Rett syndrome (RTT) is a disorder in which the nervous system does not develop properly. RTT generally affects girls, but there are some boys who have been diagnosed with RTT. Symptoms of RTT include small brain size, poor language skills, repetitive hand movements, and seizures. This study will evaluate the effectiveness of two drugs in treating the symptoms of RTT.

Condition	Treatment or Intervention	Phase
Rett Syndrome	Drug: dextromethorphan  Drug: donepezil hydrochloride	Phase III

RTT is a neurodevelopmental disorder characterized by apparently normal early development followed by loss of purposeful hand use, distinctive hand stereotypies, slowed brain growth, loss of language, respiratory irregularities, GI disturbances, gait abnormalities, seizures, and mental retardation. These symptoms appear between ages 6 and 18 months (stage 2 of the disease) following apparently normal development (stage 1). Subsequently, there is gradual stabilization of severe mental retardation and motor compromise (stage 3). The majority (70% to 80%) of patients demonstrate mutations in the methyl-CpG-binding-protein-2 (MeCP2) gene, a transcription repressor located on chromosome Xq28. The disorder predominantly affects females, but a few males with mutations in MeCP2 have been identified, even though many of them do not have the classic symptoms recognized in females.

Recent studies demonstrate increased brain N-methyl-D-aspartate (NMDA) receptors in stages 2 and 3 of the disease. This age-specific increase in glutamate levels and their receptors contribute to brain damage. This study will examine the effectiveness of dextromethorphan, an NMDA receptor antagonist, to ameliorate symptoms. Participants will be randomized to receive one of three doses of dextromethorphan. All participants will be admitted to the hospital for three days at the beginning of the study. During this hospital stay, participants will undergo physical exam, Dexascan, MRI, EEG, behavioral assessment, laboratory testing, and neuropsychological evaluations. Participants will be have a follow-up 3-day hospital admission after 6 months, which will include similar assessments.

Reduction in choline acetyltransferase activity in RTT patients may also contribute to disturbed cortical development and psychomotor retardation in RTT. Therefore, the study will also evaluate the effect of donepezil hydrochloride, an inhibitor of acetylcholine-esterase, on acetylcholine levels. This portion of the study will not begin until pharmacokinetic data for donepezil in children is available.

Ages Eligible for Study:  1 Year   -   15 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria

• Diagnosis of Rett syndrome
• Mutation in MeCP2 gene
• Typical EEG abnormalities (disorganized background, frontal central spikes, rhythmic theta)

Exclusion Criteria

• Features of Rett syndrome with absence of MeCP2 mutation
• Non-specific EEG changes

SakkuBai R. Naidu, MD      443-923-2778 
Barbara Ann Bradford      443-923-2778    bradford@kennedykrieger.org

Maryland
      Kennedy Krieger Institute, Baltimore,  Maryland,  United States

Study chairs or principal investigators

SakkuBai R. Naidu, MD,  Principal Investigator,  Kennedy Krieger Research Institute   

Study ID Numbers:  HD024448; 5 PO1 HD024448
Record last reviewed:  September 2003
Record first received:  September 29, 2003
ClinicalTrials.gov Identifier:  NCT00069550
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2004-11-10