Browsing by Author "Zimmerman, Kanecia"
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Item Open Access Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature.(Genetics in medicine : official journal of the American College of Medical Genetics, 2020-05) Khan, Aleena A; Case, Laura E; Herbert, Mrudu; DeArmey, Stephanie; Jones, Harrison; Crisp, Kelly; Zimmerman, Kanecia; ElMallah, Mai K; Young, Sarah P; Kishnani, Priya SPurpose
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.Item Open Access New Insights into Gastrointestinal Involvement in Late-Onset Pompe Disease: Lessons Learned from Bench and Bedside.(Journal of clinical medicine, 2021-07-30) Korlimarla, Aditi; Lim, Jeong-A; McIntosh, Paul; Zimmerman, Kanecia; Sun, Baodong D; Kishnani, Priya SBackground
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.Item Open Access Novel approaches to quantify CNS involvement in children with Pompe disease.(Neurology, 2020-06-09) Korlimarla, Aditi; Spiridigliozzi, Gail A; Crisp, Kelly; Herbert, Mrudu; Chen, Steven; Malinzak, Michael; Stefanescu, Mihaela; Austin, Stephanie L; Cope, Heidi; Zimmerman, Kanecia; Jones, Harrison; Provenzale, James M; Kishnani, Priya SOBJECTIVE:To characterize the extent of central nervous system involvement in children with Pompe disease using brain magnetic resonance imaging (MRI) and developmental assessments. METHODS:The study included fourteen 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 ten 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 two 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.