A Randomized Controlled Trial of Levodopa in Patients with Angelman Syndrome

Authors

Wen-Hann Tan, Harvard Medical School
Lynne M. Bird, University of California
Anjali Sadhwani, Harvard Medical School
Rene L. Barbieri-Welge, Rady Children's Hospital San Diego
Steven A. Skinner, Greenwood Genetic Center
Lucia T. Horowitz, Greenwood Genetic Center
Carlos A. Bacino, Baylor College of Medicine
Lisa M. Noll, Baylor College of Medicine
Cary Fu, Vanderbilt University
Rachel J. Hundley, Vanderbilt University
Logan K. Wink, Cincinnati Children's Hospital
Craig A. Erickson, Cincinnati Children's Hospital Medical Center
Gregory N. Barnes, Vanderbilt University
Anne Slavotinek, University of California
Rita Jeremy, University of California
Alexander Rotenberg, Harvard Medical School
Sanjeev V. Kothare, Harvard Medical School
Heather E. Olson, Harvard Medical School
Annapurna Poduri, Harvard Medical School
Mark P. Nespeca, University of California
Hillary C. Chu, Harvard Medical School
Jennifer M. Willen, Harvard Medical School
Kevin F. Haas, Vanderbilt University
Edwin J. Weeber, University of South Florida
Paul A. Rufo, Harvard Medical School

Document Type

Article

Publication Date

2018

Keywords

calcium-calmodulin-dependent protein kinase type 2, clinical trial, developmental disabilities, inborn genetic diseases, rare disease, UBE3A

Digital Object Identifier (DOI)

https://doi.org/10.1002/ajmg.a.38457

Abstract

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 calcium/calmodulin-dependent kinase II. Further studies demonstrated 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.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

American Journal of Medical Genetics Part A, v. 176, issue 5, p. 1099-1107

Scholar Commons Citation

Tan, Wen-Hann; Bird, Lynne M.; Sadhwani, Anjali; Barbieri-Welge, Rene L.; Skinner, Steven A.; Horowitz, Lucia T.; Bacino, Carlos A.; Noll, Lisa M.; Fu, Cary; Hundley, Rachel J.; Wink, Logan K.; Erickson, Craig A.; Barnes, Gregory N.; Slavotinek, Anne; Jeremy, Rita; Rotenberg, Alexander; Kothare, Sanjeev V.; Olson, Heather E.; Poduri, Annapurna; Nespeca, Mark P.; Chu, Hillary C.; Willen, Jennifer M.; Haas, Kevin F.; Weeber, Edwin J.; and Rufo, Paul A., "A Randomized Controlled Trial of Levodopa in Patients with Angelman Syndrome" (2018). Molecular Pharmacology & Physiology Faculty Publications. 79.
https://digitalcommons.usf.edu/mpp_facpub/79