Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation

Western Sydney Genetics Program, the Children's Hospital at Westmead, New South Wales, Australia.
The American Journal of Human Genetics (Impact Factor: 10.93). 01/2005; 75(6):1079-93. DOI: 10.1086/426462
Source: PubMed


Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G-->A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps--but is not identical to--that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.

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    • "All the mutations are proved to be de novo, and no mutations are further detected in their parents. Among the detected mutations in this paper, p.R178Q carried by a boy and a splicing mutation IVS6 + 1G > A carried by a girl are reported previously [3,4,16,21]. "
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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.
    Full-text · Article · Feb 2014 · BMC Medical Genetics
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    • "Since we also reported a significant reduction of cocaine self-administration following HDAC inhibition (Romieu et al., 2008), the interaction between Mecp2 and HDAC in transcriptional repression (Jones et al., 1998; Nan et al., 1998) may play a preponderant role in cocaine-induced behavior. On the other hand, MeCP2 mutations are known to cause Rett syndrome (Amir et al., 1999), a leading cause of mental retardation and autistic behavior in females, while CDKL5 mutations are associated with its " early-onset seizure " variant (Weaving et al., 2004). We identified CDKL5 as a Mecp2-target gene repressed by DNA methylation in response to cocaine (Carouge et al., 2010) and the role of Mecp2 in its repression recently confirmed (Kilstrup-Nielsen et al., 2012) has shed new light into the mechanism by which mutations within two genes are leading to closely related syndromes with overlapping neurological symptoms . "
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    ABSTRACT: Repeated cocaine exposure induces epigenetic factors such as DNA methyl-binding proteins, indicating that resulting changes in gene expression are mediated by alterations in brain DNA methylation. While the activity of protein phosphatase type-1 (PP1) is involved in cocaine effects and in brain plasticity, the expression of the PP1Cβ catalytic subunit gene was identified here as modulated by cocaine. Its expression was induced together with that of PP1Cγ in the brain of Methyl-CpG Binding Protein-2 (Mecp2) mutant mice, whereas PP1α expression was not affected, illustrating a different regulation of PP1C isoforms. Repeated cocaine administration was found to increase DNA methylation at the PP1Cβ gene together with its binding to Mecp2 in rat caudate putamen, establishing a link between two genes involved in cocaine-related effects and in learning and memory processes. Cocaine also increased DNMT3 expression, resulting in PP1Cβ repression that did not occur in the presence of DNMT inhibitor. Cocaine-induced PP1Cβ repression was observed in several brain structures, as evaluated by RT-qPCR, immunohistochemistry and Western blot, but did not occur after a single cocaine injection. Our data demonstrate that PP1Cβ is a direct MeCP2-target gene in vivo. They suggest that its repression may participate to behavioral adaptations triggered by the drug.
    Full-text · Article · May 2013 · Neuropharmacology
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    • "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]. Mutations in males, on the other hand, appear less common, having been reported in 10 boys to date with a more severe phenotype characterized by early-onset tonic and myoclonic seizures, intractable infantile spasms, severe global developmental delay, cortical visual impairment, sleep disturbances, and hand stereotypies in some patients [13] [20] [21] [22] [23] [24] [25]. ARX was the first gene implicated in nonsyndromic early-onset epilepsy and has been associated with a wide spectrum of developmental disorders with and without brain malformations. "
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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.
    Full-text · Article · May 2013 · Pediatric Neurology
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