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.
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 first 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 the
hospitalization, participants will undergo physical exam, Dexascan, MRI, EEG, behavioral
assessment, laboratory testing, and neuropsychological evaluations. Six months after
baseline assessment, participants will be rehospitalized for 3 days for similar assessments.
Reduction in choline acetyltransferase activity in RTT patients may also contribute to
disturbed cortical development and psychomotor retardation in RTT. Therefore, the second
part of the study will 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.
- Diagnosis of Rett syndrome
- Mutation in MeCP2 gene
- Typical EEG abnormalities (disorganized background, frontal central spikes, rhythmic
- Features of Rett syndrome with absence of MeCP2 mutation
- Non-specific EEG changes