Dietary Supplements for the Treatment of Angelman Syndrome

NCT ID: NCT00348933

Last Updated: 2012-09-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-07-31
• Study Completion Date: 2010-02-28

Brief Summary

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.

Detailed Description

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.

Conditions

Angelman Syndrome; Nervous System Diseases

Keywords

Developmental Delay; Mental Retardation; Ataxia; Microcephaly; Seizures

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

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

Group Type: EXPERIMENTAL

Betaine

Intervention Type: DRUG

100-200 mg per kg per day by mouth with a maximum of 6 grams divided in two daily doses

Creatine

Intervention Type: DRUG

200 mg per kg per day with a daily maximum of 5 grams divided in two daily doses

Metafolin

Intervention Type: DRUG

0.5 mg per kg per day by mouth with a maximum of 8 milligrams divided in two daily doses

Vitamin B12

Intervention Type: DRUG

1 mg by mouth per day for all weights and ages

Interventions

Betaine

100-200 mg per kg per day by mouth with a maximum of 6 grams divided in two daily doses

Intervention Type: DRUG

Creatine

200 mg per kg per day with a daily maximum of 5 grams divided in two daily doses

Intervention Type: DRUG

Metafolin

0.5 mg per kg per day by mouth with a maximum of 8 milligrams divided in two daily doses

Intervention Type: DRUG

Vitamin B12

1 mg by mouth per day for all weights and ages

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 1 Day
• Maximum Eligible Age: 5 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Baylor College of Medicine

OTHER

Sponsor Role: collaborator

Rady Children's Hospital, San Diego

OTHER

Sponsor Role: collaborator

Boston Children's Hospital

OTHER

Sponsor Role: collaborator

Greenwood Genetic Center

OTHER

Sponsor Role: collaborator

Rare Diseases Clinical Research Network

NETWORK

Sponsor Role: collaborator

University of California, San Diego

OTHER

Sponsor Role: lead

Responsible Party

Lynne M. Bird

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Arthur L. Beaudet, MD

Role: PRINCIPAL_INVESTIGATOR

Department of Molecular and Human Genetics, Baylor College of Medicine

Carlos A. Bacino, MD

Role: PRINCIPAL_INVESTIGATOR

Department of Molecular and Human Genetics, Baylor College of Medicine

Wen-Hann Tan, BMBS

Role: PRINCIPAL_INVESTIGATOR

Harvard Medical School, Children's Hospital Boston

Lynne M. Bird, MD

Role: PRINCIPAL_INVESTIGATOR

Division of Dysmorphology/Genetics, Children's Hospital San Diego, Department of Pediatrics, University of California, San Diego

Steven A. Skinner, MD

Role: PRINCIPAL_INVESTIGATOR

Greenwood Genetic Center

Locations

Rady Children's Hospital San Diego

San Diego, California, United States

Children's Hospital Boston

Boston, Massachusetts, United States

Greenwood Genetics Center

Greenwood, South Carolina, United States

Baylor College of Medicine

Houston, Texas, United States

Countries

United States

References

Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet. 1997 Jan;15(1):70-3. doi: 10.1038/ng0197-70.

Reference Type: BACKGROUND

PMID: 8988171 (View on PubMed)

Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, Magenis RE, Moncla A, Schinzel AA, Summers JA, Wagstaff J. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006 Mar 1;140(5):413-8. doi: 10.1002/ajmg.a.31074.

Reference Type: BACKGROUND

PMID: 16470747 (View on PubMed)

Williams CA, Lossie A, Driscoll D; R.C. Phillips Unit. Angelman syndrome: mimicking conditions and phenotypes. Am J Med Genet. 2001 Jun 1;101(1):59-64. doi: 10.1002/ajmg.1316.

Reference Type: BACKGROUND

PMID: 11343340 (View on PubMed)

Han J, Bichell TJ, Golden S, Anselm I, Waisbren S, Bacino CA, Peters SU, Bird LM, Kimonis V. A placebo-controlled trial of folic acid and betaine in identical twins with Angelman syndrome. Orphanet J Rare Dis. 2019 Oct 22;14(1):232. doi: 10.1186/s13023-019-1216-0.

Reference Type: DERIVED

PMID: 31640736 (View on PubMed)

Bird LM, Tan WH, Bacino CA, Peters SU, Skinner SA, Anselm I, Barbieri-Welge R, Bauer-Carlin A, Gentile JK, Glaze DG, Horowitz LT, Mohan KN, Nespeca MP, Sahoo T, Sarco D, Waisbren SE, Beaudet AL. A therapeutic trial of pro-methylation dietary supplements in Angelman syndrome. Am J Med Genet A. 2011 Dec;155A(12):2956-63. doi: 10.1002/ajmg.a.34297. Epub 2011 Oct 14.

Reference Type: DERIVED

PMID: 22002941 (View on PubMed)

Other Identifiers

RDCRN 5204

Identifier Type: -

Identifier Source: org_study_id