Dietary Supplements for the Treatment of Angelman Syndrome

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 Overview

• Status: Completed
• Conditions: Nervous System Diseases; Angelman Syndrome
• Intervention / Treatment: Drug: Betaine; Drug: Creatine; Drug: Metafolin; Drug: Vitamin B12

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 Type: Interventional
• Enrollment (Actual): 90
• Phase: Not Applicable

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 3 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills	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)	Baseline, 1 year

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: Baylor College of Medicine; Boston Children's Hospital; Rare Diseases Clinical Research Network; Rady Children's Hospital, San Diego; Greenwood Genetic Center
• Investigators: 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

Publications and helpful links

General 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.
• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2006
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): February 1, 2010

Study Registration Dates

• First Submitted: July 3, 2006
• First Submitted That Met QC Criteria: July 3, 2006
• First Posted (Estimate): July 6, 2006

Study Record Updates

• Last Update Posted (Estimate): September 24, 2012
• Last Update Submitted That Met QC Criteria: September 21, 2012
• Last Verified: September 1, 2012

More Information

Terms related to this study

• Keywords: Seizures; Mental Retardation; Ataxia; Developmental Delay; Microcephaly
• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Movement Disorders; Abnormalities, Multiple; Chromosome Disorders; Syndrome; Nervous System Diseases; Angelman Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Gastrointestinal Agents; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Hematinics; Lipotropic Agents; Vitamin B 12; Hydroxocobalamin; Betaine
• Other Study ID Numbers: RDCRN 5204