Critical account of clinical and physiological studies in Rett syndrome

Rett syndrome is the manifestation of an X linked, mainly female, genetic, neurodevelopmental disorder that usually produces profound intellectual and physical disabilities including abnormal muscle tone, with a tendency to develop limb contractures, scoliosis, epilepsy and irregular respiration. There is characteristic hand stereotypy with· poor voluntary hand use, locomotion is compromised and speech is rare. Although the disorder is not progressive many sequele shorten life especially in the most severely affected. Subtle abnormalities, present from birth, are frequently overlooked because there is some developmental progress until a period of regression at around one year of age when speech and hand use diminish. This thesis gives an account of clinical, physiological and genetic studies carried out between 1982 and 2005 with the aim of recording the natural history of the disorder and understanding its clinical manifestations. The subjects of these studies have been people of all ages, mainly from the British Isles, reported to have Rett syndrome by their physicians and families or carers (British Isles Survey, n=l228). Most have been examined and recorded on video by myself, many repeatedly. Fully informed parental consent and appropriate ethical approval has been given for all procedures. The early manifestations of the disorder were investigated from developmental histories and donated videos (78) taken by families before they were aware of the problem. The abnormal respiratory rhythms were investigated and characterised, using non-invasive measures of respiratory rhythm, carbon dioxide, oxygen, heart rate and blood pressure. The poor control of voluntary movement was investigated using electromagnetic stimulation of the cortex to record conduction in the motor pathways. Stereotyped hand movements were analysed from three-dimensional live recording and informal two-dimensional video. The prevalence of a toe anomaly was estimated, visual evoked potentials were recorded and a reported increase in urinary neopterin was investigated. The health of people in the British Survey was monitored longitudinally from family and physician reports and direct clinical examinations, data being stored on computer. Simple scores were generated to indicate separately the severity of the condition and health of the individual. The survey data has been used to estimate the prevalence of the disorder (I in 10,000 females), natural history from birth to death, the predictive value of the earliest signs, survival at different levels of severity, the impact of scoliosis surgery on health and has provided a foundation for studies relating clinical manifestations to specific mutations on the affected gene MECP 2 (Xq28). The studies have indicated the nature of the Rett disorder to be developmental and non-progressive, with primary impact on the processing functions of the brain, probably beginning in the brain stem before birth.

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