Effects of Creatine Supplementation in Rett Syndrome

Study Overview
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Brief Summary
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Creatine supplementation in RTT: a randomized controlled trial Rett Syndrome (RTT) is a neurodevelopmental disorder characterised by apparently normal early development (stage 1 of RTT) followed by loss of purposeful hand use, distinctive hand stereotypes, slow brain growth, loss of language, respiratory irregularities, gastrointestinal disturbances, gait abnormalities, seizures, and mental retardation. These symptoms typically appear between 6 and 18 months of age (stage 2). Subsequently, there is gradual stabilisation of severe mental retardation and motor compromise (stage 3). The majority (70% to 80%) of patients show mutations in the methyl-CpG-binding-protein-2 (MeCP2) gene, located on chromosome Xq28. MeCP2 encodes a transcription repressor protein that is ubiquitously expressed in all tissues. As RTT primarily affects females, only very few males with mutations in MeCP2 have been identified. Mutations in MeCP2 have also been identified in children with X-linked mental retardation, autism and a clinical phenotype that resembles Angelman Syndrome. The aim of this study is to investigate the effects of a dietary supplement on the biochemical and clinical parameter of RTT. About 80 % of labile methyl groups generated through the re-methylation cycle are used for the synthesis of creatine within the human organism. Supplementation of creatine will therefore increase the availability of labile methyl groups for different methylation reactions including methylation of DNA. The study will be double blind and cross-over. The patients will get creatine monophosphate (200 mg/kg/d in three dosages per day) or placebo. After 6 months and a wash-out period of 4 weeks the groups are changed for the next 6 months. All participants with RTT and mutations in MeCP2 will undergo physical and neurological exam, quantitative EEG, behavioral assessment, laboratory testing, and neuropsychological evaluations. Participants will have a follow-up after 3, 6, 10, 13 and 16 months (3 months after finishing the study), which will include similar assessments.

Official Title
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Effects of Creatine Supplementation in Rett Syndrome: A Randomized, Placebo-controlled Trial

Conditions
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Rett Syndrome

Intervention / Treatment
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* Dietary Supplement: Creatine monohydrate
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RTT Syndrome, diagnosed by current consensus criteria Exclusion Criteria: taking supplements containing either folic acid or vitamin B12 or knowingly consuming any vitamin-fortified food items

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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Female

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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Creatine monohydrate<br>The patients received orally 200 mg CMH per kg body weight divided in three doses per day. Following period 1 (6 months) of supplementation and a wash-out period of 4 weeks without CMH respectively the groups were switched for another 6 months (period 2). | Dietary Supplement: Creatine monohydrate<br>* The patients received orally 200 mg CMH per kg body weight divided in three doses per day. Following period 1 (6 months) of supplementation and a wash-out period of 4 weeks without CMH the groups were switched for another 6 months (period 2).<br>|
| Placebo Comparator: Placebo<br>The patients received orally 200 mg Placebo per kg body weight divided in three doses per day in identically prepared capsules. Following period 1 (6 months) of supplementation and a wash-out period of 4 weeks without Placebo respectively the groups were switched for another 6 months (period 2). | Dietary Supplement: Placebo<br>* The patients received orally 200 mg Placebo per kg body weight divided in three doses per day. Following period 1 (6 months) of supplementation and a wash-out period of 4 weeks without placebo the groups were switched for another 6 months (period 2).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global DNA Methylation in serum | Global DNA methylation as one primary outcome measure is analyzed at time 0 and after 6 months. | 6 months | 
| Rett Syndrome Motor and Behavioral Assessment (RSMBA) |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic markers of methylation cycle | Markers: Methionine (µmol/l), Homocysteine (µmol/l), SAM (µmol/l), SAH (µmol/l) | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rett Syndrome, Randomized, Methylation