Angelman Syndrome, Nervous System Diseases
Conditions
Keywords
Developmental Delay, Mental Retardation, Ataxia, Microcephaly, Seizures
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.
Interventions
DRUGBetaine
100-200 mg per kg per day by mouth with a maximum of 6 grams divided in two daily doses
DRUGCreatine
200 mg per kg per day with a daily maximum of 5 grams divided in two daily doses
DRUGMetafolin
0.5 mg per kg per day by mouth with a maximum of 8 milligrams divided in two daily doses
DRUGVitamin B12
1 mg by mouth per day for all weights and ages
Sponsors
Baylor College of Medicine
Rady Children's Hospital, San Diego
Boston Children's Hospital
Greenwood Genetic Center
Rare Diseases Clinical Research Network
University of California, San Diego
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Days to 5 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills | 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
| Measure | Time frame |
|---|---|
| Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine. | Baseline, 1 year |
| Change in RBC Folate | Baseline, 1 year |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metafolin, Betaine, Creatine, B12 Treatment Participants will receive two daily doses of Metafolin, betaine, and creatine, and one daily dose of vitamin B12 for 12 months. | 90 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 7 |
| Overall Study | Lost to Follow-up | 6 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Withdrawal by Subject | 10 |
Baseline characteristics
| Characteristic | Metafolin, Betaine, Creatine, B12 Treatment |
|---|---|
| Age, Categorical <=18 years | 90 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age Continuous | 2.9 years STANDARD_DEVIATION 1.2 |
| Region of Enrollment United States | 90 participants |
| Sex: Female, Male Female | 43 Participants |
| Sex: Female, Male Male | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 5 / 90 |
| serious Total, serious adverse events | 48 / 90 |
Outcome results
Primary
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)
Time frame: Baseline, 1 year
Population: Analysis per protocol
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment (Metafolin/Creatine/Betaine/B12) | Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills | Bayley Scales Psychomotor Developmental Index | 4.7 units on a scale | Standard Deviation 8.6 |
| Treatment (Metafolin/Creatine/Betaine/B12) | Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills | Bayley Scales Mental Developmental Index | 5.7 units on a scale | Standard Deviation 7.8 |
| Treatment (Metafolin/Creatine/Betaine/B12) | Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills | VABS Communication | 5.8 units on a scale | Standard Deviation 8.3 |
| Treatment (Metafolin/Creatine/Betaine/B12) | Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills | VABS Daily Living Skills | 3.7 units on a scale | Standard Deviation 7.9 |
| Treatment (Metafolin/Creatine/Betaine/B12) | Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills | VABS Socialization | 4.7 units on a scale | Standard Deviation 5.2 |
| Treatment (Metafolin/Creatine/Betaine/B12) | Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills | VABS Motor Skills | 2.0 units on a scale | Standard Deviation 6.1 |
| Treatment (Metafolin/Creatine/Betaine/B12) | Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills | PLS Auditory Comprehension | 2.0 units on a scale | Standard Deviation 10.8 |
| Treatment (Metafolin/Creatine/Betaine/B12) | Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills | PLS Expressive Communication | 5.5 units on a scale | Standard Deviation 9.6 |
Secondary
Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine.
Time frame: Baseline, 1 year
Population: analysis per protocol
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment (Metafolin/Creatine/Betaine/B12) | Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine. | Dimethylglycine | 93.7 mmol/L | Standard Deviation 129 |
| Treatment (Metafolin/Creatine/Betaine/B12) | Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine. | Guanidinoacetate | 0.11 mmol/L | Standard Deviation 0.34 |
| Treatment (Metafolin/Creatine/Betaine/B12) | Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine. | Betaine | 206.9 mmol/L | Standard Deviation 224.5 |
| Treatment (Metafolin/Creatine/Betaine/B12) | Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine. | Creatine | 83.3 mmol/L | Standard Deviation 165.9 |
| Treatment (Metafolin/Creatine/Betaine/B12) | Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine. | Homocysteine | 2.3 mmol/L | Standard Deviation 2.1 |
| Treatment (Metafolin/Creatine/Betaine/B12) | Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine. | Methionine | 5.5 mmol/L | Standard Deviation 12.1 |
Secondary
Change in RBC Folate
Time frame: Baseline, 1 year
Population: Analysis per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Metafolin/Creatine/Betaine/B12) | Change in RBC Folate | 77 ng/mL | Standard Deviation 267 |