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Rett Syndrome, atypical; Early Infantile Epileptic Encephalopathy-2 (EIEE2) [F84.9]

OMIM numbers: 312750, 300203 (CDKL5), 613454, 164874 (FOXG1)

Dr. rer. biol. hum. Soheyla Chahrokh-Zadeh

Scientific Background

The atypical Rett syndrome is an X chromosomal dominant disease, which was first seen in 1985 in a girl displaying BNS seizures and, in the on-going course, signs and symptoms very similar to the classical Rett syndrome. The literature characterized 43 patients until 2009, all of them displaying therapy-resistant epilepsy at a young age as well as severe psychomotor developmental delay in the on-going course. Other forms of seizures besides BNS seizures are seen as well; there are no typical EEG findings, but rather they depend on age and type of seizure. In contrast to the Rett syndrome, there is no early stage with seemingly normal development.

The diagnostic criteria according to Artuso et al. (2010) are:

  • Normal prenatal development
  • Irritability, vigilance impairment, sucking problems in early postnatal phase, prior to the start of first epileptic seizures
  • Epilepsy during early childhood, onset between the first week and fifth month
  • Stereotypic hand movements
  • Severe psychomotor developmental delay
  • Severe hypotonia

In 2005 it was found out that the cause of this type of atypical Rett syndrome is mutations in the CDKL5 gene (Xp22). The CDKL5 gene encodes the Cyclin Dependent Kinase-like 5 protein which, along with the methyl-CpG-Binding protein 2 (MECP2) plays a major role in the regulation of gene expression by methylation. Mutations in the CDKL5 gene lead to erroneous regulation of expression of various genes.

Furthermore mutations in the FOXG1 gene were detected in male and female patients with a congenital variant of Rett syndrome, but also in females with the classic Rett syndrome (without MECP2 mutations). Patients with mutations in the FOXG1 gene exhibit clinical symptoms that overlap with a severe developmental encephalopathy, however, with a very heterogeneous phenotype. In studies of genotype-phenotype correlation it was shown that this group of patients always have a severe microcephaly (-4 to -6 standard deviations).

The gene product of FOXG1 acts as a transcriptional repressor which is expressed in neural precursors in the developing neural epithelium. Concluding from the data known so far a FoxG1 haploinsufficiency results in microcephaly and a thin cortex with abnormal cortical architecture thereby causing developmental delay and cognitive impairment.