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)

Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been detected in patients presenting with seizures in the first few months of life and Rett syndrome features. Twenty-seven cases have been detected to date. Generalized intractable seizures, as infantile spasms, and generalized tonic-clonic seizures and myoclonic seizures characterize the clinical picture of CDKL5 mutations. Here we report on a patient who presented with sleep-related hyperkinetic seizures. Our observation and review of the literature suggest that a broader polymorphic electroclinical pattern with both generalized and focal seizures may occur in patients with CDKL5 mutations. A screen for CDKL5 mutations is useful in patients, mainly females, with a history of early onset intractable seizures and becomes mandatory when idiopathic infantile spasms and/or atypical Rett syndrome features are also present.
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PMID:Seizures and electroencephalographic findings in CDKL5 mutations: case report and review. 1704 93

Rett syndrome is the second most common cause of severe mental retardation in females, with an incidence of approximately 1 out of 10,000 live female births. In addition to the classic form, a number of Rett variants have been described. MECP2 gene mutations are responsible for about 90% of classic cases and for a lower percentage of variant cases. Recently, CDKL5 mutations have been identified in the early onset seizures variant and other atypical Rett patients. While the high percentage of MECP2 mutations in classic patients supports the hypothesis of a single disease gene, the low frequency of mutated variant cases suggests genetic heterogeneity. Since 1998, we have performed clinical evaluation and molecular analysis of a large number of Italian Rett patients. The Italian Rett Syndrome (RTT) database has been developed to share data and samples of our RTT collection with the scientific community (http://www.biobank.unisi.it). This is the first RTT database that has been connected with a biobank. It allows the user to immediately visualize the list of available RTT samples and, using the "Search by" tool, to rapidly select those with specific clinical and molecular features. By contacting bank curators, users can request the samples of interest for their studies. This database encourages collaboration projects with clinicians and researchers from around the world and provides important resources that will help to better define the pathogenic mechanisms underlying Rett syndrome.
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PMID:Italian Rett database and biobank. 1718 95

We describe a male patient with a deletion at Xp22, detected by high resolution X-array CGH. The clinical phenotype present in this infant boy, consists of severe encephalopathy, congenital cataracts and tetralogy of Fallot and can be attributed to the deletion of the genes within the interval. Among these deleted genes are the gene for Nance-Horan syndrome and the cyclin-dependent kinase-like 5 gene (CDKL5), responsible for the early seizure variant of Rett syndrome. This is the first description of a male patient with a deletion of these genes, showing the involvement of CDKL5 in severe epileptic encephalopathy in males. Moreover it illustrates the added value of high resolution array-CGH in molecular diagnosis of mental retardation-multiple congenital anomaly cases.
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PMID:Encephalopathy and bilateral cataract in a boy with an interstitial deletion of Xp22 comprising the CDKL5 and NHS genes. 1725 98

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.
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PMID:Clinical and electroencephalographic features in patients with CDKL5 mutations: two new Italian cases and review of the literature. 1806 13

Since it was first described by Andrea Rett 50 years ago, Rett syndrome (RS) has been the subject of further investigations, nonetheless it continues to be a not well known condition. Our own experience and an updated literature review on RS is presented. RS is a severe dominant X chromosome-linked neurodevelopmental disorder with a characteristic clinical picture that mostly occurs in girls, most of the cases are sporadic and genetically determined. The diagnosis of RS is made based on observation and clinical assessment. Main clinical features are mental retardation, behavioural changes, stereotypes, loss of speech and hand skills, gait apraxia, irregular breathing with hyperventilation while awake, and frequent seizures. The internationally established criteria are reviewed. RS is caused by mutations in MECP2 in the majority of cases, but a proportion of atypical cases may result from mutations in CDKL5, particularly the early onset seizure variant. However, the molecular pathogenesis of this disorder remains unclear, as well as the relation between the mutations in MECP2 and other neurodevelopmental disorders. Neuroimaging, neuropathological and biochemical findings in RS are reviewed. Besides symptomatic treatment, no therapeutic trials have shown effectiveness. Some perspectives in the treatment of RS have been provided by a recent work showing a phenotypic reversal by activation of MeCP2 expression in a mouse model.
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PMID:[Rett syndrome: 50 years' history of a still not well known condition]. 1842 79

Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome (RTT), West syndrome, and X-linked infantile spasms, sharing the common feature of mental retardation and early seizures. CDKL5 is a rather uncharacterized kinase, but its involvement in RTT seems to be explained by the fact that it works upstream of MeCP2, the main cause of Rett syndrome. To understand the role of this kinase for nervous system functions and to address if molecular mechanisms are involved in regulating its distribution and activity, we studied the ontogeny of CDKL5 expression in developing mouse brains by immunostaining and Western blotting. The expression profile of CDKL5 was compared with that of MeCP2. The two proteins share a general expression profile in the adult mouse brain, but CDKL5 levels appear to be highly modulated at the regional level. Its expression is strongly induced in early postnatal stages, and in the adult brain CDKL5 is present in mature neurons, but not in astroglia. Interestingly, the presence of CDKL5 in the cell nucleus varies at the regional level of the adult brain and is developmentally regulated. CDKL5 shuttles between the cytoplasm and the nucleus and the C-terminal tail is involved in localizing the protein to the cytoplasm in a mechanism depending on active nuclear export. Accordingly, Rett derivatives containing disease-causing truncations of the C terminus are constitutively nuclear, suggesting that they might act as gain of function mutations in this cellular compartment.
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PMID:CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail. 1870 57

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

Mutations of the cyclin-dependent kinase-like 5 gene (CDKL5), reported almost exclusively in female subjects, have been recently found to be the cause of a phenotype overlapping Rett syndrome with early-onset epileptic encephalopathy. We describe the first CDKL5 mutation detected in a male individual with 47,XXY karyotype. This previously unreported, de novo, mutation truncates the large CDKL5 COOH-terminal region, thought to be crucial for the proper sub-cellular localization of the CDKL5 protein. The resulting phenotype is characterized by a severe early-onset epileptic encephalopathy, global developmental delay, and profound intellectual and motor impairment with features reminiscent of Rett syndrome. In light of the data presented we discuss the possible phenotypic modulatory effects of the supernumerary wild type X allele and pattern of X chromosome inactivation and stress the importance of considering the causal involvement of CDKL5 in developmentally delayed males with early-onset seizures.
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PMID:A novel CDKL5 mutation in a 47,XXY boy with the early-onset seizure variant of Rett syndrome. 1916 Nov 56

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have recently been reported in patients with severe neurodevelopmental disorder characterized by early-onset seizures, infantile spasms, severe psychomotor impairment and very recently, in patients with Rett syndrome (RTT)-like phenotype. Although the involvement of CDKL5 in specific biological pathways and its neurodevelopmental role have not been completely elucidated, the CDKL5 appears to be physiologically related to the MECP2 gene. Here we report on the clinical and CDKL5 molecular investigation in a very unusual RTT case, with severe, early-neurological involvement in which we have shown in a previous report, a novel P388S MECP2 mutation [Conforti et al. (2003); Am J Med Genet A 117A: 184-187]. The patient has had severe psychomotor delay since the first month of life and infantile spasms since age 5 months. Moreover, at age 5 years the patient suddenly presented with renal failure. The severe pattern of symptoms in our patient, similar to a CDKL5 phenotype, prompted us to perform an analysis of the CDKL5, which revealed a novel missense mutation never previously described. The X-inactivation assay was non-informative. In conclusion, this report reinforces the observation that the CDKL5 phenotype overlaps with RTT and that CDKL5 analysis is recommended in patients with a seizure disorder commencing during the first months of life.
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PMID:A novel mutation in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene associated with a severe Rett phenotype. 1925 88

To date, 43 patients have been described with mutations in or involving the CDKL5 gene. The typical phenotype includes early-onset, often intractable epileptic seizures and severe mental retardation with very limited progress in psychomotor development. Most patients also show impaired social interaction with avoidance of eye-to-eye contact, and some clinical features reminiscent of Rett syndrome (RTT), including stereotypic hand movements, lack of purposeful hand use, acquired microcephaly, and generalized hypotonia. We report on the case of a 5-year-old girl with a de novo CDKL5 gene mutation who developed early puberty, which has not been described before.
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PMID:A CDKL5 mutated child with precocious puberty. 1939 24


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