Clinical trial NCT00348933: Dietary Supplements for the Treatment of Angelman Syndrome
Official title: Efficacy of a Therapeutic Treatment Trial in Angelman Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Angelman Syndrome
Nervous System Diseases
Keywords: Developmental Delay
Mental Retardation
Ataxia
Microcephaly
Seizures
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: Baylor College of Medicine
name: Rady Children's Hospital, San Diego
name: Boston Children's Hospital
name: Greenwood Genetic Center
name: Rare Diseases Clinical Research Network
First posted: 2006-07-06
Enrollment: 90
Sex: ALL
Minimum age (years): 1
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Average Change in Functioning in Specific Areas of Development, Including Speech and Communications Skills, Cognitive Abilities and Daily Living Skills
timeFrame: Baseline, 1 year
Secondary outcomes:
measure: Change in Levels of Betaine, Creatine, Dimethylglycine, Guanidinoacetate, Homocysteine, and Methionine.
timeFrame: Baseline, 1 year
measure: Change in RBC Folate
timeFrame: Baseline, 1 year
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Rady Children's Hospital San Diego
state: California
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Greenwood
country: United States
facility: Greenwood Genetics Center
state: South Carolina
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine
name: Arthur L. Beaudet, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine
name: Carlos A. Bacino, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Harvard Medical School, Children's Hospital Boston
name: Wen-Hann Tan, BMBS
role: PRINCIPAL_INVESTIGATOR
affiliation: Division of Dysmorphology/Genetics, Children's Hospital San Diego, Department of Pediatrics, University of California, San Diego
name: Lynne M. Bird, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Greenwood Genetic Center
name: Steven A. Skinner, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.