Angelman syndrome (AS) is a rare, neurogenetic condition characterized by severe developmental delay, movement disorder, speech impairment (often with a complete lack of speech) and an unusually happy demeanor. Nearly every individual with AS faces at least two major challenges in their daily life: cognitive or intellectual disability, and movement disorder, usually in the form of ataxic (uncoordinated) gait, unsteadiness, jerky movements or tremors. Seizures are also common, and present a daunting health challenge.
Arising in one out of every 10,000 to 20,000 children from the loss of an enzyme on chromosome 15 called Ube3A, AS falls in the category of orphan diseases: ones that affect fewer than one in 200,000 Americans. There is no cure for AS, but there are therapies and medications that can help the symptoms. Seizures can be controlled with the right medications, physical therapy can improve ataxia, and speech therapy helps improve communication skills.
Like nearly all orphan diseases, research on AS has historically not been well-funded, but orphan diseases have lately gained growing attention, especially at Children’s Hospital Boston.
Here at Children’s, we are enthusiastically pursuing clinical research in AS and other neurodevelopmental conditions. Children’s is one of five sites across the country taking part in the Angelman Syndrome Natural History study, through which we are following individuals with AS to learn about their development and growth through the years.
Children’s is also the sponsor site for a drug trial of levodopa – a drug commonly used in adults who have Parkinson disease to control tremors and involuntary movements – in AS. Studies in a mouse model of AS suggest that levodopa may affect cognition because it turns down the activity of a brain protein called CaMKII (Calcium-calmodulin kinase II), which affects cognitive flexibility, the ability to adjust behavior appropriately to a particular context. An illustration of cognitive flexibility is being able to run on the playground, but then sit quietly and listen in the classroom.
Levodopa, however, is not FDA-approved for children, and no formal studies have been conducted to assess its true efficacy in AS. That’s where our study – a double-blind trial with collaborators at five other medical centers – hopes to make a difference. Children in this year-long study have a 50/50 chance of receiving levodopa or a placebo, which is essentially a sugar pill used as a control to assess whether or not levodopa truly works. It is called “double-blind” because neither the parents nor we, the researchers, will know whether each individual receives levodopa or placebo until the end of the study.
Children who complete the first year of the study are then eligible to move on to an additional year-long “open label” study, in which all of the children receive levodopa. This study is just beginning, but we expect to enroll many more patients.
We have high hopes that levodopa really can help kids with AS. Last year, we completed an initial “dose-tolerability” study of levodopa, in which we determined the appropriate dose for the current study. Parents whose children took part told us that they saw improvements in tremors and other abnormal movements, and some noticed improvements in their child’s cognition.
Studies like ours provide a unique opportunity for families of children with rare genetic conditions to receive additional support. Many of the families in our natural history study tell us their child is their pediatrician’s only Angelman patient. But the doctors, psychologists and nurses involved with our study see dozens of children and adult patients with AS, either clinically or through their participation in the study.
In turn, the families also have an opportunity to give back to the community of patients. Raising a child with a rare condition like AS and living with it day to day make parents specialists in their child’s disorder. Parents really are the experts in our study, and by participating, they are helping other kids with AS and contributing to the future care of the condition.
Hillary Chu, BA, is the Angelman syndrome study coordinator at Children’s Hospital Boston. She has the best post-undergrad job imaginable thanks in large part to the wonderful families who come from all over the country to participate in research and the support of the Angelman community.
[Ed note: The levodopa study described in this article is also being conducted at Rady Children’s Hospital in San Diego, CA; UCSF Children’s Hospital in San Francisco, CA; Baylor College of Medicine in Houston, TX; Vanderbilt University Medical Center in Nashville, TN; and Greenwood Genetic Center in Greenwood, SC. To learn more, visit ClinicalTrials.gov or email Hillary.]