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A rare genetic neurological disorder almost exclusively affecting females, characterized by rapid developmental regression in infancy with loss of purposeful hand movements, loss of speech, gait abnormalities, and repetitive stereotypic hand movements. Commonly associated are severe intellectual disability, microcephaly, seizures, breathing abnormalities, disturbed sleeping patterns, scoliosis, and impaired social interactions or social withdrawal, among other symptoms. The disease progresses in stages, with late motor deterioration eventually leading to decreased mobility, muscle weakness, rigidity, spasticity, and dystonia.
ORPHA:778Classification level: Disorder
RTT primarily affects females, making it one of the most common genetic causes of severe intellectual disability in females. Prevalence is estimated at 1/9,000 in girls under the age of 12, whereas prevalence in the general population is estimated at approximately 1/30,000.
Classical RTT is characterised by apparently normal development for the first 6-18 months of life followed by the loss of acquired fine and gross motor skills and the ability to engage in social interaction, and the development of stereotypic hand movements. Scoliosis is seen in most patients by the age of 25. There is a wide variability in the rate of disease progression and severity, and several atypical variants are recognised. In addition, a number of males with a phenotype comparable to females with classical or atypical RTT have been described, as well as rare males with a severe neonatal-onset encephalopathy and prominent breathing abnormalities.
Despite the identification of mutations in the X-linked gene methyl CpG-binding protein 2 (MECP2) in the majority of RTT patients, the aetiology remains unclear. More recently mutations in two other genes, cyclin-dependent kinase like 5 (CDKL5) and Netrin G1, have been identified in patients with a clinical phenotype that strongly overlaps with RTT.
The diagnosis of RTT is clinical, based on Trevathan diagnostic criteria, recently revised following a meeting of an expert group of the European Paediatric Neurology Society.
Differential diagnosis includes autism and Angelman syndrome; cataract, retinopathy, or optic atrophy; history of perinatal or postnatal brain damage; confirmed inborn error of metabolism or neurodegenerative disorder; acquired neurological disorder due to severe head trauma or infection. Storage disorder is usually excluded by the presence of organomegaly.
Prenatal screening should be discussed for families with a proband having a pathogenic mutation.
As pathogenic MECP2 mutations in RTT patients are mostly de novo, the recurrence risk for future pregnancies is low, although gonadal mosaicism has been reported.
Management and treatment
Management is mainly symptomatic, focussed on optimising each patient's abilities. A multidisciplinary approach (involving dieticians, physiotherapists, occupational therapists, speech therapists and music therapists) is most effective. Attention should be paid to scoliosis and the development of spasticity, as well as to the development of effective communication strategies. Psychosocial support for families is essential. Pharmacological approaches aim at improving sleep disturbances, breathing disturbances, seizures, stereotypic movements and general well-being.
As RTT patients have an increased risk of life threatening arrhythmias associated with a prolonged QT interval, avoidance of a number of drugs is recommended. The clinical picture evolves in stages over a number of years and prognosis is poor.
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