous support by the many letters from patients and the very personal contacts. Patient organisations and charities like the AGSD (UK), the AMDA (USA), the Prinses Beatrix Fonds and the Sophia Foundation for Medical Research have made financial contributions to keep us going. This weekend, here at VSN, patients from around the world have come together to join forces and to found the International Pompe Association. The scientists are here to communicate their latest results and to witness with their industrial partners this joyful event. Congratulations to the IPA!>
Dr. M.G.E.M. Ausems
Department of Medical Genetics, University Medical Centre
Utrecht, the Netherlands
Glycogen storage disease type II (or GSD II, acid maltase deficiency, Pompe’s disease) has been estimated to be a rare disease. The usually quoted figure of 1 in 100.000 for the frequency of GSD II is not supported by strong data. The first retrospective studies on the frequency of the disease were limited to infantile GSD II and indicated that the frequency of infantile GSD II may range between 1/125.000 and 1/548.000(1,2).
In a recent study from Australia including early and late-onset phenotypes the estimated birth prevalence of GSD II was 1 in 146.000 (3). We previously predicted the theoretical frequency of GSD type II on the basis of mutation analysis in an unselected sample of over 3000 Dutch new-borns (4). Based on the calculated carrier frequencies, the predicted frequency of GSD II was 1 in 40.000, divided over 1 in 138.000 for infantile GSD II and 1 in 57.000 for adult GSD II. A recent study on the carrier frequency in the United States also indicated a disease frequency of 1 in 40.000 (5).
The apparent discrepancy of figures could be explained by ‘under-diagnosis’ of the disease. To investigate whether GSD II is under-diagnosed, we identified all pre- and postnatal diagnoses in the Netherlands over the period 1972 through 1996. Based on the number of diagnoses we calculated the birth prevalence of the various phenotypes and compared these data with the calculated frequencies from our previous study based on mutation screening. In addition, we compared the medical discipline and professional setting (university or general hospital) of the clinicians referring their patients for diagnosis. Our results suggest that the world wide frequency of GSD II must be higher than 1 in 100.000 and that the birth prevalence of adult GSD II is two times higher than that of infantile GSD II.
- Loonen MCB. The variability of Pompe’s disease. A clinical, biochemical and genetic study of glycogen storage disease type II. Academic Thesis. 1979.
- Schaub J, Bayerl P. Incidence of glycogen storage disease in the German Federal Republic. Z. Kinderheilk. 1975; 120:79-85.
- Meike PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA 1999; 281: 249-254.
- Ausems MGEM, Verbiest J, Herman MMP, et al. The frequency of Glycogen Storage Disease type II in the Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet in press.
- Martiniuk F, Chen A, Mack A et al. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet 1998; 79:69-72.
Dr. M.B.C. Loonen
Rotterdam (the Netherlands)
In 1932 the Dutch pathologist J.C. Pompe described for the first time an infant with a combination of clinical and pathological signs later indicated with the eponym ‘Pompe’s disease’. Based on descriptions of similar patients in the following years it appeared to be a uniform entity. Feeding difficulties, failure to thrive, attacks of dyspnoea, peri-oral cyanosis particularly during feeding, and/or weakness with hypotonia in the first months of life are the presenting symptoms. The infant looks severely ill, has a greyish-pale colour and is dyspnoeic. The tongue may be enlarged. Crying is weak and the baby is hypo-active. The liver and especially the heart are enlarged. The legs assume a ‘frog-like’ position. The muscles feel firm. Most patients die in their first year of life from cardiorespiratory failure. On post-mortem examination Pompe found massive accumulation of glycogen in heart and skeletal muscles and other tissues. His was the second form of glycogen storage (the first form being that described by Von Gierke). Therefore Pompe’s disease has been given the name of glycogen storage disease type 2 (GSD II).
In 1955 De Duve and his co-workers introduced the concept of lysosomes, being intracellular organelles, rich in hydrolytic enzymes. In 1963 Hers described the occurrence of the lysosomal enzyme acid maltase (acid a-glucosidase) in normal human tissues as well as the absence of this enzyme in the liver, the heart, and the skeletal muscles of patients with Pompe’s disease. So some other synonyms for Pompe’s disease were introduced namely acid maltase deficiency (AMD) and acid alpha-glucosidase deficiency. In 1964 Baudhuin et al. demonstrated glycogen storage in the liver of Pompe patients to be present mainly within the lysosomes.
Courtecuisse et al (1965), Zellweger et al. (1965) and Engel and Dale (1968) described that the disease may also occur after infancy and these so-called late-onset forms are somewhat arbitrary subdivided according to the age at onset in childhood, juvenile and adult types. In contrast to the infantile type, patients with these types lack cardiac signs and after death glycogen storage is found in skeletal muscles but not in the heart.
The patients present with gradually progressive weakness of the muscles of the trunk, the limb-girdles, and /or respiration. In the childhood and juvenile types the patients mostly become wheelchair-bound and/or dependent on artificial respiration within the first or second decade of life. In patients with the adult form, the occurrence of symptoms may be delayed until late adulthood and respiratory problems may vary considerably. Ultimately patients with the late-onset forms mostly die from respiratory failure, often many years after the beginning of the disease.
In view of evaluating the outcome of enzyme replacement it is extremely important to obtain a clear insight in the variability and the natural course of the disease.
- There are two main clinical variants of Pompe’s disease: The infantile form and the variant with late on-set, which is subdivided in childhood, juvenile, and adult onset forms.
- The activities of the enzymes involved in extralysosomal degradation of glycogen are normal.
- The infantile and late-onset patients show such a different clinical picture that it is hard to believe that they suffer from the same disease.
- The pathogenesis is poorly understood.
- Why do we see such a variation in biochemical and pathological expression in different organs?
- What is the reason that glycogen degradation occurs in two different pathways: lysosomal and extralysosomal? Does the lysosomal pathway have a specific meaning?
Prof. Dr. J.J. Hopwood
Women’s and Children’s Hospital
Pompe´s disease, acid maltase deficiency or glycogen storage disease type II (GSDII) is an inherited disorder of glycogen metabolism resulting from defects in the activity of the lysosomal hydrolase alpha-glucosidase and the lysosomal storage of glycogen fragments. The clinical presentation of GSDII, like all other lysosomal disorders, may present within a range of phenotypes, all of which include varying degrees of myopathy but differ with respect to age of onset and extent of organ involvement and rate of progression. The earliest onset is the classic infantile, first described by Pompe, and at the other extreme, a slowly progressive adult onset phenotype that involves only skeletal muscle.
The biochemical diagnosis of GSDII is a difficult process currently involving the measurement of alpha-glucosidase activities in muscle and/or skin samples from the clinically presenting patient. Diagnosis using blood samples is complicated by the presence of other alpha-glucosidase activities. As a consequence, determination of acid alpha-glucosidase is generally not the first option with young children or adult patients presenting with muscle weakness. Infantile patients, presenting in the first few months of life with marked cardiomegaly and rapidly progressing weakness, would benefit from rapid and early diagnosis to maximise the efficacy from enzyme replacement therapies, as well as other symptomatic treatment.
A new methodology
We have been developing a new methodology to achieve fast, inexpensive and non-invasive procedures for the early detection and diagnosis of GSDII in individuals from newborns to adult populations. Immunoquantification assays were developed to separately quantify lysosomal total (mature and precursor) alpha-glucosidase and mature alpha-glucosidase. We have determined the lysosomal alpha-glucosidase protein concentration in plasma samples and Guthrie blood spots from normal controls and GSDII patients. Protein amounts in both plasma and blood samples from affected patients were generally below the control range. Tandem Mass Spectrometry methodology has been developed to determine amounts of derivatised alpha-glucosidase oligo-saccharides in blood spots from GSDII patients and control individuals.