Official Title: “Efficacy of a Therapeutic Treatment Trial in Angelman Syndrome”

Angelman syndrome (AS) is a complex genetic disorder that affects the nervous system. The purpose of this study is to determine the effectiveness of certain dietary supplements in treating the symptoms of AS.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Efficacy Study

Study Primary Completion Date: February 2009

AS is a neurologic disorder that may cause developmental delay, mental retardation, severe speech impairment, seizures, small head size, and problems with movement and balance in young children. AS is caused by a missing or incomplete chromosome 15 that is inherited from the mother. Diagnosis of AS is usually made between three and seven years of age, when the characteristic behaviors and features of the disease become most evident. Prior to AS diagnosis, the symptoms may be mistaken for cerebral palsy or autism. Physical, occupational, and speech therapy, communication skills development, and behavior modification help to improve the quality of life of these children, but other treatments are needed.

In a previous study, decreased DNA methylation, which is a type of chemical change in DNA, was observed in an individual with AS; this condition may be a primary cause of AS. It is hypothesized that promoting increased DNA methylation might reduce the severity of AS symptoms. Betaine, creatine, Metafolin, and vitamin B12 are compounds normally found in the body that are involved in the DNA methylation pathway. Increasing the concentrations of these compounds in the body may enhance DNA methylation. This study will evaluate the efficacy of four dietary supplements in treating the symptoms of AS.

This study will last 12 months. Study visits will occur at study entry and Month 12. A selected group of participants, those who meet the diagnostic criteria for autism, will also be evaluated at Month 6. At study visits, participants will undergo an electroencephalogram (EEG). Medical history, physical exam, neurological exams, and developmental assessments will also be performed. Urine and blood collection, including tests to determine the blood levels of the dietary supplements, will occur at study entry and Months 6 and 12. Participants will receive two daily doses of Metafolin, betaine, and creatine, and one daily dose of vitamin B12 for the duration of the study. Parents will be asked to complete a questionnaire at each visit to report their child's behavior while taking the dietary supplements. Parents will also be contacted by phone periodically to assess changes and/or progress in their children.

Intervention(s) in this Clinical Trial

• Drug: Betaine
  • 100-200 mg per kg per day by mouth with a maximum of 6 grams divided in two daily doses
• Drug: Creatine
  • 200 mg per kg per day with a daily maximum of 5 grams divided in two daily doses
• Drug: Metafolin
  • 0.5 mg per kg per day by mouth with a maximum of 8 milligrams divided in two daily doses
• Drug: Vitamin B12
  • 1 mg by mouth per day for all weights and ages

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Participants will receive two daily doses of Metafolin, betaine, and creatine, and one daily dose of vitamin B12 for 12 months.

Primary Measures

• Improvement in functioning across development, including acquisition of milestones, improvements in speech and communications skills, and behavioral or physical changes
  • Time Frame: Measured at Months 6 and 12
    Safety Issue?: No

Secondary Measures

• Comparison of pre- and post-treatment levels of S-adenosyl homocysteine (SAH), S-adenosyl methionine (SAM), dimethylglycine, methionine, homocysteine, betaine, creatine, guanidinoacetate, red blood cell folate, and DNA methylation response
  • Time Frame: Measured at Months 6 and 12
    Safety Issue?: No

Inclusion Criteria:

• Diagnosis of AS
• In stable condition with relatively good control of seizures
• Willing to comply with treatment, study visit schedule, and study assessments
• Willing to take oral or G-tube medication
• Willing to be contacted monthly during the course of the study
• Parent or guardian willing to provide informed consent

Exclusion Criteria:

• History of liver or kidney disease
• Currently being treated for a serious acute illness
• Known hypersensitivity to any of the study drugs
• Received high-dose folate drug treatment in the 12 months prior to study entry
• Other significant medical problems, including those involving the liver, kidney, or heart
• Other comorbidities, genetic disorders, or extreme prematurity; children with autism are not excluded

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 5 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Office of Rare Diseases (ORD)

Overall Clinical Trial Officials and Contacts

Arthur L. Beaudet, MD Principal Investigator Department of Molecular and Human Genetics, Baylor College of Medicine  

Overall Contact: Carlos A. Bacino, MD 832-822-4292 cbacino@bcm.tmc.edu

Information obtained from ClinicalTrials.gov on August 28, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00348933

Study ID Number: RDCRN 5204

ClinicalTrials.gov Identifier: NCT00348933

Health Authority: United States: Federal Government