DEXTROMETHORPHAN IN RETT SYNDROME

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rett syndrome (RTT) is a neurodevelopmental disorder that occurs in 1:10,000-22,000 girls with devastating consequences to brain and systemic neurons. In 70% of individuals having the prescribed clinical features, mutations in the gene encoding for methyl-CpG-binding protein-2 (MeCP2) located on chromosome Xq28 have been identified. MeCP2 is associated with nuclear DNA, and binds to methylated CpG nucleotides, playing a vital role in transcriptional silencing. To date, there is no effective therapy for RTT, and treatment remains palliative. Unfortunately, the brain bears the brunt of the disease during its most vigorous phase of growth, resulting in severe mental retardation. Postmortem brain autoradiographic studies demonstrate a striking and disproportionate increase in the number of glutamate/NMDA (N-methyl-D-aspartate) subtype of receptors in the prefrontal cortex, particularly in younger girls. After the age of 10 years, this dramatic increase in the number of NMDA receptors is reduced to below control values. Furthermore, increased glutamate, but not any other amino acid, has been documented in cerebrospinal fluid (CSF), as well as in brain gray matter by 1H spectroscopic (MRS) studies in RTT patients. The aberrant increase in the excitatory amino acid (EAA) receptors in younger RS patients coincides with the behavioral and epileptic profile, and GI disturbances seen in RTT stages 2 and 3 (18 months-15yrs). Moreover, sudden unexplained death in RTT patients below the age of 15 years is unrelated to seizure frequency and coincides with this period of neuroexcitotoxicity. Commencement of the pathognomonic clinical features in RTT (18 months), with reported increases in EAA glutamate/glycine and NMDA receptors at 2 years, suggests a causal relationship between the onset of autistic-like features, seizures, hand wringing, irritability, and neurotransmitter alterations. The gradual amelioration of symptoms after 15 years of age coincides with a reduction of glutamate/NMDA receptors to below that of control values. Additionally, NMDA receptors that are present in osteoblasts may play a role in the osteopenia seen in RS. It would be important to note if blocking excessive numbers of NMDA receptors in brain and osteoblasts by use of dextromethorphan a competitive blocker of the NMDA receptors could improve spike activity in brain, and bone density. Similar effects could also improve esophageal autonomic dysfunction, measurable by improved motility and reduced reflux. The study will include 90 mutation positive patients. 30 subjects in each age group ranging from <5 years, 5-10 years, and 11-14.99 year will be assigned to each of the 3 treatment arms consisting of 0.25 mg/Kg/day, 2.5 mg/Kg/day, 5 mg/Kg/day in 2 divided doses. As per the FDA guidelines we can only include those patients between 5-14.99 years. Once safety has been established in this age group we will extend the study to those < 5 years, with their approval.