Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rett syndrome (RTT) is a severe neurodevelopmental disorder almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Most patients affected by classic RTT and a smaller percentage of patients with the milder form 'preserved speech variant' have either point mutations or deletions/duplications in the MECP2 gene. Recently, mutations in the CDKL5 gene, coding for a putative kinase, have been found in female patients with a phenotype overlapping with that of RTT. Here, we report two patients with the early seizure variant of RTT, bearing two novel CDKL5 truncating mutations, strengthening the correlation between CDKL5 and RTT. Considering the similar phenotypes caused by mutations in MECP2 and CDKL5, it has been suggested that the two genes play a role in common pathogenic processes. We show here that CDKL5 is a nuclear protein whose expression in the nervous system overlaps with that of MeCP2, during neural maturation and synaptogenesis. Importantly, we demonstrate that MeCP2 and CDKL5 interact both in vivo and in vitro and that CDKL5 is indeed a kinase, which is able to phosphorylate itself and to mediate MeCP2 phosphorylation, suggesting that they belong to the same molecular pathway. Furthermore, this paper contributes to the clarification of the phenotype associated with CDKL5 mutations and indicates that CDKL5 should be analyzed in each patient showing a clinical course similar to RTT but characterized by a lack of an early normal period due to the presence of seizures.
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PMID:CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome. 1591 71

Mutations in the CDKL5 gene (also known as STK9) have recently been shown to cause early onset epilepsy and severe mental retardation (ISSX or West syndrome). Patients with CDKL5 mutations sometimes also show features similar to those seen in Rett Syndrome (RTT). We have screened the CDKL5 gene in 94 patients with RTT or a RTT-like phenotype who had tested negative for MECP2 mutations (13 classical RTT female subjects, 25 atypical RTT female subjects, 40 RTT-like female and 16 RTT-like male subjects; 33 of the patients had early onset seizures). Novel pathogenic CDKL5 mutations were identified in three girls, two of whom had initially been diagnosed with the early onset seizure variant of RTT and the other with early onset seizures and some features of RTT. In addition, the 33 patients with early seizures were screened for the most common mutations in the ARX gene but none were found. Combining our three new cases with the previously published cases, 13/14 patients with CDKL5 mutations presented with seizures before the age of 3 months.
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PMID:Early onset seizures and Rett-like features associated with mutations in CDKL5. 1601 84

We aimed to improve the understanding of genotype-phenotype correlations in Rett syndrome (RS) by adopting a novel approach to categorising phenotypic dimensions - separating typicality of presentation, outcome severity and age of onset - and by classifying MECP2 mutations strictly by predicted functional attributes. MECP2 mutation screening results were available on 190 patients with a clinical diagnosis of RS (140 cases with classic RS, 50 with atypical RS). 135 cases had identified mutations. Of the 140 patients, 116 with classic RS (82.9%) had an identified mutation compared with 19 of 50 patients (38%) with an atypical presentation. Cases with early onset of regression and seizures, and those with clinical features that might indicate alternative aetiologies, were less likely to have mutations. Individuals with late truncating mutations had a less typical presentation than cases with missense and early truncating mutations, presumably reflecting greater residual function of MECP2 protein. Individuals with early truncating mutations had a more severe outcome than cases with missense and late truncating mutations. These findings held when restricting the analysis to cases over 15 years of age and classic cases only. Previous findings of variation in severity among the common mutations were confirmed. The approach to phenotypic and genotypic classification adopted here allowed us to identify genotype-phenotype associations in RS that may aid our understanding of pathogenesis and also contribute to clinical knowledge on the impact of different types of mutations.
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PMID:Dimensional phenotypic analysis and functional categorisation of mutations reveal novel genotype-phenotype associations in Rett syndrome. 1607 36

We describe a clinical profile of a male with Rett syndrome who presented initially with significant axial and peripheral hypotonia, head and truncal titubation and global delay. He is non-ambulatory, lost the few words he had learned and gradually developed hand stereotypes, breathing difficulties, seizures, scoliosis and has osteoporosis sleep problems and sludging in his gall bladder. Prior to diagnosis he underwent comprehensive neurological, metabolic and genetic investigations. After his older sister was diagnosed with atypical Rett syndrome; MECP2 mutation studies on him revealed a pathogenic mutation. His mother is a Rett carrier with a skewed inactivation of chromosome X. Clinical signs and symptoms required to meet the criteria for diagnosis of Rett syndrome have gradually evolved over time. This case demonstrates an unusual family history for Rett syndrome and alerts readers to the utility of screening males for Rett syndrome.
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PMID:Clinical profile of a male with Rett syndrome. 1618 90

Rett syndrome is a leading cause of postnatal neurodevelopmental regression. Rett syndrome is caused by mutations in MECP2, the gene encoding methyl-CpG binding protein 2. In up to 96% of all classic cases, Rett syndrome cases are caused by mutations or deletions in MECP2. The phenotypic spectrum of MECP2 mutations is broad and includes mental retardation with or without seizures, Angelman syndrome-like phenotype, and autism. Mecp308/Y mice carry a truncating mutation and display many of the features seen in Rett syndrome. Social behavior abnormalities and impaired social interactions in Mecp308/Y mice suggest that MeCP2 plays a role in modulating the activity of genes and neurons important for social interactions. Mice that overexpress MeCP2 at twice the endogenous levels develop a progressive neurologic disorder, demonstrating that MeCP2 levels are tightly regulated and raising the possibility that duplications or gain-of-function mutations of MECP2 might underlie some cases of neurodevelopmental X-linked disorders.
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PMID:MeCP2 dysfunction in humans and mice. 1622 28

Rett syndrome is a neurodevelopmental disorder that in most cases is consequent to a mutation in the MECP2 gene. The central nervous system is the primary organ system involved in Rett syndrome. Neurophysiologic evaluations provide information concerning the developmental aspects of Rett syndrome and the character and extent of involvement of the central, peripheral, and autonomic nervous system pathways. Evoked potentials typically demonstrate intactness of peripheral auditory and visual pathways and suggest dysfunction of central or "higher" cortical pathways. Somatosensory evoked potentials can be characterized by "giant" responses, suggesting cortical hyperexcitability. Cortical hyperexcitability is further suggested by the findings of the electroencephalogram (EEG), which are primarily characterized by a loss of expected developmental features; the appearance of focal, multifocal, and generalized epileptiform abnormalities; and the occurrence of rhythmic slow (theta) activity, primarily in the frontal-central regions. Epileptic seizures are reported to occur frequently in Rett syndrome. However, many events presumed to be seizures have no EEG correlate during video-EEG monitoring. Impairment of the autonomic nervous system in Rett syndrome is suggested by an increased incidence of long Q-T intervals during electrocardiographic recordings and diminished heart rate variability. Autonomic nervous system dysfunction can contribute to the increased incidence of sudden unexpected death in Rett syndrome.
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PMID:Neurophysiology of Rett syndrome. 1622 29

A 20-year-old female with an established diagnosis of Rett syndrome was found dead in bed. There had been no history of recent deterioration in health and at autopsy no acute lesions were found. There was no evidence of trauma. Toxicological analysis of blood revealed therapeutic levels of carbamazepine and clonazepam. Death was attributed to the complications of Rett syndrome, an uncommon developmental disorder characterized by autistic type behaviour, hypotonia, stereotyped movements, seizures and growth failure, caused by mutations in the MECP2 gene on the X chromosome. Establishing the precise cause of sudden death in individuals with Rett syndrome may be difficult as epilepsy, defective autonomic nervous system control and cardiac arrhythmias may relate more to functional problems rather than to defects that can be demonstrated at autopsy. Thus, although there are a variety of well-documented underlying mechanisms that may cause sudden death in this condition, determining the exact sequence of events in an unwitnessed death may be more by inference and elimination, given the absence of pathognomonic and acute lethal lesions that are able to be found histopathologically. 'Complications of Rett syndrome' may, therefore, be the most accurate designation when individuals with this condition are found unexpectedly dead and no anatomical cause of death can be identified at autopsy.
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PMID:Forensic issues and possible mechanisms of sudden death in Rett syndrome. 1626 20

X-linked cyclin-dependent kinase-like 5 (CDKL5 or STK9) has recently been implicated in atypical Rett and X-linked West syndromes, severe neurological disorders associated with mental retardation, loss of communication and motor skills and infantile spasms and seizures in predominantly females. Besides CDKL5, these disease phenotypes are also linked to mutations in the MECP2 and ARX genes. Here, we have expressed and characterized CDKL5 and its mutant forms. CDKL5 is a 118 kDa protein that is widely distributed in all tissues, with highest levels in brain, thymus and testes. Whole mount embryo staining reveals CDKL5 to be ubiquitous. Within cells, CDKL5 is localized primarily in the nucleus. Removal of the C-terminal domain increases CDKL5 expression, enhances autophosphorylation activity and causes perinuclear localization, indicating that the C-terminus regulates CDKL5 function. Although we detect MeCP2 but not ARX binding to CDKL5, our results suggest that neither of these proteins are direct substrates of the CDKL5 kinase. Finally, the CDKL5 mutations associated with the disease phenotype cause loss of kinase activity as assessed by autophosphorylation. These results suggest that inactivation of the CDKL5 kinase can lead to severe neurodevelopmental disorders.
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PMID:CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders. 1633 Apr 82

A translocation that disrupted the netrin G1 gene (NTNG1) was recently reported in a patient with the early seizure variant of Rett syndrome (RTT). The netrin G1 protein (NTNG1) has an important role in the developing central nervous system, particularly in axonal guidance, signalling and NMDA receptor function and was a good candidate gene for RTT. We recruited 115 patients with RTT (females: 25 classic and 84 atypical; 6 males) but no mutation in the MECP2 gene. For those 52 patients with epileptic seizure onset in the first 6 months of life, CDKL5 mutations were also excluded. We aimed to determine whether mutations in NTNG1 accounted for a significant subset of patients with RTT, particularly those with the early onset seizure variant and other atypical presentations. We sequenced the nine coding exons of NTNG1 and identified four sequence variants, none of which were likely to be pathogenic. Mutations in the NTNG1 gene appear to be a rare cause of RTT but NTNG1 function demands further investigation in relation to the central nervous system pathophysiology of the disorder.
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PMID:NTNG1 mutations are a rare cause of Rett syndrome. 1650 28

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by cognitive regression, loss of purposeful hand movements and speech, stereotypies, ataxia, seizures, mental retardation and acquired microcephaly. Mutations in MECP2, encoding methyl-CpG-binding protein 2, are responsible for approximately 90% of classic RTT cases. RTT displays phenotypic overlap with Angelman syndrome, a disorder caused by loss of expression of the imprinted gene UBE3A. MeCP2 binds to methylated DNA and may alter the expression of imprinted genes, thereby suggesting a mechanistic link between the two disorders. Here, we tested the hypothesis that MeCP2 deficiency affects expression of Ube3a in mouse models of RTT. As Ube3a is only imprinted in brain, we evaluated Ube3a expression in brains of 15 different litters of neonatal or 8-week-old male Mecp2 mutant mice by real-time quantitative RT-PCR and western blot analysis. We found no significant differences between Mecp2(tm1.1Bird/Y) or Mecp2(tm1.1Jae/Y) mutants and their wild-type male siblings that served as negative controls. In positive control mice carrying a maternally inherited Ube3a deletion, Ube3a sense transcript and protein levels were drastically reduced. Our data contrast with two recent reports of substantially decreased Ube3a expression in brain tissues of MeCP2-deficient mice. We, therefore, challenge the conclusion that decreased UBE3A/Ube3a expression contributes to the pathophysiology of RTT.
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PMID:Ube3a expression is not altered in Mecp2 mutant mice. 1675 45


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