Rett syndrome is an X-linked dominant neurodegenerative disorder (frequency 1:10,000) that occurs predominantly in females. In the classic course, children lose previously acquired abilities including meaningful hand movements, speech, and social interaction after initially inconspicuous development between 6 and 18 months of age. A leading symptom is the development of stereotypical hand movements. Other symptoms include delayed growth, microcephaly, gait ataxia, episodes of apnea or hyperpnea, sleep disturbances, increasing scoliosis, and seizures. The few affected males predominantly present with severe neonatal encephalopathy.
The disorder is caused by pathogenic variants in the MECP2 gene which encodes a protein involved in the regulation of gene expression by methylation. The severity of the disorder is influenced by the pattern of X inactivation and the type of variant. Most pathogenic variants arise de novo resulting in a low risk of recurrence. In rare cases, the pathogenic variant in combination with a non-random X-inactivation is already present in the clinically inconspicuous mother which can already indicate a diagnosis in the mother of an affected child. Since germ cell mosaicism has also been observed in isolated cases, prenatal diagnosis may also be appropriate in the absence of maternal variant detection. Pathogenic variants in the CDKL5 gene have been found in a few patients with a non-classical form of Rett syndrome with early-onset seizures (see Rett syndrome, atypical, early-onset epilepsy).
Gold et al. 2018, ACS Chem Neurosci 9:167 / Leonard et al. 2017, Nat Rev Neurol 13: 37 / Temudo et al. 2011, Brain Dev 33:69 / Psoni et al. 2010, Pediatr Res 67:551 / Saunders et al. 2009, Am J Med Genet A 149A:1019 / Hite et al. 2009, Biochem Cell Biol 87:219 / Ghosh et al. 2008, J Biol Chem 283:20523 / Williamson et Christodoulou 2006, Eur J Hum Genet 14:896 / Bienvenu et Chelly 2006, Nat Rev Genet 7:415, Erratum in: 7:583 (2006) / Weaving et al. 2006, Clin Genet 69:1 / Wan et al. 1999, Am J Hum Genet 65:1520 / Rett 1966, Wien Med Wschr, 116:723