Rett networked database: an integrated clinical and genetic network of Rett syndrome databases.

Rett syndrome (RTT) is a neurodevelopmental disorder with one principal phenotype and several distinct, atypical variants (Zappella, early seizure onset and congenital variants). Mutations in MECP2 are found in most cases of classic RTT but at least two additional genes, CDKL5 and FOXG1, can underlie some (usually variant) cases. There is only limited correlation between genotype and phenotype. The Rett Networked Database (http://www.rettdatabasenetwork.org/) has been established to share clinical and genetic information. Through an "adaptor" process of data harmonization, a set of 293 clinical items and 16 genetic items was generated; 62 clinical and 7 genetic items constitute the core dataset; 23 clinical items contain longitudinal information. The database contains information on 1838 patients from 11 countries (December 2011), with or without mutations in known genes. These numbers can expand indefinitely. Data are entered by a clinician in each center who supervises accuracy. This network was constructed to make available pooled international data for the study of RTT natural history and genotype-phenotype correlation and to indicate the proportion of patients with specific clinical features and mutations. We expect that the network will serve for the recruitment of patients into clinical trials and for developing quality measures to drive up standards of medical management.

Epilepsy in Rett syndrome: association between phenotype and genotype, and implications for practice.

PURPOSE: To investigate the association between genotype (methyl-CpG-binding protein 2 (MECP2 gene mutation)) and epileptic seizure phenotype in Rett syndrome. METHODS: We used the British Isles Rett syndrome survey to identify 137 subjects with one of the nine most frequent MECP2 gene mutations and invited their parents or carers to participate in a postal questionnaire and telephone interview. The questionnaire recorded information about epileptic seizure types, non-epileptic vacant spells and treatments. Two investigators conducted telephone interviews and three epileptologists classified their epileptic seizures. RESULTS: 89 subjects (65%) responded. The epilepsy prevalence was 67%, and 74% had non-epileptic vacant spells. The epilepsy prevalence within specific genotypes ranged from 47% (mutation C-terminal deletion, downstream of the Transcription Repression Domain) to 100% (mutation p.R270X, c.808C>T). The prevalence of non-epileptic vacant spells within genotypes ranged from 50% (mutation p.R306C, c.916C>T) to 100% (mutation p.R106W, c.316C>T). The epileptologists differed considerably in their classification of events, particularly of non-epileptic vacant spells. CONCLUSIONS: The large majority of people with Rett syndrome have epilepsy. Most have multiple epileptic seizure types, although generalised tonic-clonic seizures are the most common. There were no significant clinical differences between genotypes. The clinical differentiation of non-epileptic vacant spells is difficult. Discordance in epileptic seizure classification between clinicians suggests that caution is needed, since the clinical history alone cannot adequately classify the epileptic seizure type in Rett syndrome.