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Wednesday June 18, 2014 Dr. Carine van Capelle received her PhD on 'Children with Pompe disease: clinical characteristics, peculiar features and effects of enzyme replacement therapy'.
Pompe disease presents as a continuous spectrum of clinical phenotypes in which progressive muscle weakness is the main manifestation. Patients with the classic-infantile form of this disease have virtually no residual enzyme activity and are at the severe end of the spectrum, while patients with a certain level of residual enzyme activity present milder phenotypes at the other end of the spectrum.
The first results of enzyme replacement therapy (ERT) with recombinant human alfa glucosidase were promissing since most patients with the classic-infantile form of Pompe disease survived far beyond the first year of life. But, there is still little known about the long-term treatment effects in this group of patients. Much less is known about the natural course of disease in children with less progressive phenotypes and how they respond to ERT. This thesis describes the clinical spectrum of children with Pompe disease, compares them with adult patients, and evaluates the effects of ERT in these childhood Pompe patients. Furthermore it describes the long-term outcome of ERT in patients with classic-infantile Pompe disease, for a maximum period of 14 years, and compares the functioning of these treated infants with that of children with less progressive forms of Pompe disease.
In this study the initial presentation and the clinical and genetic characteristics of 31 children with less progressive forms of Pompe disease are described. These children usually present with delayed motor development or limb-girdle weakness, but the disease should also be considered in the differential diagnosis of less familiar signs such as disproportional weakness of the neck flexors, unexplained fatigue, persistent diarrhea, and an elevation of transaminase levels (commonly the transaminases alanine transaminase (ALT) and aspartate transaminase (AST)). Disease presentation, distribution of muscle weakness or ptosis appear to be different from adult patients.
The pulmonary function in 17 children and 75 adults with Pompe disease. Seventy-four percent of all patients, including 53% of the children, had some degree of respiratory dysfunction. Forty-seven percent of the children had a decreased vital capacity in sitting position and 59% in supine position. Male patients appeared to have more severe pulmonary involvement than female patients. During an average follow-up period of 1.6 years, there were significant declines in vital capacity in upright and supine position. Pulmonary dysfunction in Pompe disease is much more common than generally thought.
The presence and extent of cardiac involvement is described in children and adults with the common c.-32-13T>G genotype is described. Sixty-eight patients were evaluated, of which 23 had symptom onset before the age of 18 years. Since all 4 patients with cardiac abnormalities were detected by electrocardiography, an electrocardiogram should be performed as first level of screening in this group of patients.
Facial muscle weakness, speech disorders and dysphagia are common in patients with classic-infantile Pompe disease treated by ERT. Eleven patients were included in the study. Age at final assessment ranged from 7.7 months to 12.2 years (median 4.3 years). All patients developed facial muscle weakness before the age of 15 months. Speech assessments showed that articulation was disordered with hyper nasal resonance and reduced speech intelligibility. More important swallowing was ineffective and patients appeared to be at risk for aspiration and related complications. Therefore early treatment by a speech therapist and regular assessments of swallowing is recommended.
Hearing was analyzed in a group of 24 children with Pompe disease using repetitive auditory brainstem response measurements and pure tone audiometry. Only 1 out of 13 children with non-classic forms of Pompe disease showed conductive hearing loss, while 10 out of 11 patients with classic-infantile Pompe disease had sensorineural hearing loss. These infants also had a high prevalence of conductive hearing loss. Five patients showed evidence of mild retro cochlear pathology, suggestive of glycogen accumulation in the central nervous system. Auditory function should be carefully monitored in patients with classic-infantile Pompe disease and early implementation of hearing aids is pivotal to preserve adequate speech development.
Also the results of almost 14 years of treatment with alglucosidase alpha on cardiac structure and function are described. The study shows that significant reduction of cardiac size and improvement of cardiac function is maintained over this period of time. This is an important finding as the reduction of cardiac mass is associated with decreased morbidity and mortality in this group of patients. Arrhythmias remain a threat to these patients and close cardiac follow-up is required.