Overview
Classic Rett syndrome, an X-linked dominant neurodegenerative disorder, mainly affects women and leads to a loss of acquired skills between 6 and 18 months of age. It is primarily caused by pathogenic variants in the MECP2 gene. Atypical forms can arise from variants in the CDKL5 or FOXG1 gene. In Rett syndrome-like disorders, exome diagnostics are recommended for a more accurate diagnosis and prognosis.
Classic Rett syndrome is an X-linked dominant neurodegenerative disease (frequency 1:10,000) that occurs predominantly in females. 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. Classic Rett syndrome is caused by pathogenic variants in the MECP2 gene.
Non-classical, atypical forms of Rett syndrome with early-onset seizures may be caused by pathogenic variants in the CDKL5 gene.
Atypical Rett syndrome was first described in 1985 in a girl with benign neonatal seizures (BNS) and a clinical picture that later became very similar to classic Rett syndrome. The patients described to date are mainly characterized by early-onset therapy-resistant epilepsy and, in later stages, by severe psychomotor developmental delay. In addition to BNS, other types of seizures also occur; the EEG is not typical, but depends on age and the type of seizure. Unlike Rett syndrome, there is no initial phase with apparently normal development.
The diagnostic criteria according to Artuso et al. (2010) are:
- Unremarkable prenatal development
- Irritability, vigilance disturbances, and poor sucking in the early postnatal phase before the onset of the first epileptic seizures
- Early childhood epilepsy with onset between the first week and the fifth month of life
- Stereotypical hand movements
- Severe psychomotor developmental delay
- Severe hypotonia
Since 2005, it has been known that variants in the CDKL5 gene (Xp22) are causative for this X-linked dominant atypical Rett syndrome. The CDKL5 gene encodes the cyclin-dependent kinase-like 5 protein, which, together with methyl-CpG-binding protein 2 (MECP2), plays an important role in the regulation of gene expression through methylation. Pathogenic variants in the CDKL5 gene lead to the faulty regulation of gene expression in several genes.
Furthermore, pathogenic variants in the FOXG1 gene have also been identified in female and male patients with a congenital variant of Rett syndrome and also in patients with symptoms of classical Rett syndrome (without pathogenic MECP2 variants). Patients with pathogenic FOXG1 variants show, among other things, variable clinical symptoms associated with severe developmental delay. Genotype-phenotype studies have shown that this patient group always has severe microcephaly (-4 to -6 standard deviations).
Pathogenic variants in the FOXG1 gene have been described in both classic and atypical forms of Rett syndrome, and show considerable clinical heterogeneity. In recent years, several other genes have been discovered in which pathogenic variants have been described that can lead to Rett syndrome-like clinical pictures or courses. In patients with Rett syndrome-like disorders, exome diagnostics may therefore be indicated, which in individual cases can lead to a diagnosis and thus to more accurate statements about the prognosis and the risk of recurrence.
References
Schonewolf-Greulich et al. 2019 Clin Genet 95:221 / Vidal et al. 2019 Eur J Paediatr Neurol / Allou et al. 2016, Clin Genet 91:431 / Le Meur et al. 2010, J Med Genet 47:22 / Tran Mau-Them et al. 2014, Eur J Hum Genet 22:289 / Olson et al. 2015, Am J Med Genet A 167:2017
