Atypical Rett syndrome was first described in 1985 in a girl with BNS seizures with a very similar clinical course to classical Rett syndrome. To date, these patients have been mainly characterized by an early-onset therapy-resistant epilepsy and, in the later course, by severe psychomotor developmental retardation. In addition to BNS seizures, other seizure types may occur. The EEG is not typical but depends on age and the seizure type. Unlike Rett syndrome, there is no initial phase of seemingly normal development.
The diagnostic criteria according to Artuso et al. (2010) are:
- inconspicuous prenatal development
- irritability, vigilance disturbance, and sucking weakness in the early postnatal period 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 retardation
- severe hypotonia
Since 2005, it is 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 plays an important role in the regulation of gene expression by methylation together with the Methyl-CpG-Binding Protein 2 (MECP2). Pathogenic variants in the CDKL5 gene lead to misregulation of gene expression in several genes.
Furthermore, pathogenic variants in the FOXG1 gene were later 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 variant). Patients with pathogenic FOXG1 variants show a variable clinical presentation associated with severe developmental delay among other symptoms. Genotype-phenotype studies have shown that severe microcephaly (-4 to -6 standard deviations) is always present in this group of patients.
The FOXG1 gene product is a transcriptional repressor expressed in neural precursor cells of the developing neuroepithelium. Based on data collected to date, it can be predicted that FOXG1 haploinsufficiency leads to microcephaly, a thin cortex with abnormal cortical architecture, and consequent cognitive and developmental deficits.
Olson et al. 2019, Pediatr Neurol. / Mitter et al. 2018, Genet Med 20:8 / Takahashi et al. 2018, J Pediatr Epilepsy 07:001 / Allou et al. 2012, Eur J of Hum Genet 20:1216 / Kortüm et al. 2011, J Med Genet 48:396 / Artuso et al. 2010, Brain Dev 32:17 / Saletti et al. 2009, Am J Med Genet A 149A:1046 / Grosso et al. 2007, Brain Dev 29:239 / Bertani et al. 2006, J Biol Chem 42:32048 / Archer et al. 2006, J Med Genet 43:729 / Scala et al. 2005, J Med Genet 42:103 / Weaving et al. 2004, Am J Hum Genet 75:1079 / Goutieres et al. 1986, Am J Med Genet Suppl 1:183 / Hanefeld 1985, Brain Dev 7:320