J Med Genet. 2006 Apr 12; [Epub ahead of print]
CDKL5 mutations cause infantile spasms, early onset seizures and severe mental retardation in female patients
Archer HL, Evans JC, Edwards S, Colley J, Newbury-Ecob R, O'callaghan F, Huyton M, O' Regan M, Tolmie J, Sampson J, Clarke AJ, Osborne J.
Cardiff University, University Hopital of Wales, Cardiff, UK
Abstract
INTRODUCTION: Studies of the CDKL5 gene have focussed on patients with atypical Rett syndrome. Our aim was to ascertain the frequency of mutations in CDKL5 in both male and female patients with Infantile Spasms (IS) or early onset epilepsy of unknown cause, and to consider whether the breadth of the reported phenotype would be extended by studying this additional patient group. METHODS: Two groups of patients were investigated for CDKL5 mutations. Group 1 comprised 73 patients (57 females, 16 males) referred for CDKL5 analysis, of which 49 (42 females, 7 males) had epileptic seizure onset in the first 6 months of life. Group 2 was composed of 56 patients (23 females, 33 males) with infantile spasms (IS) previously recruited to a clinical trial, the UK Infantile Spasms Study. Where a likely pathogenic mutation was identified, further clinical data were reviewed. RESULTS: Seven likely pathogenic mutations were found amongst female patients from group 1 with epileptic seizure onset on the first 6 months of life, accounting for 7/42 (17%) of this group. No further mutations, other than the already published mutation, were found in female patients from group 2 nor in any male patients from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information was available for 6 PATIENTS: autistic features and tactile hypersensitivity were common but only one had Rett-like features. All had a severe epileptic seizure disorder, all but one having myoclonic jerks. The EEG showed focal or generalised changes and, in those with IS, hypsarrhythmia. Slow frequencies were seen frequently with a frontal or fronto-temporal predominance and high amplitudes. CONCLUSIONS: The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported. CDKL5 mutations are a significant cause of IS and early epileptic seizures in female patients and a later intractable seizure disorder, irrespective of whether they have suspected Rett syndrome, and analysis should be considered in these patients in the clinical setting.
Lay Summary
Mutations in the CDKL5 gene were initially found in two female patients with severe mental retardation and infantile spasms (IS) - a severe seizure disorder that usually starts early in life. Subsequently, CDKL5 mutations were further identified in patients with suspected Rett Syndrome. Thus, recent studies on CDKL5 have centred on atypical Rett Syndrome patients. However, the aim of this study was to assess the frequency of CDKL5 mutations by looking beyond atypical Rett Syndrome, and examine males and females with IS or early onset epilepsy of unknown cause.
Within 49 patients (42 females, 7 males) with epileptic seizure onset in the first 6 months of life, and 56 patients (56 patients (23 females, 33 males) with IS, CDKL5 mutations were found in a significant number of these patients. The main findings of this paper are the realization that the variety of epileptic seizure disorders associated with CDKL5 mutations is broader than previously reported. The data suggests that CDKL5 mutations are a common cause of severe mental retardation and early seizures in female patients, and that while CDKL5 mutations may be found in male patients, their occurrence is rare.