Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients

Abstract

BackgroundMutations in the cyclin-dependent kinase-like 5 (CDKL5) (NM_003159.2) gene have been associated with early-onset epileptic encephalopathies or Hanefeld variants of RTT(Rett syndrome). In order to clarify the CDKL5 genotype-phenotype correlations in Chinese patients, CDKL5 mutational screening in cases with early-onset epileptic encephalopathies and RTT without MECP2 mutation were performed.MethodsThe detailed clinical information including clinical manifestation, electroencephalogram (EEG), magnetic resonance imaging (MRI), blood, urine amino acid and organic acid screening of 102 Chinese patients with early-onset epileptic encephalopathies and RTT were collected. CDKL5 gene mutations were analyzed by PCR, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). The patterns of X-chromosome inactivation (XCI) were studied in the female patients with CDKL5 gene mutation.ResultsDe novo CDKL5 gene mutations were found in ten patients including one missense mutation (c.533G > A, p.R178Q) which had been reported, two splicing mutations (ISV6 + 1A > G, ISV13 + 1A > G), three micro-deletions (c.1111delC, c.2360delA, c.234delA), two insertions (c.1791 ins G, c.891_892 ins TT in a pair of twins) and one nonsense mutation (c.1375C > T, p.Q459X). Out of ten patients, 7 of 9 females with Hanefeld variants of RTT and the remaining 2 females with early onset epileptic encephalopathy, were detected while only one male with infantile spasms was detected. The common features of all female patients with CDKL5 gene mutations included refractory seizures starting before 4 months of age, severe psychomotor retardation, Rett-like features such as hand stereotypies, deceleration of head growth after birth and poor prognosis. In contrast, the only one male patient with CDKL5 mutation showed no obvious Rett-like features as females in our cohort. The X-chromosome inactivation patterns of all the female patients were random.ConclusionsMutations in CDKL5 gene are responsible for 7 with Hanefeld variants of RTT and 2 with early-onset epileptic encephalopathy in 71 girls as well as for 1 infantile spasms in 31 males. There are some differences in the phenotypes among genders with CDKL5 gene mutations and CDKL5 gene mutation analysis should be considered in both genders.

Brief Report: Systematic Review of Rett Syndrome in Males

“…The first case of a male reported with RTT was published in 1989 (Gillberg 1989) and the most recent publication included one case in 2014 (Zhao et al 2014). Prior to 1999-the year in which the MECP2 mutation was implicated in female cases of RTTa total of eight male cases had been reported.…”

“…In 1999, a mutation to the Metyl-CpG-binding protein 2 (MECP2) gene was identified as a biomarker for RTT (Amir et al 1999), and Neul et al reported that, ''[when] using a battery of modern mutation detection assays, mutations in MECP2 can be found in 95 to 97 % of individuals with typical RTT'' (Neul et al 2010, p. 945). Since locating the MECP2 biomarker for RTT, other genetic mutations have been suggested as being implicated in RTT including the FOXG1 (Van der Aa et al 2010;Le Guen et al 2011;Kumakura et al 2013) and CDKL5 (Scala et al 2005;Sartori et al 2009;Zhao et al 2014). Mutation of the MECP2 gene was previously thought to be fatal for males given its location on the X chromosome (cf., Hagberg et al 1983;Trevathan 1989;Wan et al 1999).…”

The eye-tracking of social stimuli in patients with Rett syndrome and autism spectrum disorders: a pilot study

“…The empirical observation of RS patients points to a relative preservation of social domain, as they have a very intense look and somehow respond to social stimuli. The etiology of RS has strongly been associated with mutations in MECP2 gene 2,3,4 , and more recently with alterations in CDKL5 and FOGX1 in some cases 5,6 . Although it has been ABSTRACT Objective: To compare visual fixation at social stimuli in Rett syndrome (RT) and autism spectrum disorders (ASD) patients.…”

Somatic mosaicism of a CDKL5 mutation identified by next-generation sequencing

“…CDKL5-related encephalopathy has been reported to account for 3-6% of EIEE in male individuals [5,10]. In male patients, CDKL5-related encephalopathy with somatic mosaicism was more common than with germline mutation [5].…”