Mutations in the X-Linked Cyclin-Dependent Kinase–Like 5 (CDKL5/STK9) Gene Are Associated with Severe Neurodevelopmental Retardation

Max-Planck-Institute for Molecular Genetics, Berlin, Germany.
The American Journal of Human Genetics (Impact Factor: 10.93). 01/2005; 75(6):1149-54. DOI: 10.1086/426460
Source: PubMed


Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene caused mental retardation and severe neurological symptoms in two female patients. Here, we report that de novo missense mutations in CDKL5 are associated with a severe phenotype of early-onset infantile spasms and clinical features that overlap those of other neurodevelopmental disorders, such as Rett syndrome and Angelman syndrome. The mutations are located within the protein kinase domain and affect highly conserved amino acids; this strongly suggests that impaired CDKL5 catalytic activity plays an important role in the pathogenesis of this neurodevelopmental disorder. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, it is tempting to speculate that these two genes play a role in a common pathogenic process.

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Available from: Jozef Gecz,
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    • "Kalscheuer VM et al. [19] found that the normal X chromosome in two females with heterozygous CDKL5 mutations was functionally absent, suggesting CDKL5 located in X gene was subject to inactivation in female somatic cells. Tao et al. [20] showed that variable expression of the wild-type CDKL5 allele was associated with intra-familial phenotypic variability of the disease. However, both Weaving et al. [21] and Evans JC et al. [3] reported that twin sisters with the similar XCI pattern in cells from peripheral blood exhibited completely different clinical features. "
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    ABSTRACT: 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. 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. 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. 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.
    BMC Medical Genetics 02/2014; 15(1):24. DOI:10.1186/1471-2350-15-24 · 2.08 Impact Factor
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    • "specific cortical malformations, metabolic disorders, and mutations of several recently identified genes in the absence of metabolic or structural brain abnormalities that include ARX, CDKL5, SLC25A22, STXBP1, and SPTAN1, among others [4] [5] [6] [7] [8] [9] [10] [11] [12]. Mutations in CDKL5 have been predominantly reported in females with a phenotype characterized by early-onset refractory epilepsy, severe developmental delay, absent or very limited speech, and additional features such as hand stereotypies and postnatal deceleration of head growth in some patients [13] [14] [15] [16] [17] [18]. In a large study, CDKL5 mutations were estimated to occur in approximately 8% of girls with early-onset seizures (before 9 months) and up to 28% of girls with early-onset seizures and infantile spasms [19]. "
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    ABSTRACT: Mutations in CDKL5 and ARX are known causes of early-onset epilepsy and severe developmental delay in males and females. Although numerous males with ARX mutations associated with various phenotypes have been reported in the literature, the majority of CDKL5 mutations have been identified in females with a phenotype characterized by early-onset epilepsy, severe global developmental delay, absent speech, and stereotypic hand movements. To date, only 10 males with CDKL5 mutations have been reported. Our retrospective study reports on the clinical, neuroimaging, and molecular findings of 18 males with early-onset epilepsy caused by either CDKL5 or ARX mutations. These 18 patients include eight new males with CDKL5 mutations and 10 with ARX mutations identified through sequence analysis of 266 and 346 males, respectively, at our molecular diagnostic laboratory. Our large dataset therefore expands on the number of reported males with CDKL5 mutations and highlights that aberrations of CDKL5 and ARX combined are an important consideration in the genetic forms of early-onset epilepsy in boys.
    Pediatric Neurology 05/2013; 48(5):367-77. DOI:10.1016/j.pediatrneurol.2012.12.030 · 1.70 Impact Factor
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    • "In both patients the CDKL5 gene was disrupted by a breakpoint on the X chromosome. Due to some overlapping clinical similarities between the two reported patients and the early seizure variant of Rett syndrome, in the following years, other researchers studied the CDKL5 gene in patients who had been diagnosed with classical or variant Rett and were mutation negative to MECP2 testing, and identified intragenic CDKL5 mutations/deletions in girls with early onset severe seizures (Tao et al., 2004; Weaving et al., 2004; Mari et al., 2005; Scala et al., 2005; Bahi-Buisson et al., 2008a). In the last several years, the large number of patients reported, with detailed description of epilepsy and EEG features, has permitted the delineation of a phenotypic spectrum spanning from milder forms—which include the possibility of autonomous walking and less severe epilepsy that is amenable to control—to severe forms featuring intractable seizures, more severe microcephaly and absence of motor milestones (Table 1). "
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    ABSTRACT: Rett syndrome is an X‐linked neurodevelopmental disorder that manifests in early childhood with developmental stagnation, and loss of spoken language and hand use, with the development of distinctive hand stereotypies, severe cognitive impairment, and autistic features. About 60% of patients have epilepsy. Seizure onset before the age of 3 years is unlikely, and onset after age 20 is rare. Diagnosis of Rett syndrome is based on key clinical elements that identify “typical” Rett syndrome but also “variant” or “atypical” forms. Diagnostic criteria have been modified only slightly over time, even after discovering that MECP2 gene alterations are present in >90% of patients with typical Rett syndrome but only in 50–70% of atypical cases. Over the last several years, intragenic or genomic alterations of the CDKL5 and FOXG1 genes have been associated with severe cognitive impairment, early onset epilepsy and, often, dyskinetic movement disorders, which have variably been defined as Rett variants. It is now clearly emerging that epilepsy has distinctive characteristics in typical Rett syndrome and in the different syndromes caused by CDKL5 and FOXG1 gene alterations. The progressive parting of CDKL5‐ and FOXG1‐gene–related encephalopathies from the core Rett syndrome is reflected by the effort to produce clearer diagnostic criteria for typical and atypical Rett syndrome. Efforts to characterize the molecular pathology underlying these developmental encephalopathies are pointing to abnormalities of telencephalic development, neuronal morphogenesis, maturation and maintenance, and dendritic arborization.
    Epilepsia 12/2012; 53(12). DOI:10.1111/j.1528-1167.2012.03656.x · 4.57 Impact Factor
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