Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014544 (epilepsy)
 64,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. 1549 25

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

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

Symptomatic West syndrome has heterogeneous backgrounds. Recently, two novel genes, ARX and CDKL5, have been found to be responsible for cryptogenic West syndrome or infantile spasms. Both are located in the human chromosome Xp22 region and are mainly expressed and play roles in fetal brain. Moreover, several genes responsible for brain malformations including lissencephaly, which is frequently associated with West syndrome or infantile spasms, have been found, and the mechanisms responsible for the neural network disorders in these brain malformations are rapidly being determined. Findings of animal and in vitro studies and mutation analyses in humans are delineating the molecular and cellular basis of West syndrome. Mutations of the ARX gene controlling the development of GABAergic interneurons exhibit pleiotropic effects including lissencephaly with a strong genotype-phenotype correlation. An expansion mutation of the first polyalanine tract of ARX is more strongly related to infantile spasms than is that of the second polyalanine tract. Although the phenotype of CDKL5 mutation is similar to Rett syndrome caused by MECP2 mutation, the former is characterized by early-onset seizures and association with West syndrome. Lissencephaly caused by LIS1 or DCX mutation frequently results in West syndrome, while lissencephaly due to ARX mutation is associated with the most severe form of epilepsy but never results in West syndrome nor infantile spasms. Both LIS1 and DCX participate in the development of GABAergic interneurons as well as pyramidal neurons, while ARX participates only in that of interneurons. Individuals with lissencephaly due to ARX mutation lack non-pyramidal or GABAergic interneurons. ARX is crucial for the development of GABAergic interneuron, so abnormal interneurons in patients with ARX mutation are thought to be implicated in the pathological mechanism, even though brain MRI is normal. Abnormal interneurons appear to play an essential role in the pathogenesis of West syndrome or infantile spasms, which can be considered an interneuronopathy.
Epilepsy Res 2006 Aug
PMID:A new paradigm for West syndrome based on molecular and cell biology. 1680 28

The CDKL5 gene has been implicated in infantile spasms and more recently in a Rett syndrome-like phenotype. We report a case of a young girl presenting generalized convulsions at 10 days of life. Subsequent mutation analysis by denaturing high-performance liquid chromatography of MECP2 and CDKL5 genes revealed heterozygosity for a c.47_48insAGG insertion in exon 1 of MECP2 and heterozygosity for a new nonsense mutation p.Q834X and a new missense variant p.V999M in the CDKL5 gene. Co-segregation analysis showed that the nonsense mutation was a de novo mutation and that the insertion and the missense variant were also found in the asymptomatic mother. In the absence of skewed X inactivation in the mother, it is likely that these last two variants are not pathogenic. Reverse transcription-polymerase chain reaction from lymphoblastoid cells of the patient showed only the transcript without the nonsense and missense variations suggesting decreased stability of mature mRNA by nonsense-mediated decay. These data also suggest an occurrence of the de novo mutation in maternal germ line cells. Moreover, this report reinforces the observation that the CDKL5 phenotype overlaps with Rett syndrome and that CDKL5 gene analysis is recommended in females with a seizure disorder commencing in the first weeks of life.
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PMID:Maternal origin of a novel C-terminal truncation mutation in CDKL5 causing a severe atypical form of Rett syndrome. 1681

Studying infantile spasms is challenging because there are so many aspects of variation that introduce potential bias. These might relate to the many underlying etiologies, and variations in clinical semiology and electroencephalographic features that relate more to age or timing of investigation than to the underlying epilepsy or seizures type. New gene defects associated with the CDKL5/STK9 and ARX genes are associated with infantile spasms, but these illustrate that, when studying neurodevelopmental outcomes, it is necessary to deal also with heterogeneity at the level of genotype-phenotype correlation. We discuss these design issues with consideration of data from the United Kingdom infantile spasms study (UKISS)--in which neurodevelopmental outcomes show evidence of an interaction between underlying etiologic classification and randomised treatment--and with consideration to proposals on study design from the recent consensus statement of the West Delphi group. In the continual debate about whether we should "lump" or "split" when studying epilepsy syndromes, we propose the adoption of study designs using valid and consistent methods that permit both lumping and splitting.
Epilepsy Res 2006 Aug
PMID:The influence of etiology upon ictal semiology, treatment decisions and long-term outcomes in infantile spasms and West syndrome. 1682 60

Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been shown to cause infantile spasms as well as Rett syndrome-like phenotype. To date, fewer than 20 different mutations have been reported. So far, no clear genotype-phenotype correlation has been established. We screened the entire coding region of CDKL5 in 151 affected girls with a clinically heterogeneous phenotype ranging from encephalopathy with epilepsy to atypical Rett syndrome by denaturing high liquid performance chromatography and direct sequencing, and we identified three novel missense mutations located in catalytic domain (p.Ala40Val, p.Arg65Gln, p.Leu220Pro). Segregation analysis showed that p.Arg65Gln was inherited from the healthy father, which rules out the involvement of CDKL5 in the aetiology of the phenotype in this patient. However, the de novo occurrence was shown for p.Ala40Val and p.Leu220Pro. The p.Ala40Val mutation was observed in two unrelated patients and represented the first recurrent mutation in the CDKL5 gene. For the two de novo mutations, we analysed the cellular localisation of the wild-type and CDKL5 mutants by transfection experiments. We showed that the two CDKL5 mutations cause mislocalisation of the mutant CDKL5 proteins in the cytoplasm. Interestingly these missense mutations that result in a mislocalisation of the CDKL5 protein are associated with severe developmental delay which was apparent within the first months of life characterised by early and generalised hypotonia, and autistic features, and as well as early infantile spasms.
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PMID:Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy. 1799 79

Clinical features and electroencephalographic findings of two patients affected by a previously unreported cyclin-dependent kinase-like 5 (CDKL5) gene mutation are described. Both patients had the Hanefeld variant phenotype with early-onset seizures, but different degrees of clinical severity. In fact, patient 1 was not drug-resistant and is responding to a single drug. On the contrary, patient 2, like most reported cases, has severe epilepsy, exhibits electroencephalographic changes, and is drug resistant. We suggest that the pseudoperiodic patterns observed on the EEGs for these cases represent this genetic form of epilepsy, though differing in frequency, voltage, and associated patterns. This is in agreement with data reported by other authors indicating that no unique pattern can be identified in subjects with CDKL5 mutations. Thus, a CDKL5 investigation should be performed in developmentally delayed patients with early-onset seizures, including drug-resistant subjects with severe EEG changes, as well as in patients with milder, drug-responsive forms of epilepsy.
Epilepsy Behav 2008 Feb
PMID:Clinical and electroencephalographic features in patients with CDKL5 mutations: two new Italian cases and review of the literature. 1806 13

Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been shown to cause infantile spasms as well as Rett syndrome (RTT)-like phenotype. To date, less than 25 different mutations have been reported. So far, there are still little data on the key clinical diagnosis criteria and on the natural history of CDKL5-associated encephalopathy. We screened the entire coding region of CDKL5 for mutations in 183 females with encephalopathy with early seizures by denaturing high liquid performance chromatography and direct sequencing, and we identified in 20 unrelated girls, 18 different mutations including 7 novel mutations. These mutations were identified in eight patients with encephalopathy with RTT-like features, five with infantile spasms and seven with encephalopathy with refractory epilepsy. Early epilepsy with normal interictal EEG and severe hypotonia are the key clinical features in identifying patients likely to have CDKL5 mutations. Our study also indicates that these patients clearly exhibit some RTT features such as deceleration of head growth, stereotypies and hand apraxia and that these RTT features become more evident in older and ambulatory patients. However, some RTT signs are clearly absent such as the so called RTT disease profile (period of nearly normal development followed by regression with loss of acquired fine finger skill in early childhood and characteristic intensive eye communication) and the characteristic evolution of the RTT electroencephalogram. Interestingly, in addition to the overall stereotypical symptomatology (age of onset and evolution of the disease) resulting from CDKL5 mutations, atypical forms of CDKL5-related conditions have also been observed. Our data suggest that phenotypic heterogeneity does not correlate with the nature or the position of the mutations or with the pattern of X-chromosome inactivation, but most probably with the functional transcriptional and/or translational consequences of CDKL5 mutations. In conclusion, our report show that search for mutations in CDKL5 is indicated in girls with early onset of a severe intractable seizure disorder or infantile spasms with severe hypotonia, and in girls with RTT-like phenotype and early onset seizures, though, in our cohort, mutations in CDKL5 account for about 10% of the girls affected by these disorders.
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PMID:Key clinical features to identify girls with CDKL5 mutations. 1879 Aug 21

Mental retardation is a serious social problem. It affects 2-3% of the population. It is estimated that mutations in the ARX gene can be found in 1 in 12,000 live male births. This is the second most common cause of X-linked mental retardation after fragile X syndrome. The ARX gene belongs to transcription factors involved in differentiation of specific neuronal cells in the central nervous system. The most common mutation in the ARX gene is c. 428_451dup24, duplication of 24 bp in exon 2 of the gene, causing elongation of the second alanine tract (polyA12_II). Described disorders caused by mutations in the ARX gene include: hydrocephaly with abnormal genitalia (HYD-AG), lissencephaly with abnormal genitalia (XLAG), agenesis of corpus callosum with abnormal genitalia (ACC-AG), Partington syndrome (PRTS), X-linked infantile spasms (ISSX), myoclonic epilepsy with spasticity and mental retardation (XMESID), and nonspecific mental retardation (NS-XLMR).
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PMID:[ARX--one gene--many phenotypes]. 1897 39


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