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: 10.99). 01/2005; 75(6):1079-93. DOI: 10.1086/426462
Source: PubMed

ABSTRACT 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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    • "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.
    Neuropharmacology 05/2013; 73. DOI:10.1016/j.neuropharm.2013.05.005 · 4.82 Impact Factor
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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.
    Pediatric Neurology 05/2013; 48(5):367-77. DOI:10.1016/j.pediatrneurol.2012.12.030 · 1.50 Impact Factor
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    • "The CDKL5, encoded by the CDKL5 gene on Xp22, is a serine/threonine kinase of 1030 amino acids [22]. CDKL5 mutations show a severe epileptic encephalopathy that is characterized by intractable seizures with infantile spasms, mental retardation, and a Rett-like phenotype (secondary deceleration of head growth, sleep disturbances, hand apraxia, and stereotypies) [23] [24] [25] [26]. The SLC25A22 gene maps to 11p15.5 and encodes for a mitochondrial glutamate/H + transporter [27]. "
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    ABSTRACT: Early-onset epileptic encephalopathies include various diseases such as early-infantile epileptic encephalopathy with suppression burst. We experimentally investigated the unique clinicopathological features of a 28-month-old girl with early-onset epileptic encephalopathy. Her initial symptom was intractable epilepsy with a suppression-burst pattern of electroencephalography (EEG) from 7days of age. The suppression-burst pattern was novel, appearing during sleep, but disappearing upon waking and after becoming 2months old. The EEG showed multifocal spikes and altered with age. Her seizures demonstrated various clinical features and continued until death. She did not show any developmental features, including no social smiling or head control. Head MRI revealed progressive atrophy of the cerebral cortex and white matter after 1month of age. (123)IMZ-SPECT demonstrated hypo-perfusion of the cerebral cortex, but normo-perfusion of the diencephalon and cerebellum. Such imaging information indicated GABA-A receptor dysfunction of the cerebral cortex. The genetic analyses of major neonatal epilepsies showed no mutation. The neuropathology revealed atrophy and severe edema of the cerebral cortex and white matter. GAD-immunohistochemistry exhibited imbalanced distribution of GABAergic interneurons between the striatum and cerebral cortex. The results were similar to those of focal cortical dysplasia with transmantle sign and X-linked lissencephaly with ARX mutation. We performed various metabolic examinations, detailed pathological investigations and genetic analyses, but could not identify the cause. To our knowledge, her clinical and pathological courses have never been described in the literature.
    Journal of the neurological sciences 02/2013; DOI:10.1016/j.jns.2013.01.038 · 2.26 Impact Factor
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