RETT syndrome

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CDKL5

The CDKL5 gene (also called STK9) is located on the X chromosome. In 2003, two patients affected by West syndrome were found to have an abnormal CDKL5 gene because of the presence of a chromosomal rearrangement in her cells (Kalscheuer et al. 2003). West syndrome patients suffer from intellectual disability and early epilepsy.  CDKL5 became the second gene involved in West syndrome in addition to the ARX gene that was already known to cause this disease.  The following year, in 2004, two studies published simultaneously have identified mutations in the CDKL5 gene in patients sharing clinical signs with Rett syndrome patients (Tao et al. 2004; Weaving et al. 2004). An italian group will describe in 2005 mutations in the CDKL5 gene in a variant form of Rett syndrome with early epilepsy (Scala et al. 2005). Several subsequent studies will confirm this finding. However, the clinical picture of the children carrying a mutation in the CDKL5 gene is only partially overlapping with that of classical Rett syndrome (Bahi-Buisson et al. 2008). The normal neonatal period is usually absent together with the typical, intense, «eye pointing» of Rett syndrome girls.


The CDKL5 protein is a kinase. It seems that this protein could be able to phosphorylate MECP2, at least in vitro (Mari et al. 2005), but these findings have not been confirmed in vivo. A role for CDKL5 in the splicing machinery was also described (Ricciardi et al. 2009). More recently, CDKL5 was found to be an important protein for normal neuronal morphology (Chen et al. 2010).


Several authors question the classification of patients mutated for CDKL5 in the group of «rett syndrome» patients. Rather, they propose that these children suffer from a different disease (Fehr et al. 2013).


Two CDKL5 family associations exist at the following location, in Italy (click here) or in the USA (click here).

FOXG1

The Foxg1 gene was identified in 1994. It is an important gene for brain development, specifically for the first differentiated neurons in the cerebral cortex (Hanashima et al. 2004; Manuel et al. 2010).


Before it was shown to be responsible for a variant form of Rett syndrome, defects of the FOXG1 gene had been described in 2005 in patients with severe intellectual disability, cerebral malformations and microcephaly (Shoichet et al. 2005). The involvement of FOXG1 in a variant form of Rett syndrome was published in 2008 (Ariani et al. 2008), in children affected by the congenital variant of Rett syndrome. This discovery was made possible by the previous finding of a chromosomal rearrangement involving the FOXG1 gene in a patient with clinical signs overlapping that of Rett syndrome (Papa et al. 2008).

The key message is that mutations in CDKL5 or FOXG1 are a RARE cause of Rett syndrome and that the clinical phenotype of these patients is somewhat different from that of classical Rett syndrome patients.