Levodopa Fails to Improve Symptoms of Angelman Syndrome Patients, Study Shows

Levodopa failed to improve the neurodevelopment or behavior of children with Angelman’s syndrome, a study shows.

Patients tolerated the therapy well, however, researchers reported.

The study, titled “A randomized controlled trial of levodopa in patients with Angelman syndrome,” was published in the American Journal of Medical Genetics.

Intellectual and developmental disability are hallmarks of Angelman’s syndrome. There is no cure for it. Treatments are limited to measures to help children develop and to therapies that address symptoms such as seizures, sleep disturbances, and hyperactivity.

Studies in mice have linked AS to a decrease in the activity of an enzyme called CaMKII — for calcium/calmodulin-dependent kinase II. Scientists attribute the drop in activity to a process called phosphorylation, or the body adding phosphate groups at specific places on the enzyme.

Research has linked mutations that alter the phosphorylation of CaMKII to a process called impaired hippocampal long-term potentiation (LTP), which is necessary for learning. The hippocampus is a part of the brain that is involved in memory formation and emotion as well as learning. Long-term potentiation refers to the long-lasting enhancement of signal transmission between neurons.

Restoring normal phosphorylation of CaMKII in mice led to the enzyme having normal activity in the hippocampus again, studies have shown. In other words, it restored normal learning. This suggested that regulating the phosphorylation of CaMKII could reverse AS patients’ learning development shortcomings.

Researchers have also found abnormal phosphorylation of CaMKII in animal models of Parkinson’s disease. Levodopa reversed excess phosphorylation in those animals. Scientists were unable to identify how it did it, however.

Previous studies also showed that levodopa normalized phosphorylation of CaMKII in mice with AS, improving their motor learning ability. In addition, it improved the AS of two patients. This prompted researchers to surmise that it would improve neurodevelopment and tremors in children with the disease.

The team decided to conduct a multi-center, double-blind, randomized, placebo-controlled one-year trial (NCT00829439) to see how levodopa would work in children. The study covered 67 children with AS who randomly received one of two doses of levodopa a day 10 or a placebo.

Researchers measured outcomes with the Bayley Scales of Infant Development or the Mullen Scales of Early Learning, the Vineland Adaptive Behavior Scales, and the Aberrant Behavior Checklist. Among the 55 patients who completed the one-year study, 29 took levodopa and 26 a placebo.

The results showed no significant changes in outcomes between the levodopa and placebo groups.

Interestingly, there was actually a slower rate of improvement across all categories in the levodopa group than in the placebo group. Levodopa failed to improve the children’s tremors, attention span, aggression, and bizarre behaviors. Adverse events were similar between the two groups, but no adverse events were levodopa-related.

The authors concluded that “treatment with 15 mg/kg/day of levodopa does not appear to be beneficial in children with AS between the ages of 4–12 years old. We believe that, ultimately, a more effective treatment for AS is likely to come from therapies that restore UBE3A [gene] expression in neurons, although treatment of specific symptoms and complications may always be needed.”