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

BMC Medical Genetics

Xiru Wu¹  Hong Pan¹  Liping Wei²  Jiarui Li²  Jie Zhang²  Guangna Cao¹  Jingjing Zhang¹  Qingping Zhang¹  Xinhua Bao¹  Xiaoying Zhang¹  Ying Zhao¹ 

[1] Department of Pediatrics, Peking University First Hospital, Beijing 100034, China;National Institute of Biological Sciences, Peking University, Beijing 100871, China

关键词: X chromosome inactivation;    Early-onset epileptic encephalopathy;    CDKL5 mutations;   

Others  :  1122512
DOI  :  10.1186/1471-2350-15-24

 received in 2013-10-17, accepted in 2014-02-12,  发布年份 2014

【 摘 要 】

Background

Mutations 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.

Methods

The 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.

Results

De 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.

Conclusions

Mutations 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.

【 授权许可】

   
2014 Zhao et al.; licensee BioMed Central Ltd.

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