CDKL5 mutations in early epileptic encephalopathy and in atypical forms of Rett syndrome

Abstract

Rett syndrome (RTT, MIM #312750) is a neurodevelopmental disorder defined by a distinct set of clinical features, notably a regression that robs the affected individuals of spoken language and volitional hand use [1]. Additionally, affected people develop characteristic hand stereotypies that are classically wringing or washing in nature, although they make take on a variety of forms such as clapping, finger rubbing, or hand mouthing. Gait is also impaired or absent: Those who can walk display a characteristic dyspraxic gait. Most affected individuals are girls, which is one of the features that lead to the discovery of the genetic cause for the majority of cases, mutations in Methyl-CpG-Binding Protein 2 (MECP2) [2]. Ninety-five percent of people who fulfill the clinical criteria for typical, or classic RTT have mutations in MECP2 [3]. In addition to the defining clinical characteristics outlined above, people with typical RTT have a number of additional clinical features such as irregular awake breathing patterns, growth failure, sleep disruption, dystonia, and scoliosis. The majority of individuals have seizures at some point in their life and have grossly abnormal electroencephalograms. Seizure onset is typically in school age and is very rare amongst infants. In contrast to the pattern of seizures found in people with typical RTT, a subset of individuals have been identified who have some features of RTT but have severe, early-onset epilepsy [4]. Mutations in MECP2 are not typically found in these variants, which have been termed early seizure variant [1]. In the last couple of years mutations in a different genetic locus, Cyclin dependent kinase 2 (CDKL5), have been identified in people with severe infantile epilepsy with infantile spasms and early infantile epileptic encephalopathy (EIEE2, MIM#300672), some of whom have also been characterized as having the early seizure variant of RTT [5,6]. In this issue of Journal of Pediatric Epilepsy, Martinez et al. [7] describe a Spanish experience looking for CDKL5 mutations in a cohort of people characterized as having atypical RTT but lacking mutations in MECP2. They screened 53 of the collection of 150 people lacking MECP2 mutations and found de novo genetic changes in eight individuals. Seven of the eight individuals presented had relatively early onset of seizures (between 25 days and 3 yr), however, this is a later and more variable presentation of seizure onset than has been previously reported, with seizures typically starting in the first 1-3 mo of life [8,9]. The authors also attempt *Address for correspondence: Jeffrey L. Neul, Duncan Neurological Research Institute, 1250 Moursund Street, Suite 1250.018, Houston, TX 77030, USA. Tel.: +1 832 824 8808; Fax: +1 832 824 8858; E-mail: jneul@bcm.edu. Journal of Pediatric Epilepsy 1 (2012) 3–4 DOI 10.3233/PEP-2012-002 IOS Press 3