Dietary Supplements for the Treatment of Angelman Syndrome

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ClinicalTrials.gov Identifier: NCT00348933

Recruitment Status : Completed

First Posted : July 6, 2006

Results First Posted : September 24, 2012

Last Update Posted : September 24, 2012

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborators:

Baylor College of Medicine

Rady Children's Hospital, San Diego

Boston Children's Hospital

Greenwood Genetic Center

Rare Diseases Clinical Research Network

Information provided by (Responsible Party):

Lynne M. Bird, University of California, San Diego

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Angelman Syndrome Nervous System Diseases	Drug: Betaine Drug: Creatine Drug: Metafolin Drug: Vitamin B12	Not Applicable

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	90 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Efficacy of a Therapeutic Treatment Trial in Angelman Syndrome
Study Start Date :	July 2006
Actual Primary Completion Date :	February 2010
Actual Study Completion Date :	February 2010

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Angelman syndrome

Genetic and Rare Diseases Information Center resources: Angelman Syndrome Microcephaly Microencephaly

U.S. FDA Resources

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills [ Time Frame: Baseline, 1 year ]
Primary:

Bayley Scales of Infant Development measures Mental Developmental Index standard scores 0 (least skilled) - 100 (most skilled) Psychomotor Developmental Index standard scores 0 (least skilled - 10 (most skilled) Vineland Adaptive Behavior Scales (VABS), Communication standard scores 0 (least skilled) - 100 (most skilled) Daily Living Skills standard scores 0 (least skilled) - 100 (most skilled) Socialization standard scores 0 (least skilled) - 100 (most skilled) Motor Skills standard scores 0 (least skilled) - 100 (most skilled) Preschool Language Scale (PLS), Auditory Comprehension 0 (least skilled) - 100 (most skilled) Expressive Communication 0 (least skilled) - 100 (most skilled)

Secondary Outcome Measures :

Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine. [ Time Frame: Baseline, 1 year ]
Change in RBC Folate [ Time Frame: Baseline, 1 year ]

Eligibility Criteria

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Ages Eligible for Study:	1 Day to 5 Years (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00348933

Locations

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United States, California
Rady Children's Hospital San Diego
San Diego, California, United States, 92123
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States
United States, South Carolina
Greenwood Genetics Center
Greenwood, South Carolina, United States
United States, Texas
Baylor College of Medicine
Houston, Texas, United States

Sponsors and Collaborators

University of California, San Diego

Baylor College of Medicine

Rady Children's Hospital, San Diego

Boston Children's Hospital

Greenwood Genetic Center

Rare Diseases Clinical Research Network

Investigators

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Principal Investigator:	Arthur L. Beaudet, MD	Department of Molecular and Human Genetics, Baylor College of Medicine
Principal Investigator:	Carlos A. Bacino, MD	Department of Molecular and Human Genetics, Baylor College of Medicine
Principal Investigator:	Wen-Hann Tan, BMBS	Harvard Medical School, Children's Hospital Boston
Principal Investigator:	Lynne M. Bird, MD	Division of Dysmorphology/Genetics, Children's Hospital San Diego, Department of Pediatrics, University of California, San Diego
Principal Investigator:	Steven A. Skinner, MD	Greenwood Genetic Center

More Information

Publications:

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. Erratum In: Nat Genet 1997 Apr;15(4):411.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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Responsible Party:	Lynne M. Bird, Principal Investigator, University of California, San Diego
ClinicalTrials.gov Identifier:	NCT00348933
Other Study ID Numbers:	RDCRN 5204
First Posted:	July 6, 2006 Key Record Dates
Results First Posted:	September 24, 2012
Last Update Posted:	September 24, 2012
Last Verified:	September 2012

Keywords provided by Lynne M. Bird, University of California, San Diego:


Developmental Delay Mental Retardation Ataxia Microcephaly Seizures

Additional relevant MeSH terms:

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Nervous System Diseases Angelman Syndrome Syndrome Disease Pathologic Processes Movement Disorders Central Nervous System Diseases Abnormalities, Multiple Congenital Abnormalities Chromosome Disorders Genetic Diseases, Inborn Vitamin B 12 Hydroxocobalamin	Betaine Vitamins Micronutrients Physiological Effects of Drugs Vitamin B Complex Hematinics Gastrointestinal Agents Lipotropic Agents Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents

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