Efficacy of a Therapeutic Treatment Trial in Angelman Syndrome

This study has been designed to evaluate the possible therapeutic benefits of L-5-methyltetrahydrofolate (Metafolin), vitamin B12, creatine and betaine in children with Angelman Syndrome (AS).

This study is based on the hypotheses 1) that dietary manipulation may increase global DNA methylation; 2) that increased methylation of the paternal chromosome in AS participants may increase expression of the Angelman gene causing clinical benefit; and 3) that dietary interventions with Metafolin in conjunction with creatine, betaine, and vitamin B12 would represent little risk, but some chance for benefit. The dietary regimen is felt to be quite benign and safe. The clinical response will be measured by recording: changes in seizure activity, changes in communication skills, changes in developmental skills and changes in behavioral patterns as indicated by formal developmental assessments and clinical evaluations. We will assess the progress of the participants by monitoring their changes from baseline throughout their participation in the study and measure their improvement in particular in the developmental parameters.

As a secondary aim, we plan to measure the biochemical response to these compounds by obtaining levels of homocysteine, methionine, S-adenosyl-methionine (SAM), and S-adenosyl-homocysteine (SAH). The molecular response will be measured by global DNA methylation analysis.

As an exploratory aim, we hope to use control data we have previously obtained from a double blind placebo-controlled trial done in the past using betaine and folic acid to compare the development of those children who have and those who have not received medications. More specifically, we wish to compare differences in the rate of development for those children who have never received study medications (from the first trial) with those who have received medications from the present trial. Developmental parameters used in the previous trial will be consistent with those used in the present trial in order to permit these comparisons. The previous trial was conducted at Baylor College of Medicine, Rady San Diego Children's Hospital and Boston Children's Hospital whereas a group of AS participants received folic acid and betaine or placebo in a randomized double-blind basis.

All the participants for the study will include patients who have a documented molecular diagnosis of AS. The participants will be seen at Baylor College of Medicine, Rady Children's Hospital of San Diego, Boston Children's Hospital and the Greenwood Genetics Center at 0 months and at 12 months for follow-up. Clinical and relevant historical data will be collected during the clinical visit and examination and also by reviewing medical and laboratory records. This information will then be entered into a HIPAA compliant clinical research database.

• Study Weblinks:
  • Clinical Trials: Angelman Syndrome
• Study Design:
  • Interventional
• Study Type:
  • Prospective
  • Interventional
• Total number of consented subjects: 91
• Subject Sample Telemetry Report (SSTR)

To be eligible for the study all the inclusion criteria should be met:

1. Confirmed diagnosis of AS by cytogenetic and/or molecular studies.
2. In stable condition with relatively good control of seizures and no other significant medical problems including liver, kidney, or heart problems at the time of entrance in the protocol trial.
3. Age between 1 day and 5 years old.
4. Patients should NOT have received a recent treatment with high dose folate drugs (in the last 12 months).
5. Willing to comply with the treatment.
6. Able to take oral or G-tube medication.
7. Agrees to travel to participating centers for enrollment and at study completion at 1 year.
8. Agrees to have blood drawn at designated laboratory every 6 months and to be contacted by somebody from the laboratory every month while on the studied medication.
9. Lives in the United States of America, or would be willing to travel to the U.S. for the 0, 6 and 12 months evaluations.

To be eligible for the study, no exclusion criterion should be present:

1. Participant has a history of liver or renal disease.
2. Participant is currently being treated for a serious acute illness.
3. Participant has known hypersensitivity to any of the given medicines.
4. Participant has taken high dose folinic/ folic acid within the past 12 months.
5. Participant has chronic or other significant illnesses in addition to AS.
6. Participant has uncontrolled seizures.

The laboratory of Dr. Beaudet has worked on AS for many years and his contributions have included the identification of the gene for AS (UBE3A) and the subsequent demonstration that this gene is subject to genomic imprinting in the mouse. The ultimate goal for this trial is to ameliorate the clinical symptoms of AS by modifying the imprint and effectively "turning on" the silent paternal UBE3A gene.

Dr. Beaudet and collaborators at Baylor College of Medicine, Dr. Lynne Bird at Rady San Diego Children's Hospital, and Dr. Wen-Hann Tan at Boston Children's Hospital, have conducted a similar trial using folic acid and betaine therapy in a group of 57 participants with AS. A comprehensive clinical, biochemical and developmental evaluation was done on 57 participants. After analysis of the data, there was a suggestion of benefit for a subgroup of the participants studied who were receiving the medications. These participants who appeared to have the benefit were those who did not have a co-morbid diagnosis of autism. All participants in this previous study were studied comprehensively using formal developmental evaluations.

As part of this work, one of the Co-investigators in the previous protocol, Dr. Sarika Peters, has performed standardized testing for autism (Autism Diagnostic Observation Scale-Generic, ADOS-G and Autism Diagnostic Interview - Revised, ADI-R). A pilot study done by Dr. Peters showed that about half of the AS patients met criteria for a co-morbid diagnosis of autism when these diagnostic tools are applied. This data was ultimately very important as the most benefit in the previous trial was observed in those children taking the medications that did not meet criteria for autism.

• Primary Phenotype: Angelman Syndrome

• UBE3A

• BioProject
• PubMed
• MeSH
• Gene
• PMC
• Clinical Trials
  • NCT00348933

• Principal Investigator
  • Arthur L. Beaudet MD. Baylor College of Medicine, Houston, TX, USA.
• Funding Source
  • National Institutes of Health, Bethesda, MD, USA.