Cyclin dependent kinase like 5 (CDKL5) mutation screening in Rett Syndrome and related clinical disorders

Abstract

Rett Syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females, with an incidence of 1 in 8,000 by 15 yrs of age. The disorder encompasses a wide spectrum of clinical phenotypes. Up to 95% of classical RTT and a lesser proportion (20%-60%) of those with atypical forms of RTT patients carry mutations in the X-linked MECP2 gene (Methyl-CpG binding protein 2), the first gene discovered to be associated with this disorder. Mutations in the X-Iinked CDKL5 gene (cyclin-dependent kinase-like 5) have also been found to cause atypical RTT (in particular, the early onset seizure variant), autism, X-Iinked infantile spasm syndrome (ISSX), intellectual disability and other severe neurological disorders.

This study investigates the speculation that CDKL5 deficiency may underlie a significant proportion of RTT cases that were not linked to MECP2 mutations. It is also investigates the possibility that CDKL5 mutations may lead to other non-RTT syndrome neurological disorders.

The clinical cohort consisted of MECP2 mutation-negative RTT patients (91), males with X-Iinked mental retardation (8), patients with ISSX (52), patients with autism (59) and other patients with intellectual disability with or without seizures (39). The 21 coding exons of CDKL5 were screened by Denaturing High Performance Liquid Chromatography and direct sequencing.

In all, six polymorphic variations and one probably pathogenic mutation were identified, accounting for 46 of the 249 patients in this cohort (17%). Each individual identified with a variation had the clinical feature of seizures. Based on other studies, it appears that the key feature that points to a CDKL5 mutation will be the presence of severe early onset seizures, particularly infantile spasms. The results of mutation screening in this cohort lead us to conclude that pathogenic CDKL5 mutations are unlikely to be identified in neurological disorders unless a RTT-like phenotype with severe early-onset seizures are present.