C.M. van Gelder

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.

Cognitive outcome of patients with classic infantile Pompe disease receiving enzyme therapyAuthor Response

Editors’ Note: In their article “Cognitive outcome of patients with classic infantile Pompe disease receiving enzyme therapy,” Ebbink et al. reported data consistent with Drs. Spiridigliozzi et al.s findings that CNS glycogen does not significantly impair cognitive function through the middle childhood years but may be related to delayed processing speed. Drs. Walters et al. report the results of their investigation into possible etiologies behind chocolate consumption lowering stroke risk. Megan Alcauskas, MD, and Robert C. Griggs, MD We would like to inquire whether glycogen …

Cognitive outcome of classic infantile Pompe patients receiving enzyme therapy

Methods We prospectively assessed cognitive functioning in 10 children with classic infantile Pompe disease who had been treated with ERT since 1999. Until 2004, infants and young children were assessed with the Bayley Scales of Infant Development (BSID-II; number of tests = 23). After 2004, we switched to the Griffiths Mental Developmental Scales (Griffiths; number of tests = 19), expecting it to differentiate better between various domains. Older children were assessed using the Wechsler Intelligence Scales for Children (WISC-III; number of tests = 5). For children with tetraplegia, we used the Raven Colored or Standard Progressive Matrices (number of tests = 3). For those with impaired hearing, we used the Snijders Oomen Nonverbal Intelligence testRevised (SON-R 21⁄2-7, number of tests = 1). In total, 51 tests were performed. Brain imaging was performed in six children.

Antibody formation to enzyme therapy in classic infantile Pompe disease: implications of patient age

Enzyme-replacement therapy (ERT) with alglucosidase alfa has improved the lifespan of patients with classic infantile Pompe disease, although ERT is not effective in a subset of patients who mount an immune response to the exogenous enzyme. We studied the development of antibodies in response to ERT and its effect on clinical outcomes in 11 patients with classic infantile Pompe disease treated with ERT since 1999 for a median of 4.2 years (range 3 months to 12 years).

A higher dose of enzyme therapy in patients with classic infantile Pompe disease seems to improve ventilator-free survival and motor function.

Enzyme replacement therapy (ERT) with Myozyme® has significantly improved the prospect for patients with classic infantile Pompe disease. Yet, about 50% of patients still do not survive ventilator-free beyond 2.5 years. In the present study we compared the safety and efficacy of treatment with 40 mg/kg/week to that of 20 mg/kg/ every other week (eow) in 10 infantile patients to determine if a higher/more frequent dose would improve outcomes. All patients were treated for at least one year and received the same dose throughout the study.

P.17.1 Phenotypic variation within 22 families with Pompe disease

Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α -glucosidase (GAA) leading to glycogen accumulation in different tissues. Pompe disease has a broad clinical spectrum, in which the phenotype can vary widely, even in patients with a similar GAA genotype. The aim of this study was to describe phenotypic variation among siblings with non-classic Pompe disease in the Netherlands. We identified 22 families consisting of two or three siblings (50 patients: 42 adults and eight children). All carried the most common mutation c.-32-13T>G in combination with another pathogenic mutation. Siblings typically all had symptom onset either in childhood or in adulthood, however, there was a wide variation in age of symptom onset between siblings (median difference of nine years). Presenting symptoms were similar across siblings in 14 families and limb girdle weakness was most frequently reported. In certain families ptosis, bulbar weakness or scapular winging were present in all siblings. The majority of wheelchair and/or ventilator dependent patients had an ambulant or non-ventilated sibling; half of these less affected siblings had a longer disease duration. Gender, GAA activity and co-morbidity did not appear to explain differences in phenotype between siblings. Since the course of disease and its severity in some families varied to the same extent as seen in unrelated patients with an identical genotype, other factors like epigenetic and environmental effects are likely to influence the clinical presentation and disease course. Additional studies are needed to identify these factors, as possible prognostic factors for disease course and outcome on ERT of an individual patient.