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Dietary Supplements for the Treatment of Angelman Syndrome

Primary Purpose

Angelman Syndrome, Nervous System Diseases

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Betaine
Creatine
Metafolin
Vitamin B12
Sponsored by
University of California, San Diego
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Angelman Syndrome focused on measuring Developmental Delay, Mental Retardation, Ataxia, Microcephaly, Seizures

Eligibility Criteria

1 Day - 5 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Rady Children's Hospital San Diego
  • Children's Hospital Boston
  • Greenwood Genetics Center
  • Baylor College of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

1

Arm Description

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

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine.
Change in RBC Folate

Full Information

First Posted
July 3, 2006
Last Updated
September 21, 2012
Sponsor
University of California, San Diego
Collaborators
Baylor College of Medicine, Rady Children's Hospital, San Diego, Boston Children's Hospital, Greenwood Genetic Center, Rare Diseases Clinical Research Network
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1. Study Identification

Unique Protocol Identification Number
NCT00348933
Brief Title
Dietary Supplements for the Treatment of Angelman Syndrome
Official Title
Efficacy of a Therapeutic Treatment Trial in Angelman Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
September 2012
Overall Recruitment Status
Completed
Study Start Date
July 2006 (undefined)
Primary Completion Date
February 2010 (Actual)
Study Completion Date
February 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, San Diego
Collaborators
Baylor College of Medicine, Rady Children's Hospital, San Diego, Boston Children's Hospital, Greenwood Genetic Center, Rare Diseases Clinical Research Network

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Angelman Syndrome, Nervous System Diseases
Keywords
Developmental Delay, Mental Retardation, Ataxia, Microcephaly, Seizures

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
90 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
Participants will receive two daily doses of Metafolin, betaine, and creatine, and one daily dose of vitamin B12 for 12 months.
Intervention Type
Drug
Intervention Name(s)
Betaine
Intervention Description
100-200 mg per kg per day by mouth with a maximum of 6 grams divided in two daily doses
Intervention Type
Drug
Intervention Name(s)
Creatine
Intervention Description
200 mg per kg per day with a daily maximum of 5 grams divided in two daily doses
Intervention Type
Drug
Intervention Name(s)
Metafolin
Intervention Description
0.5 mg per kg per day by mouth with a maximum of 8 milligrams divided in two daily doses
Intervention Type
Drug
Intervention Name(s)
Vitamin B12
Intervention Description
1 mg by mouth per day for all weights and ages
Primary Outcome Measure Information:
Title
Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills
Description
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)
Time Frame
Baseline, 1 year
Secondary Outcome Measure Information:
Title
Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine.
Time Frame
Baseline, 1 year
Title
Change in RBC Folate
Time Frame
Baseline, 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Day
Maximum Age & Unit of Time
5 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Arthur L. Beaudet, MD
Organizational Affiliation
Department of Molecular and Human Genetics, Baylor College of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Carlos A. Bacino, MD
Organizational Affiliation
Department of Molecular and Human Genetics, Baylor College of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Wen-Hann Tan, BMBS
Organizational Affiliation
Harvard Medical School, Children's Hospital Boston
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lynne M. Bird, MD
Organizational Affiliation
Division of Dysmorphology/Genetics, Children's Hospital San Diego, Department of Pediatrics, University of California, San Diego
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Steven A. Skinner, MD
Organizational Affiliation
Greenwood Genetic Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Rady Children's Hospital San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92123
Country
United States
Facility Name
Children's Hospital Boston
City
Boston
State/Province
Massachusetts
Country
United States
Facility Name
Greenwood Genetics Center
City
Greenwood
State/Province
South Carolina
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
8988171
Citation
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.
Results Reference
background
PubMed Identifier
16470747
Citation
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.
Results Reference
background
PubMed Identifier
11343340
Citation
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.
Results Reference
background
PubMed Identifier
31640736
Citation
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.
Results Reference
derived
PubMed Identifier
22002941
Citation
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.
Results Reference
derived

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Dietary Supplements for the Treatment of Angelman Syndrome

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