Journal
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Volume 176, Issue 5, Pages 1099-1107Publisher
WILEY
DOI: 10.1002/ajmg.a.38457
Keywords
calcium-calmodulin-dependent protein kinase type 2; clinical trial; developmental disabilities; inborn genetic diseases; rare disease; UBE3A
Categories
Funding
- U.S. Food and Drug Administration [R01 FD003523]
- Angelman Syndrome Foundation
- Clinical Investigator Training Program: Harvard/MIT Health Sciences and Technology-Beth Israel Deaconess Medical Center
- Pfizer Inc.
- Merck Co
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [U54 HD061222]
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Treatment for Angelman syndrome (AS) is currently limited to symptomatic interventions. A mouse model of AS has reduced calcium/calmodulin-dependent kinase II activity due to excessive phosphorylation of specific threonine residues, leading to diminished long-term potentiation. In a rat model of Parkinson disease, levodopa reduced phosphorylation of various proteins, including ed that AS mice treated with levodopa performed better on rotarod testing than untreated AS mice. We conducted a multi-center double-blind randomized placebo-controlled 1-year trial of levodopa / carbidopa with either 10 or 15 mg/kg/day of levodopa in children with AS. The outcome of this intervention was assessed using either the Bayley Scales of Infant Development or the Mullen Scales of Early Learning, as well as the Vineland Adaptive Behavior Scales, and the Aberrant Behavior Checklist. Of the 78 participants enrolled, 67 participants received study medication (33 on levodopa, 34 on placebo), and 55 participants (29 on levodopa, 26 on placebo) completed the 1-year study. There were no clinically or statistically significant changes in any of the outcome measures over a 1-year period comparing the levodopa and placebo groups. The number of adverse events reported, including the more serious adverse events, was similar in both groups, but none were related to treatment with levodopa. Our data demonstrate that levodopa is well-tolerated by children with AS. However, in the doses used in this study, it failed to improve their neurodevelopment or behavioral outcome.
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