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.

New Insights into Gastrointestinal Involvement in Late-Onset Pompe Disease: Lessons Learned from Bench and Bedside.

BACKGROUND: There are new emerging phenotypes in Pompe disease, and studies on smooth muscle pathology are limited. Gastrointestinal (GI) manifestations are poorly understood and underreported in Pompe disease. METHODS: To understand the extent and the effects of enzyme replacement therapy (ERT; alglucosidase alfa) in Pompe disease, we studied the histopathology (entire GI tract) in Pompe mice (GAAKO 6neo/6neo). To determine the disease burden in patients with late-onset Pompe disease (LOPD), we used Patient-Reported Outcomes Measurements Information System (PROMIS)-GI symptom scales and a GI-focused medical history. RESULTS: Pompe mice showed early, extensive, and progressive glycogen accumulation throughout the GI tract. Long-term ERT (6 months) was more effective to clear the glycogen accumulation than short-term ERT (5 weeks). GI manifestations were highly prevalent and severe, presented early in life, and were not fully amenable to ERT in patients with LOPD (n = 58; age range: 18-79 years, median age: 51.55 years; 35 females; 53 on ERT). CONCLUSION: GI manifestations cause a significant disease burden on adults with LOPD, and should be evaluated during routine clinical visits, using quantitative tools (PROMIS-GI measures). The study also highlights the need for next generation therapies for Pompe disease that target the smooth muscles.

Behavioral, social and school functioning in children with Pompe disease.

PURPOSE: To improve our understanding of the behavioral, social, and emotional functioning of children and adolescents with Pompe disease. METHOD: Parents/guardians of 21 children (age 5-18y) with infantile (IPD) or late-onset (LOPD) Pompe disease on long-term enzyme replacement therapy completed three standardized checklists regarding their child's behavior: the Child Behavior Checklist (CBCL), Conners 3 Parent (Conners-3), Behavior Rating Inventory of Executive Function-2 (BRIEF2), and a survey of their child's educational services. RESULTS: Descriptive statistics were used to summarize the findings for each behavior checklist. Age standard scores from each checklist were reported for the IPD (n = 17, 9 females, mean age = 9y, 4 mo; SD = 3y, 8mo) and LOPD (n = 4, 1 female; mean = 11y, 2mo; SD = 2y, 1mo) groups. The majority of children with Pompe exhibited age-appropriate behavior and emotional functioning on these standardized checklists. However, negative mood symptoms, learning problems, decreased participation in structured social activities, and attentional difficulties were more frequently reported in children with IPD in comparison to same-aged peers. Parents of children with LOPD reported fewer problematic behaviors but endorsed negative mood symptoms and difficulties with peer relations. Most children received accommodations in regular education classrooms at school. CONCLUSIONS: These standardized behavior checklists are useful screening tools for the early identification and treatment of behavior, emotional, and social concerns in children with Pompe disease.

Novel approaches to quantify CNS involvement in children with Pompe disease.

OBJECTIVE: To characterize the extent of CNS involvement in children with Pompe disease using brain MRI and developmental assessments. METHODS: The study included 14 children (ages 6-18 years) with infantile Pompe disease (IPD) (n = 12) or late-onset Pompe disease (LOPD) (n = 2) receiving enzyme replacement therapy. White matter (WM) hyperintense foci seen in the brain MRIs were systematically quantified using the Fazekas scale (FS) grading system with a novel approach: the individual FS scores from 10 anatomical areas were summed to yield a total FS score (range absent [0] to severe [30]) for each child. The FS scores were compared to developmental assessments of cognition and language obtained during the same time period. RESULTS: Mild to severe WM hyperintense foci were seen in 10/12 children with IPD (median age 10.6 years) with total FS scores ranging from 2 to 23. Periventricular, subcortical, and deep WM were involved. WM hyperintense foci were seen throughout the path of the corticospinal tracts in the brain in children with IPD. Two children with IPD had no WM hyperintense foci. Children with IPD had relative weaknesses in processing speed, fluid reasoning, visual perception, and receptive vocabulary. The 2 children with LOPD had no WM hyperintense foci, and high scores on most developmental assessments. CONCLUSION: This study systematically characterized WM hyperintense foci in children with IPD, which could serve as a benchmark for longitudinal follow-up of WM abnormalities in patients with Pompe disease and other known neurodegenerative disorders or leukodystrophies in children.

An emerging phenotype of central nervous system involvement in Pompe disease: from bench to bedside and beyond.

Pompe disease (PD) is a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acid-alpha glucosidase (GAA). Pathogenic variants in the GAA gene lead to excessive accumulation of lysosomal glycogen primarily in the cardiac, skeletal, and smooth muscles. There is growing evidence of central nervous system (CNS) involvement in PD. Current research is focused on determining the true extent of CNS involvement, its effects on behavior and cognition, and effective therapies that would correct the disease in both muscle and the CNS. This review article summarizes the CNS findings in patients, highlights the importance of research on animal models, explores the probable success of gene therapy in reversing CNS pathologies as reported by some breakthrough preclinical studies, and emphasizes the need to follow patients and monitor for CNS involvement over time. Lessons learned from animal models (bench) and from the literature available to date on patients will guide future clinical trials in patients (bedside) with PD. Our preliminary studies in infantile PD show that some patients are susceptible to early and extensive CNS pathologies, as assessed by neuroimaging and developmental assessments. This article highlights the importance of neuroimaging which could serve as useful tools to diagnose and monitor certain CNS pathologies such as white matter hyperintense foci (WMF) in the brain. Longitudinal studies with large sample sizes are warranted at this time to better understand the emergence, progression and consequences of CNS involvement in patients with PD.