Dietary Supplements for the Treatment of Angelman Syndrome

Study Overview
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Brief Summary
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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
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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.

Official Title
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Efficacy of a Therapeutic Treatment Trial in Angelman Syndrome

Conditions
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Angelman Syndrome, Nervous System Diseases

Intervention / Treatment
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* Drug: Betaine
* Drug: Creatine
* Drug: Metafolin
* Drug: Vitamin B12


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Participants will receive two daily doses of Metafolin, betaine, and creatine, and one daily dose of vitamin B12 for 12 months. | Drug: Betaine<br>* 100-200 mg per kg per day by mouth with a maximum of 6 grams divided in two daily doses<br>Drug: Creatine<br>* 200 mg per kg per day with a daily maximum of 5 grams divided in two daily doses<br>Drug: Metafolin<br>* 0.5 mg per kg per day by mouth with a maximum of 8 milligrams divided in two daily doses<br>Drug: Vitamin B12<br>* 1 mg by mouth per day for all weights and ages<br>|

What is the study measuring?
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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 | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine. |  | Baseline, 1 year | 
| Change in RBC Folate |  | Baseline, 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Developmental Delay, Mental Retardation, Ataxia, Microcephaly, Seizures