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.

Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature.

PURPOSE: Enzyme replacement therapy (ERT) with recombinant human acid-α glucosidase (rhGAA) at standard dose of 20 mg/kg every other week is insufficient to halt the long-term progression of myopathy in Pompe disease. METHODS: We conducted a retrospective study on infantile-onset Pompe disease (IPD) and late-onset Pompe disease (LOPD) patients with onset before age 5 years, ≥12 months of treatment with standard dose ERT, and rhGAA immunogenic tolerance prior to dose escalation. Long-term follow-up of up to 18 years was obtained. We obtained physical therapy, lingual strength, biochemical, and pulmonary assessments as dose was escalated. RESULTS: Eleven patients with IPD (n = 7) or LOPD (n = 4) were treated with higher doses of up to 40 mg/kg weekly. There were improvements in gross motor function measure in 9/10 patients, in lingual strength in 6/6 patients, and in pulmonary function in 4/11. Significant reductions in urinary glucose tetrasaccharide, creatine kinase, aspartate aminotransferase, and alanine aminotransferase were observed at 40 mg/kg weekly compared with lower doses (p < 0.05). No safety or immunogenicity concerns were observed at higher doses. CONCLUSION: Higher rhGAA doses are safe, improve gross motor outcomes, lingual strength, pulmonary function measures, and biochemical markers in early-onset Pompe disease, and should be considered in patients with clinical and functional decline.

Early-onset of symptoms and clinical course of Pompe disease associated with the c.-32-13 T > G variant.

BACKGROUND: Individuals with late-onset Pompe disease (LOPD) and the common c.-32-13 T > G variant are widely thought to have milder, adult-onset disease. This belief, and the consequent low suspicion of clinical involvement in children, has led to delays in diagnosis and treatment initiation in patients with early onset of symptoms. Previous reports of LOPD in children do not include description of the early-onset phenotype. This description of signs and symptoms, some of which are subtle and less known, is important to facilitate prompt identification and appropriate treatment in symptomatic children. METHODS: Retrospective chart review of a cohort of 84 LOPD patients with the c.-32-13 T > G variant was conducted to identify patients diagnosed clinically (as opposed to through newborn screening) who had clinically documented symptom-onset within the first two years of life. RESULTS: Four patients had early onset of symptoms, with age at onset ranging from 10 days to 20 months. Initial symptoms included delay in achievement of gross motor milestones, signs of proximal muscle weakness, swallow and feeding difficulties, and sleep apnea. Early and characteristic alterations in posture and movement were identified in all patients. Age at diagnosis ranged from 10 months to 26 months. Median age at enzyme replacement therapy (ERT) initiation was 23.5 months. Despite ERT, progression of musculoskeletal involvement and residual muscle weakness was evident in all patients, as evidenced by ptosis, myopathic facies, scoliosis, lumbar lordosis, scapular winging, and trunk and lower extremity weakness. Standardized functional assessments showed gross motor function below age level as measured by the Alberta Infant Motor Scales, the Peabody Developmental Motor Scales-2, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, and the six-minute walk test. CONCLUSIONS: Onset of symptoms including delay in achievement of gross motor milestones, signs of proximal muscle weakness, swallow and feeding difficulties, and sleep apnea in the first two years of life is not uncommon in individuals with LOPD and the c.-32-13 T > G variant. Patients with early-onset disease appear to have a more, rapid and severe progression of disease with persistent residual muscle deficits which partially improve with higher doses of ERT. Careful evaluation for specific and characteristic patterns of posture and movement in patients with this variant is necessary to identify those who have early onset of disease. Increased awareness of the early-onset signs and symptoms may also enable early identification of disease onset in children who are diagnosed through newborn screening.

Role of continuous glucose monitoring in the management of glycogen storage disorders.

Management of liver glycogen storage diseases (GSDs) primarily involves maintaining normoglycemia through dietary modifications and regular glucose monitoring. Self-monitoring of blood glucose is typically done 3-6 times per day, and may not sufficiently capture periods of asymptomatic hypoglycemia, particularly during sleep. Continuous glucose monitoring systems (CGMS) provide 24-h continuous glucose data and have been used effectively in diabetes mellitus to monitor metabolic control and optimize treatment. This is a relatively new approach in GSDs with only a handful of studies exploring this modality. In this study we used Dexcom CGMS to study the glycemic profile of 14 pediatric and six adult patients with GSD I, III, and IX. A total of 176 days of CGMS data were available. The CGMS was found to be a reliable tool in monitoring glucose levels and trends at all times of the day with good concordance with finger-stick glucose values. This study revealed that in addition to overnight hypoglycemia, CGMS can uncover previously undetected, subclinical, low glucose levels during daytime hours. Additionally, the CGMS detected daytime and overnight hyperglycemia, an often overlooked concern in liver GSDs. The CGMS with concurrent dietary adjustments made by a metabolic dietitian improved metabolic parameters and stabilized blood glucose levels. The CGMS was found to be a safe, effective, and reliable method for optimizing treatment in patients with GSD I, III, and IX.

Severe Cardiac Involvement Is Rare in Patients with Late-Onset Pompe Disease and the Common c.-32-13T>G Variant: Implications for Newborn Screening.

Based on a review of a large patient cohort, published literature, and 3 newborn screening cohorts, we concluded that children diagnosed through newborn screening with late-onset Pompe disease and the common heterozygous c.-32-13T>G variant require frequent cardiac follow-up with electrocardiography for arrhythmias. However, there is limited evidence for performing repeated echocardiography for cardiomyopathy.

Community perception regarding rabies prevention and stray dog control in urban slums in India.

BACKGROUND: The lack of community awareness about rabies control is a major issue that thwarts efforts to prevent human deaths caused by rabies. The objectives of this study were (1) to assess community knowledge and attitudes about rabies, rabies prevention and stray dog control in an urban slum community and (2) to determine the factors that influence rabies awareness in urban slums. METHODOLOGY: Using a systematic random sampling strategy, 185 participants were selected from 8 urban slums. The data were collected by direct interview using a pre-tested, structured questionnaire. RESULTS: In the study population, 74.1% of the participants had heard about rabies, and 54.1% knew that rabies is a fatal disease. Only 33.5% of the interviewees felt that people in the community had a role to play in controlling the stray dog population. Gender, age and educational status were significantly associated with rabies awareness. CONCLUSIONS: Our study indicates that there are gaps in the knowledge and attitudes of individuals living in urban slums regarding rabies prevention and control. Efforts to promote awareness should be targeted at men, older people and uneducated individuals.