Angelman

Upcoming Paper on Dopamine and Angelman Syndrome

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New data published by teams led by Drs. C.J. Malanga and Ben Philpot at UNC Chapel Hill suggest that in Angelman syndrome model mice, there are changes in two different neural circuits in the brain that use the chemical dopamine to transmit information. These dopaminergic pathways in the brain – the nigrostriatal and the mesolimbic pathways – might explain some of the characteristics seen in individuals with Angelman syndrome. Problems in the nigrostriatal pathway are involved in involuntary movements such as tremors, while problems in the mesolimbic pathway are involved in attention span, some behavioral traits such as obsessive-compulsive behaviors, and mood. In this paper, the authors showed that in Angelman syndrome model mice, dopamine release is decreased in the nigrostriatal pathway but increased in the mesolimbic pathway compared to normal, control mice.

We do not know if people with Angelman syndrome show similar findings in their nigrostriatal or mesolimbic pathways. We do not know how supplementation with oral levodopa (L-DOPA), as is done in the ongoing Angelman syndrome levodopa trial funded by the Angelman Syndrome Foundation, would affect these dopaminergic pathways in children with Angelman syndrome. Theoretically, treatment with levodopa could increase the activity in the nigrostriatal pathway, leading to a more normal level of motor movements and lessening the involuntary movements. However, treatment with levodopa might increase the activity in the mesolimbic pathway, leading to an even higher (more abnormal) level of dopamine. Although increased dopamine could worsen behavioral problems, the effects of oral levodopa on the mesolimbic pathway could be more complex and are currently unknown.

As the Angelman syndrome levodopa trial is a double-blind study, none of the investigators know which patients are on levodopa and which are on placebo. We do not know whether any of the changes that we have observed in study participants are truly due to the effects of levodopa. The intent of the study was to determine if levodopa could improve motor function and cognitive development. Among the more than 50 participants whom we have enrolled in this study, we have not observed changes in mood or new behaviors (particularly negative effects) that were not previously present in the participants. However, in light of these new findings, we will be implementing a new set of questionnaires for all participants who enroll in the study from January 2013 to examine the potential effects of levodopa on mood and behavior more closely.

Please feel free to contact the study sponsor, Dr. Wen-Hann Tan (wen-hann.tan@childrens.harvard.edu), or any of the site principal investigators, if you have further questions or concerns about these new findings.


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