RETT SYNDROME PANEL

Overview

Rett syndrome is an X-linked dominant neurodegenerative disorder that mainly affects females. It is characterized by a sudden loss of previously acquired skills (hand functions, language, and social interaction) between 6 and 18 months of age. The disease is caused by pathogenic variants in the MECP2 gene. The severity varies depending on the X inactivation pattern and mutation type. Most cases are due to de novo variants.

Symptoms

In the classic course of the disease, children initially develop normally but then, between 6 and 18 months of age, lose previously acquired skills, especially meaningful hand functions, language skills, and social interaction. A key symptom is the development of stereotypical hand movements. Other symptoms include delayed growth, microcephaly, gait ataxia, episodes of apnea or hyperpnea, sleep disorders, increasing scoliosis, and seizures. The few male patients affected predominantly show severe neonatal encephalopathy.

Frequency

Classic Rett syndrome is an X-linked dominant neurodegenerative disease (frequency 1:10,000) that occurs predominantly in females.

Cause

The disease is caused by pathogenic variants in the MECP2 gene, which codes for a protein involved in the regulation of gene expression through methylation. The severity of the disease is influenced by the pattern of X inactivation and the type of mutation. Most pathogenic variants arise de novo, so the risk of recurrence is low. In rare cases, the pathogenic mutation is already present in combination with non-random X inactivation in the asymptomatic mother, so that diagnosis can be made in the mother of an affected child. Since germ cell mosaicism has also been observed in individual cases, prenatal diagnosis may also be indicated in the absence of maternal mutation evidence.

In a few patients with a non-classical form of Rett syndrome with early-onset seizures, pathogenic variants have been found in the CDKL5 gene (see Rett syndrome and similar disorders).

References

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