A. J. J. Reuser

The natural course of non-classic Pompe's disease; a review of 225 published cases

AbstractPompe’s disease is a neuromuscular disorder caused by deficiency of lysosomal acid α–glucosidase. Recombinant human α– glucosidase is under evaluation as therapeutic drug. In light of this development we studied the natural course of cases not fitting the definition of classic infantile Pompe’s disease. Our review of 109 reports including 225 cases shows a continuous spectrum of phenotypes. The onset of symptoms ranged from 0 to 71 years. Based on the available literature, no criteria to delineate clinical sub–types could be established.A common denominator of these cases is that first symptoms were related to or caused by muscle weakness. In general, patients with a later onset of symptoms seemed to have a better prognosis. Respiratory failure was the most frequent cause of death. CK, LDH, ASAT, ALAT and muscle glycogen levels were frequently but not always elevated. In most cases a muscle biopsy revealed lysosomal pathology, but normal muscle morphology does not exclude Pompe’s disease. In 10% of the cases in which the enzyme assay on leukocytes was used, a normal α–glucosidase activity was reported.Data on skeletal muscle strength and function, pulmonary function, disability, handicap and quality of life were insufficiently reported in the literature. Studies of non–classic Pompe’s disease should focus on these aspects, before enzyme replacement therapy becomes generally available.

Disease severity in children and adults with Pompe disease related to age and disease duration

Information about 255 children and adults with Pompe disease was gathered through a questionnaire. Disease severity was associated with disease duration and not with age; an early manifestation of the disease implied earlier wheelchair or ventilator dependency. The patient group under age 15 included a subgroup with a more severe and rapid course of the disease. They require more intensive follow-up and early intervention, before irreversible damage has occurred.

Intravenous administration of phosphorylated acid alpha-glucosidase leads to uptake of enzyme in heart and skeletal muscle of mice.

The lysosomal storage disorder glycogenosis type II is caused by acid alpha-glucosidase deficiency. In this study we have investigated the possible applicability of mannose 6-phosphate receptor-mediated enzyme replacement therapy to correct the enzyme deficiency in the most affected tissues. Bovine testes acid alpha-glucosidase containing phosphorylated mannose residues was intravenously administered to mice and found to be taken up by heart (70% increase of activity) and skeletal muscle (43% increase); the major target organs. The uptake of nonphosphorylated human placenta acid alpha-glucosidase by heart and skeletal muscle appeared to be significantly less efficient, whereas uptake of dephosphorylated bovine testes enzyme was not detectable. The phosphorylated bovine testes acid alpha-glucosidase remained present in mouse skeletal muscle up to 9-15 d after administration, with a half-life of 2-4 d. Besides being measured in skeletal muscle and heart, uptake of phosphorylated bovine testes and nonphosphorylated human placenta acid alpha-glucosidase was measured in several other organs, but not in brain. The increase of acid alpha-glucosidase activity was highest in liver and spleen. We concluded that application of mannose 6-phosphate receptor-mediated enzyme replacement therapy may offer new perspectives for treatment of glycogenesis type II.

Late-onset Pompe disease primarily affects quality of life in physical health domains

Objective: To investigate quality of life in an international population of patients with late-onset Pompe disease. Methods: Data on quality of life (SF-36), age, sex, disease duration, wheelchair use, and use of artificial ventilation were collected for 210 adults with Pompe disease from Australia, Germany, the Netherlands, the United Kingdom, and the United States. SF-36 scores were compared between countries and related to patient characteristics. In addition, for the Dutch subgroup (n = 51), comparisons with the general population and 1-year follow-up assessments were performed. Results: No significant differences between countries were found for the four physical health scales. Mean scores on the vitality, role functioning-emotional, and mental health scale differed between countries, but these differences were not consistent. Wheelchair use was associated with lower physical and social functioning scores (B = −23.6 and −15.1, p < 0.001), and the use of artificial ventilation with lower physical functioning scores (B = −8.4, p = 0.004). Patients reported significantly poorer quality of life than the general population on the physical functioning, role functioning-physical, general health, vitality, and social functioning scales. No significant differences in SF-36 scores were found between the baseline and 1-year follow-up measurement. Conclusions: Patients with late-onset Pompe disease are, on average, markedly affected on the physical health domains of quality of life, but score only slightly lower than the general population on the mental health domains.

A diagnostic protocol for adult-onset glycogen storage disease type II

Article abstract To analyze the diagnostic value of various laboratory tests for the confirmation of adult-onset glycogen storage disease type II (GSD II), we performed a clinical, biochemical, and genetic study of 18 patients with this disease. Measurement of acid α-glucosidase (GAA) activity in muscle and histopathologic analysis of muscle tissue appeared to have no additional value when GAA activity in leukocytes was clearly deficient. Our study showed that creatine kinase elevation is a sensitive marker of GSD II. A diagnostic protocol is formulated.

Seven cases of Pompe disease from Greece

SummaryWe present seven cases of Pompe disease (McKusick 232300; glycogen storage disease type II; acid maltase deficiency) from Greece. The onset of symptoms varied from early childhood to late adulthood, and the patients had quite variable duration of disease. All but one of them had muscle weakness and all had mildly to highly elevated serum creatine kinase. The diagnosis in all cases was confirmed by the finding of acid α-glucosidase (EC 3.2.1.3/20) deficiency in cultured skin fibroblasts. Thirteen mutant alleles were identified and nine different pathogenic mutations were encountered. Four were new: c.2071_2072insAGCCG leads to frameshift and total loss of function; c.1856G > A (p.Ser619Asn) leads to 90–95% loss of function; and the splice-site mutations c.1552−3C > G and c.2331+4A > G reduce the number of correct splicing events by more than 90%. The splice-site mutation c.-32-13T > G (IVS1-13T > G) was encountered four times and seems equally common among Greek and other caucasians. The other mutations: c.925G > A (p.Gly309Arg), c.[307T > G; 271G > A] (p.Cys103Gly; Asp91Asn), c.271del and c.1655T > C (p.Leu552Pro) have been reported earlier. Our study highlights the heterogeneity of Pompe disease in Greece and provides tools for diagnosis and carrier detection.

Rat heart perfusion as model system for enzyme replacement therapy in glycogenosis type II.

ABSTRACT: Cardiac failure and skeletal muscle weakness are the main clinical features of glycogenosis type II, a lysosomal storage disorder caused by acid α-glucosidase deficiency. In our study, we have investigated in a rat heart perfusion-recirculation system whether acid α-glucosidase can be taken up from the vascular system into cardiomy-ocytes. When rat hearts were perfused with mannose 6-phosphate-containing acid α-glucosidase purified from bovine testis, a 3− to 4-fold increase of enzyme activity was obtained, Perfusion with human placental acid α-glucosidase not containing the mannose 6-phosphate recognition marker did not have such an effect. The presence of bovine testis acid α-glucosidase in heart tissue was demonstrated by immunoblotting. Immunocytochemistry provides evidence for uptake of the exogenous enzyme in lysosomes of the cardiomyocytes. The relevance of these findings for enzyme therapy in glycogenosis type II is discussed. (Pediatr Res 28; 344–347,1990)

Quality of Life and Participation in the Daily Life (Activities) of Adults with Pompe Disease Receiving Enzyme Replacement Therapy: 10 Years of International Follow-Up.

Responses were available for 174 adult patients. In the periods before and after the start of ERT, the median follow-up times were 4 years each (range 0.5– 8). The SF-36 Physical Component Summary measure (PCS) deteriorated before ERT (−0.73 score Quality of Life and Participation in the Daily Life (Activities) of Adults with Pompe Disease Receiving Enzyme Replacement Therapy: 10 Years of International Follow-Up

Report on the Second National Conference on Genetics and Public Health

Abstracts Community Genet 1999;2:119–136 121 Plenary Sessions Community Genet 1999;2:119–136 121 Plenary Session