W.F.M. Arts

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.

Effect of Simvastatin on Cognitive Functioning in Children With Neurofibromatosis Type 1: A Randomized Controlled Trial

CONTEXT Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model. OBJECTIVE To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1. DESIGN, SETTING, AND PARTICIPANTS Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital. INTERVENTION Simvastatin or placebo treatment once daily for 12 weeks. MAIN OUTCOME MEASURES Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex. RESULTS No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (beta = 0.10; 95% confidence interval [CI], -0.36 to 0.56); cancellation test (beta = -0.19; 95% CI, -0.67 to 0.29); prism adaptation (odds ratio = 2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (beta = 0.06; 95% CI, -0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (beta = 0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (beta = 0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment. CONCLUSION In this 12-week trial, simvastatin did not improve cognitive function in children with NF1. Trial Registration isrctn.org Identifier: ISRCTN14965707.

Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly

Background: Porencephaly (cystic cavities of the brain) is caused by perinatal vascular accidents from various causes. Several familial cases have been described and autosomal dominant inheritance linked to chromosome 13q has been suggested. COL4A1 is an essential component in basal membrane stability. Mouse mutants bearing an in-frame deletion of exon 40 of Col4a1 either die from haemorrhage in the perinatal period or have porencephaly in survivors. A report of inherited mutations in COL4A1 in two families has shown that familial porencephaly may have the same cause in humans. Objective: To describe three novel COL4A1 mutations. Results: The three mutations occurred in three unrelated Dutch families. There were two missense mutations of glycine residues predicted to result in abnormal collagen IV assembly, and one mutation predicted to abolish the traditional COL4A1 start codon. The last mutation was also present in an asymptomatic obligate carrier with white matter abnormalities on brain magnetic resonance imaging. Conclusions: This observation confirms COL4A1 as a major locus for genetic predisposition to perinatal cerebral haemorrhage and porencephaly and suggests variable expression of COL4A1 mutations.

Course and outcome of childhood epilepsy: A 15-year follow-up of the Dutch Study of Epilepsy in Childhood

Purpose:  To study the course and outcome of childhood‐onset epilepsy during 15‐year follow‐up (FU).

The first unprovoked, untreated seizure in childhood: a hospital based study of the accuracy of the diagnosis, rate of recurrence, and long term outcome after recurrence. Dutch study of epilepsy in childhood.

OBJECTIVE To assess the accuracy of the diagnosis of a first unprovoked seizure in childhood, the recurrence rate within two years, the risk factors for recurrence, and the long term outcome two years after recurrence. METHODS One hundred and fifty six children aged 1 month to 16 years after a first seizure, and 51 children with a single disputable event were followed up. The diagnosis of a seizure was confirmed by a panel of three child neurologists on the basis of predescribed diagnostic criteria. None of the children was treated after the first episode. RESULTS Five children with a disputable event developed epileptic seizures during follow up. The diagnosis did not have to be revised in any of the 156 children with a first seizure. The overall recurrence rate after two years was 54%. Significant risk factors were an epileptiform EEG (recurrence rate 71%) and remote symptomatic aetiology and/or mental retardation (recurrence rate 74%). For the 85 children with one or more recurrences, terminal remission irrespective of treatment two years after the first recurrence was >12 months in 50 (59%), <six months in 22 (26%), and six to 12 months in 11 (13%) and unknown in two (2%). Taking the no recurrence and recurrence groups together, a terminal remission of at least 12 months was present in 121 out of the 156 children (78%). CONCLUSIONS The diagnosis of a first seizure can be made accurately with the help of strict diagnostic criteria. The use of these criteria may have contributed to the rather high risk of recurrence in this series. However, the overall prognosis for a child presenting with a single seizure is excellent, even if treatment with antiepileptic drugs is not immediately instituted.

Evolution of Epilepsy and EEG Findings in Angelman Syndrome

Summary: Purpose: To evaluate the evolution of epileptic seizures and EEG features in a large group of patients with Angelman syndrome (AS).

The early prognosis of epilepsy in childhood: The prediction of a poor outcome. The Dutch Study of Epilepsy in Childhood

Summary: Purpose: To examine which variables available early in the course of childhood epilepsy are associated with a poor short‐term outcome and to develop models to predict such an outcome.

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.

Familial Occurrence of Epilepsy in Children with Newly Diagnosed Multiple Seizures: Dutch Study of Epilepsy in Childhood

Summary: Purpose: To study the familial occurrence of epilepsy in children with newly diagnosed multiple unprovoked seizures.