On December 11, 2013 Dr. Carin van Gelder received her PhD on 'Enzyme-replacement therapy in classic infantile Pompe disease - Long-term outcome, dosing and the role of antibodies' at the Erasmus University Rotterdam.
Until recently, Pompe disease was untreatable. Registration of enzyme-replacement therapy (ERT) in 2006 has significantly improved the prospect for affected patients. At present the oldest with classic infantile Pompe patients are 15 years old thanks to the beneficial effects of ERT. With their life extension, new clinical features of Pompe disease have emerged and require attention.
In her thesis Dr. Carin van Gelder describes that ERT enabled all patients to reach previously unmet motor milestones. At the same time, motor development was often delayed or started to show abnormalities over time. Patients showed difficulties in specific motor functions, such as neck flexion, sit-up, walking stairs, jumping and standing on one leg. Over time some loss of motor function was observed, and patients developed a characteristic gait. The distal muscle (hands, feet, lower arm-and legs) became gradually more affected whereas initially proximal (shoulders and hips) muscle weakness was more prominent. This finding was unexpected as the pattern of muscle weakness is not the same as in untreated children and adults with non-classic Pompe disease. The findings emphasize the need for appropriate musculoskeletal management and exercise programs as supportive tools next to the application of ERT in classic infantile Pompe disease. Also residual weakness of the facial and bulbar (mouth and throat) muscles was found to be common and was accompanied by disordered speech and dysphagia (difficulty in swallowing) in the majority of patients. To improve speech and reduce the risk for aspiration related complications, early treatment by a speech therapist and regular swallowing assessments are recommended. Besides these problems all patients developed a myopathic facies (expressionless face due to weak face muscles), sometimes accompanied by ptosis (hanging eyelids). Sometimes the ptosis is so severe that surgery is required. It shows that a combination of ptosis, extraocular motility disorder (impairment of eye movement), and myopia (nearsightedness) may occur in long-term survivors. Ophthalmic examination is recommended in the routine follow-up of patients with classic infantile Pompe disease. In her study Dr. Carin van Gelder describes the cognitive functioning in 10 patients with classic-infantile Pompe disease treated with ERT. Although patients with classic-infantile Pompe disease store glycogen in the central nervous system (CNS), and ERT is unlikely to cross the blood-brain barrier, the cognitive developement of 5 patients at school age ranged from normal to mildly delayed. This suggests that the consequences of glycogen storage in the CNS are limited. In patients younger than 5 years cognition is easily underestimated due to poor motor functioning and hearing deficits. Dr. Carin van Gelder also studied the immunologic response to ERT (antibody formation) in relation to the endogenous production of acid alpha-glucosidase by the patient (CRIM-status). All 11 patients developed an immunological response to ERT. The antibody titers were not strictly related to the patients' CRIM status, but high antibody titers were associated with a poor outcome. Notably, the CRIM-negative status itself seems associated with early demise, irrespective of the height of the immune response to ERT. The finding that all patients who started ERT before 2 months of age had low antibody titers underlines the need to start ERT in classic infantile Pompe disease as soon as possible. Another study in her thesis is the comparison of the safety and efficacy of the recommended dose of 20mg/kg every other week (eow) (n=6) with that of a higher and more frequent dose of 40 mg/kg/week (n=4). Four of the six patients who received 20 mg/kg eow either died (n=2), became ventilator dependent (n=2), or did not learn to walk (n=2). There were no apparent differences between the two dose groups in terms of number of infusion associated reactions and extent of immune response to ERT. As treatment with 40 mg/kg/week is well tolerated and seems to improve ventilator-free survival and motor outcome as compared to treatment with 20 mg/kg eow, it is recommended using the higher dose for all affected infants with poor prospects.