Arnold J. J. Reuser

Pompe's disease

Pompes disease, glycogen-storage disease type II, and acid maltase deficiency are alternative names for the same metabolic disorder. It is a pan-ethnic autosomal recessive trait characterised by acid alpha-glucosidase deficiency leading to lysosomal glycogen storage. Pompes disease is also regarded as a muscular disorder, but the generalised storage of glycogen causes more than mobility and respiratory problems. The clinical spectrum is continuous and broad. First symptoms can present in infants, children, and adults. Cardiac hypertrophy is a key feature of classic infantile Pompes disease. For a long time, there was no means to stop disease progression, but the approval of enzyme replacement therapy has substantially changed the prospects for patients. With this new development, the disease is now among the small but increasing number of lysosomal storage disorders, for which treatment has become a reality. This review is meant to raise general awareness, to present and discuss the latest insights in disease pathophysiology, and to draw attention to new developments about diagnosis and care. We also discuss the developments that led to the approval of enzyme replacement therapy with recombinant human alpha-glucosidase from Chinese hamster ovary cells (alglucosidase alfa) by the US Food and Drug Administration and European Medicines Agency in 2006, and review clinical practice.

Recombinant human α-glucosidase from rabbit milk in Pompe patients

Summary Pompes disease is a fatal muscular disorder caused by lysosomal α-glucosidase deficiency. In an open-label study, four babies with characteristic cardiomyopathy were treated with recombinant human α-glucosidase (rhGAA) from rabbit milk at starting doses of 15 mg/kg or 20 mg/kg, and later 40 mg/kg. The enzyme was generally well tolerated. Activity of α-glucosidase normalised in muscle. Tissue morphology and motor and cardiac function improved. The left-ventricular-mass index decreased significantly. We recommend early treatment. Long-term effects are being studied.

Enzyme replacement therapy in late-onset Pompe's disease : A three-year follow-up

Pompes disease is an autosomal recessive myopathy. The characteristic lysosomal storage of glycogen is caused by acid α‐glucosidase deficiency. Patients with late‐onset Pompes disease present with progressive muscle weakness also affecting pulmonary function. In search of a treatment, we investigated the feasibility of enzyme replacement therapy with recombinant human α‐glucosidase from rabbit milk. Three patients (aged 11, 16, and 32 years) were enrolled in the study. They were all wheelchair‐bound and two of them were ventilator dependent with a history of deteriorating pulmonary function. After 3 years of treatment with weekly infusions of α‐glucosidase, the patients had stabilized pulmonary function and reported less fatigue. The youngest and least affected patient showed an impressive improvement of skeletal muscle strength and function. After 72 weeks of treatment, he could walk without support and finally abandoned his wheelchair. Our findings demonstrate that recombinant human α‐glucosidase from rabbit milk has a therapeutic effect in late‐onset Pompes disease. There is good reason to continue the development of enzyme replacement therapy for Pompes disease and to explore further the production of human therapeutic proteins in the milk of mammals. Ann Neurol 2004;55:000–000

Enzyme therapy for pompe disease with recombinant human alpha-glucosidase from rabbit milk.

Pompe disease is a metabolic myopathy caused by deficiency of lysosomal acid α-glucosidase. In this report we review the first 36 weeks of a clinical study on the safety and efficacy of enzyme therapy aimed at correcting the deficiency. Four patients with infantile Pompe disease were enrolled. They received recombinant human α-glucosidase from transgenic rabbit milk. The product is generally well tolerated and reaches the primary target tissues. Normalization of α-glucosidase activity in skeletal muscle was obtained and degradation of PAS-positive material was seen in tissue sections. The clinical condition of all patients improved. The effect on heart was most significant, with an impressive reduction of the left ventricular mass index (LVMI). Motor function improved. The positive preliminary results stimulate continuation and extension of efforts towards the realization of enzyme therapy for Pompe disease.

Broad spectrum of Pompe disease in patients with the same c.-32-13T -> G haplotype

Background: Pompe disease (acid maltase deficiency, glycogen storage disease type II; OMIM 232300) is an autosomal recessive lysosomal storage disorder characterized by acid α-glucosidase deficiency due to mutations in the GAA gene. Progressive skeletal muscle weakness affects motor and respiratory functions and is typical for all forms of Pompe disease. Cardiac hypertrophy is an additional fatal symptom in the classic infantile subtype. c.-32-13T→G is the most common mutation in adults. Objective: To delineate the disease variation among patients with this mutation and to define the c.-32-13T→G haplotypes in search for genotype–phenotype correlations. Methods: We studied 98 compound heterozygotes with a fully deleterious mutation (11 novel mutations are described) and the common c.-32-13T→G mutation. Results: All patients were Caucasian. None had the classic infantile form of Pompe disease. The clinical course varied far more than anticipated (age at diagnosis <1 to 78 years; age at onset: <1 to 52 years). The acid α-glucosidase activities in a subset of patients ranged from 4 to 19.9 nmol/mg/h. Twelve different c.-32-13T→G haplotypes were identified based on 17 single-nucleotide polymorphisms located in the GAA gene. In 76% of the cases, c.-32-13T→G was encountered in the second most common GAA core haplotype (DHRGEVVT). In only one case was c.-32-13T→G encountered in the major GAA core haplotype (DRHGEIVT). Conclusion: Patients with the same c.-32-13T→G haplotype (c.q. GAA genotype) may manifest first symptoms at different ages, indicating that secondary factors may substantially influence the clinical course of patients with this mutation.

Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating

Pompe disease was named after the Dutch pathologist Dr JC Pompe who reported about a deceased infant with idiopathic hypertrophy of the heart. The clinical findings were failure to thrive, generalized muscle weakness and cardio‐respiratory failure. The key pathologic finding was massive storage of glycogen in heart, skeletal muscle and many other tissues. The disease was classified as glycogen storage disease type II and decades later shown to be a lysosomal disorder caused by acid α‐glucosidase deficiency. The clinical spectrum of Pompe disease appeared much broader than originally recognized. Adults with the same enzyme deficiency, alternatively named acid maltase deficiency, were reported to have slowly progressive skeletal muscle weakness and respiratory problems, but no cardiac involvement. The clinical heterogeneity is largely explained by the kind and severity of mutations in the acid α‐glucosidase gene (GAA), but secondary factors, as yet unknown, have a substantial impact. The Pompe disease mutation database aims to list all GAA sequence variations and describe their effect. This update with 107 sequence variations (95 being novel) brings the number of published variations to 289, the number of non‐pathogenic mutations to 67 and the number of proven pathogenic mutations to 197. Further, this article introduces a tool to rate the various mutations by severity, which will improve understanding of the genotype‐phenotype correlation and facilitate the diagnosis and prognosis in Pompe disease.

Assignment of the gene coding for human β-glucocerebrosidase to the region q21-q31 of chromosome 1 using monoclonal antibodies

SummaryA series of man-Chinese hamster somatic cell hybrids with a variable content of human chromosomes was used to study the localization of the human gene coding for the lysosomal enzyme β-glucocerebrosidase (EC 3.2.1.45). In lysates made from hybrid cells, the human enzyme was specifically recognized by a mouse monoclonal antibody raised against human placental β-glucocerebrosidase. This monoclonal antibody did not cross-react with Chinese hamster β-glucocerebrosidase. After reaction of the antibody with the enzyme, β-glucocerebrosidase was precipitated by addition of Protein A-Sepharose beads, and was detected on the beads by its enzymatic activity. From the analysis of a series of man-Chinese hamster hybrids, among which were hybrids with specific segments of chromosome 1, we conclude that the gene coding for human β-glucocerebrosidase is localized in the region q21-q31 of chromosome 1.

Eight years experience with enzyme replacement therapy in two children and one adult with Pompe disease

Pompe disease (type 2 glycogenosis, acid maltase deficiency) is a disorder affecting skeletal and cardiac muscle, caused by deficiency of acid alpha-glucosidase. In 2006 enzyme therapy with recombinant human alpha-glucosidase received marketing approval based on studies in infants. Results in older children and adults are awaited. Earlier we reported on the 3-year follow-up data of enzyme therapy in two adolescents and one adult. In the present study these patients were followed for another 5 years. Two severely affected patients, wheelchair and ventilator dependent, who had shown stabilization of pulmonary and muscle function in the first 3 years, maintained this stabilization over the 5-year extension period. In addition patients became more independent in daily life activities and quality of life improved. The third moderately affected patient had shown a remarkable improvement in muscle strength and regained the ability to walk over the first period. He showed further improvement of strength and reached normal values for age during the extension phase. The results indicate that both long-term follow-up and timing of treatment are important topics for future studies.

Genetic heterogeneity in GM1-gangliosidosis.

GM1-GANGLIOSIDOSIS is an inherited lysosomal storage disease which is due to a deficiency of the acid hydrolase GM1-β-galactosidase1. During the past few years several clinical variants have been described2–6 that differ in time of onset of symptoms, involvement of visceral organs or skeletal tissue and in the degree of neuronal and mental deterioration. Some of these variants have been related to different properties of the deficient β-galactosidases5,7 but the significance of the experimental data8 has been questioned. Several investigators have speculated on the genetic background of the different variants2,8,9 but no experimental evidence has been provided to support the hypotheses.

Morphological changes in muscle tissue of patients with infantile Pompe's disease receiving enzyme replacement therapy

Pompes disease (glycogen storage disease type II) is an autosomal recessive myopathy caused by lysosomal α‐glucosidase deficiency. Enzyme replacement therapy (ERT) is currently under development for this disease. We evaluated the morphological changes in muscle tissue of four children with infantile Pompes disease who received recombinant human α‐glucosidase from rabbit milk for 72 weeks. The patients were 2.5–8 months of age at entry. Prior to treatment, all patients showed lysosomal glycogen storage in skeletal and smooth muscle cells, vascular endothelium, Schwann cells, and perineurium. The first response to treatment was noticed in vascular endothelium and in peripheral nerves after 12 weeks of treatment at an enzyme dose of 15–20 mg/kg. Increasing the dose to 40 mg/kg led, after 72 weeks of treatment, to a reduction of glycogen storage and substantial improvement of muscle architecture in the least affected patient. Not all patients responded equally well, possibly due to differences in degree of glycogen storage and concomitant muscle pathology at the start of treatment. We conclude that intravenous administration of recombinant human α‐glucosidase from rabbit milk can improve muscle morphology in classic infantile Pompes disease when treatment is started before irreversible damage has occurred. Muscle Nerve 27: 743–751, 2003