A.T. van der Ploeg

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.

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.

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.

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.

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.

Rate of disease progression during long-term follow-up of patients with late-onset Pompe disease

To determine the rate of disease progression in patients with late-onset Pompe disease, we collected longitudinal data on pulmonary function and skeletal muscle strength in 16 patients whose symptoms had started in childhood or adulthood. The mean duration of follow-up was 16 years (range 4-29 years). During the follow-up period, eight patients (50%) became wheelchair bound and three (19%) became ventilator dependent. At a group level, pulmonary function deteriorated by 1.6% per year, and proximal muscle weakness progressed gradually. At the individual level, however, the rate and extent of progression varied highly between patients. In two thirds of patients, pulmonary function and muscle strength declined simultaneously and to the same extent. The remaining one third of patients showed a variable, sometimes rapidly progressive course, leading to early respirator or wheelchair dependency. These individual differences, especially in pulmonary dysfunction, indicate the need for regular monitoring every 6-12 months depending on the rate of disease progression.

Glycogen storage disease type II: birth prevalence agrees with predicted genotype frequency

Objectives: To compare the overall birth prevalence of diagnosed glycogen storage disease type II (GSD II) with the predicted frequency based on mutation screening, in order to determine whether GSD II is an underdiagnosed condition, and to analyze which medical disciplines recognize GSD II. Methods: Retrospective data on all enzymatic diagnoses of GSD II were collected from diagnostic labs throughout the Netherlands, covering the period from January 1, 1972 to December 31, 1996. Age-specific diagnostic incidence rates were calculated for the entire study period. By adding together the diagnostic incidences for all age groups, we calculated the birth prevalence of diagnosed GSD II and compared these figures with the predicted frequency based on mutation screening in a random sample from the general population. The medical specialization of the referring clinicians was also recorded. Results: GSD II was diagnosed in 154 individuals, including 11 prenatal diagnoses. The birth prevalences of the various phenotypes were 1/101,000 (infantile form), 1/720,000 (juvenile form) and 1/53,000 (adult form). The birth prevalence of the adult and infantile phenotype together was 1/35,000. Eighty-two percent of the patients were diagnosed in university hospitals. Of the patients with infantile GSD II, 71% were diagnosed by a pediatrician, whereas most patients with adult GSD II were diagnosed by a neurologist (80%). Conclusions: There is no evidence for the underdiagnosis of GSD II in the Netherlands, as the calculated birth prevalences of the disease are consistent with previous predictions based on mutation screening in a random sample of newborns. The worldwide birth prevalence of the disease may well be higher than 1 in 100,000. GSD II is mainly diagnosed in university hospitals.

Rate of progression and predictive factors for pulmonary outcome in children and adults with Pompe disease

Respiratory insufficiency is a serious threat to patients with Pompe disease, a neuromuscular disorder caused by lysosomal acid alpha-glucosidase deficiency. Innovative therapeutic options which may stabilize pulmonary function have recently become available. We therefore determined proportion and severity of pulmonary involvement in patients with Pompe disease, the rate of progression of pulmonary dysfunction, and predictive factors for poor respiratory outcome. In a single-center, prospective, cohort study, we measured vital capacity (VC) in sitting and supine positions, as well as maximum inspiratory (MIP) and expiratory (MEP) mouth pressures, and end expiratory CO(2) in 17 children and 75 adults with Pompe disease (mean age 42.7 years, range 5-76 years). Seventy-four percent of all patients, including 53% of the children, had some degree of respiratory dysfunction. Thirty-eight percent had obvious diaphragmatic weakness. Males appeared to have more severe pulmonary involvement than females: at a group level, their mean VC was significantly lower than that of females (p<0.001), they used mechanical ventilation more often than females (p=0.042) and the decline over the course of the disease was significantly different between males and females (p=0.003). Apart from male gender, severe skeletal muscle weakness and long disease duration were the most important predictors of poor respiratory status. During follow-up (average 1.6 years, range 0.5-4.2 years), three patients became ventilator dependent. Annually, there were average decreases in VC in upright position of 0.9% points (p=0.09), VC in supine position of 1.2% points (p=0.049), MIP of 3.2% points (p=0.018) and MEP of 3.8% points (p<0.01). We conclude that pulmonary dysfunction in Pompe disease is much more common than generally thought. Males, patients with severe muscle weakness, and those with advanced disease duration seem most at risk.

Cognitive outcome of patients with classic infantile Pompe disease receiving enzyme therapy

Objective: Classic infantile Pompe disease affects many tissues, including the brain. Untreated infants die within their first year. Although enzyme-replacement therapy (ERT) significantly increases survival, its potential limitation is that the drug cannot cross the blood-brain barrier. We therefore investigated long-term cognitive development in patients treated with ERT. Methods: We prospectively assessed cognitive functioning in 10 children with classic infantile Pompe disease who had been treated with ERT since 1999. Brain imaging was performed in 6 children. Results: During the first 4 years of life, developmental scores in 10 children ranged from above-average development to severe developmental delay; they were influenced by the type of intelligence test used, severity of motor problems, speech/language difficulties, and age at start of therapy. Five of the children were also tested from 5 years onward. Among them were 2 tetraplegic children whose earlier scores had indicated severe developmental delay. These scores now ranged between normal and mild developmental delay and indicated that at young age poor motor functioning may interfere with proper assessment of cognition. We found delayed processing speed in 2 children. Brain imaging revealed periventricular white matter abnormalities in 4 children. Conclusions: Cognitive development at school age ranged between normal and mildly delayed in our long-term survivors with classic infantile Pompe disease treated with ERT. The oldest was 12 years. We found that cognition is easily underestimated in children younger than 5 years with poor motor functioning.