A Trial of Levodopa in Angelman Syndrome

• Developmental Outcome Measures [ Time Frame: 12 months ] [ Designated as safety issue: No ]

  Changes in raw or standard scores between baseline and after 12 months of treatment with either placebo or LD/CD of:

  I. Bayley Scales of Infant and Toddler Development, 3rd edition (or the Mullen Scales of Early Learning in the more developmentally advanced subjects) II. Vineland Adaptive Behavior Scales, 2nd edition (standard scores only) III. Preschool Language Scale, 4th edition IV. Aberrant Behavior Checklist - Community version

• Tremor and Movement Disorder [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  Changes in raw score of a modified Unified Parkinson's Disease Rating Scale (mUPDRS), a measure of tremor and movement disorder, from baseline after 12 months in the placebo or the LD/CD group.

This study is designed to determine whether levodopa will lead to an improvement in the development and tremor in children with Angelman syndrome (AS).

It has been suggested that levodopa, a medication that is usually used to treat Parkinson disease in adults, may help children with AS in their overall development and reduce the tremor that some of them have.

If levodopa is found to be beneficial for children with AS, this could lead to a new treatment for AS.

Levodopa is a prodrug that "delivers" dopamine to the brain. It is usually given with carbidopa, a peripheral decarboxylase inhibitor, to increase the bioavailability of levodopa. Animal studies have suggested that levodopa can reverse the excess phosphorylation of some enzymes involved in synaptic and neuronal function, including calcium/calmodulin-dependent kinase type 2 (CaMKII).

Recently, it was shown that excess phosphorylation of CaMKII may be responsible for some of the neurological deficits seen in Angelman syndrome. Therefore, it is hypothesized that levodopa may lead to an improvement in the neurodevelopment and abnormal movements (e.g. tremors) in children with Angelman syndrome.

Although many children have used levodopa for a variety of medical conditions over the last 30 years, it has not been approved by the Food and Drug Administration (FDA) for use in children, and it has not been formally studied in children with Angelman syndrome.

Therefore, the purpose of this study is to find out whether levodopa will lead to an improvement in the development and in the tremor in children with AS.

• Experimental: Levodopa
  Levodopa is a prodrug that "delivers" dopamine to the brain. It is usually given with carbidopa, a peripheral decarboxylase inhibitor, to increase the bioavailability of levodopa.
  Intervention: Drug: Levodopa/carbidopa
• Placebo Comparator: Placebo
  The placebo (in this study, microcellulose) is not expected to have any effect.
  Intervention: Drug: Levodopa/carbidopa

Inclusion Criteria:

1. Age between 4 years and 12 years (i.e., before the 13th birthday)
2. Molecular confirmation of the diagnosis of AS, which may include abnormal methylation studies or UBE3A mutation analyses - only subjects with a molecular diagnosis will be allowed to enroll
3. Not on LD, CD, or any dopamine agonists in the 2 weeks prior to participation

Exclusion Criteria:

1. Co-morbid disorders that may be associated with developmental or cognitive delays
2. Poorly controlled seizures - An average of more than 2 clinical seizures per month in the 12 months prior to enrollment.
3. Use of medications that may interact with LD/CD including atypical antipsychotics (aripiprazole, asenapine, iloperidone, olanzapine, paliperidone, risperidone, ziprasidone), monoamine oxidase inhibitors (isocarboxazid, phenelzine, selegiline, tranylcypromine), or phenytoin within the last 14 days, or other investigational interventions within the past 3 months
4. Presence of cardiovascular disease or instability, respiratory disease, liver disease, peptic ulcer disease, renal impairment, or hematological disorders
5. Pregnancy

• Rady Children's Hospital, San Diego
• University of California, San Francisco
• Baylor College of Medicine
• Vanderbilt University
• Greenwood Genetic Center
• Angelman Syndrome Foundation
• FDA Office of Orphan Products Development