Abstracts

Rationale: Rett syndrome (RTT) is often associated with epilepsy. However, Methyl CpG binding protein 2 (MECP2) mutation and duplication are associated with a wide phenotype, and estimates of epilepsy prevalence in RTT and MECP2 related disorders vary due to small sample sizes and cross-sectional design. Using a large prospective, longitudinal cohort with classic RTT, atypical RTT, and those with mutations and duplications of MECP2 who did not meet criteria for the clinical syndrome (Non-RTT), we examined proportion with seizure, age of seizure onset, and the influence of type of MECP2 mutation. Methods: The RTT Natural History Study (NHS) is a prospective longitudinal study. Diagnosis was based on consensus criteria, and evaluations every 6-12 months included physician assessment of clinical features, MECP2 mutations, clinical severity, and presence, frequency, and treatment of seizures. We determined proportion of epilepsy in our RTT cohort using the Kaplan-Meier estimator, and compared clinical diagnosis and mutation type using the log rank test. Results: 1187 subjects were assessed over 6211 observations. 921 classic RTT (1 male), 168 atypical (1 male), and 98 Non-RTT (48 males) subjects were followed for a mean of 3.6 years (maximum 8.2 years). 93.3% had a MECP2 mutation (90.3%) or duplication (3.0%), and 50.8% had one of the 8 common point mutations in MECP2. 36 subjects had a MECP2 duplication (28 males, 8 females) and 8 had a mutation in exon 1 (1 male and 7 females). In the entire cohort, 93% seized over the lifespan, 50% by age 6.8 years, and 75% by age 14.5 years. Regarding clinical diagnosis, those with classic and atypical RTT had a similar seizure rate (90-95% over the lifespan), but only 45% of those with non-RTT ever experienced seizures (p < .001). Presence of a MECP2 mutation did not effect proportion of seizures in classic RTT, which were present in 93% of those with a mutation and 90% of those without a mutation, with 50% experiencing seizures by ages 6.7 years and 5.2 years respectively (p = .60). However, in atypical RTT, 90% of those without a MECP2 mutation experienced seizures compared to 81% of those with a mutation, and seizures occurred earlier in those without a mutation: in 50% by age 6.3 years compared to 7.7 years for those with a mutation (p = .05). Mutation type was associated with seizure rate (p = .011), with 87.5% of those with an Exon 1 mutation experiencing seizures, versus 56.2% of those with an R306C mutation. Seizures had earlier onset in those with mutation (50% by age 6.8 years) compared to those with duplication (50% by age 12.0 years, p =.025). Conclusions: Although we previously showed that cross-sectional prevalence of seizures in RTT was 30-40% in classic RTT, the lifetime risk of epilepsy is greater than 90% and if associated with mutation type. Those with atypical RTT with a MECP2 mutation and those who lack the clinical diagnosis but possess a MECP2 mutation have lower lifetime seizure prevalence. This cohort represents over 5% of the entire US RTT population, therefore these should be the most accurate estimate of epilepsy prevalence in Rett syndrome available.