Severe CNS involvement in a subset of long-term treated children with infantile-onset Pompe disease.

INTRODUCTION: The standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD. METHOD: We identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children. RESULTS: All six IOPD patients (4 males/2 females) had been treated with ERT for 12-15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9-15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing. DISCUSSION: Among a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline.

Assessment of Dysphonia in Children with Pompe Disease Using Auditory-Perceptual and Acoustic/Physiologic Methods.

Bulbar and respiratory weakness occur commonly in children with Pompe disease and frequently lead to dysarthria. However, changes in vocal quality associated with this motor speech disorder are poorly described. The goal of this study was to characterize the vocal function of children with Pompe disease using auditory-perceptual and physiologic/acoustic methods. High-quality voice recordings were collected from 21 children with Pompe disease. The Grade, Roughness, Breathiness, Asthenia, and Strain (GRBAS) scale was used to assess voice quality and ratings were compared to physiologic/acoustic measurements collected during sustained phonation tasks, reading of a standard passage, and repetition of a short phrase at maximal volume. Based on ratings of grade, dysphonia was present in 90% of participants and was most commonly rated as mild or moderate in severity. Duration of sustained phonation tasks was reduced and shimmer was increased in comparison to published reference values for children without dysphonia. Specific measures of loudness were found to have statistically significant relationships with perceptual ratings of grade, breathiness, asthenia, and strain. Our data suggest that dysphonia is common in children with Pompe disease and primarily reflects impairments in respiratory and laryngeal function; however, the primary cause of dysphonia remains unclear. Future studies should seek to quantify the relative contribution of deficits in individual speech subsystems on voice quality and motor speech performance more broadly.