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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several X-linked mental retardation syndromes are caused by mutations in the ATRX gene. Common clinical features associated with ATRX mutations include severe mental retardation, characteristic facial anomalies and variable degrees of urogenital defects and alpha-thalassemia. Although the ATRX protein is a member of the SWI/SNF family of chromatin remodeling proteins, little is known about the biochemical activity of the ATRX protein or its in vivo function during development. Here we demonstrate that ATRX is part of a large multiprotein complex similar in size to the SWI/SNF complex. Furthermore, we have generated transgenic mice that overexpress ATRX as an initial model for studying the function of this protein during development. Misexpression of ATRX was associated with growth retardation, neural tube defects and a high incidence of embryonic death. Moreover, brains from E10.5 transgenic embryos displayed abnormal growth and organization of the ventricular zone that was highly convoluted in the most severely affected embryos. Transgenic mice that survived to birth exhibited a high incidence of perinatal death, as well as seizures, mild craniofacial anomalies and abnormal behavior. Our findings indicate that ATRX dosage is crucial for normal development and organization of the cortex, and emphasize the relevance of our model for the study of ATRX function and disease pathogenesis.
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PMID:Neurodevelopmental defects resulting from ATRX overexpression in transgenic mice. 1182 44

Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation. At least eight autosomal genes involved in idiopathic epilepsy have been identified, and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome-linked, Aristaless-related, homeobox gene (ARX), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine and polyglutamine disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.
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PMID:Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. 1188 67

Several inherited human neurological disorders can be caused by mutations in genes encoding Ca2+ channel subunits. This review deals with known human and mouse calcium channelopathies of the central nervous system (CNS). The human diseases comprise: 1) a recessive retinal disorder, X-linked congenital stationary night blindness, associated with mutations in the CACNA1F gene, encoding alpha(1)1.4 subunits of L-type channels; and 2) a group of rare allelic autosomal dominant human neurological disorders including familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6, all associated with mutations in the CACNA1A gene, encoding alpha(1)2.1 subunits of P/Q-type calcium channels. Mutations at the mouse orthologue of the CACNA1A gene cause a group of recessive neurological disorders, including the tottering, leaner, and rocker phenotypes with ataxia and absence epilepsy, and the rolling Nagoya phenotype with ataxia without seizures. Two other spontaneous mouse mutants with ataxia and absence epilepsy, lethargic and stargazer, have mutations in genes encoding a calcium channel auxiliary beta subunit and a putative calcium channel auxiliary gamma subunit. For each channelopathy, the review describes disease phenotype, channel genotype, and known functional consequences of the pathological mutations; in some cases, it also describes working hypothesis and/or speculations addressing the challenging question of how the alterations in channel function lead to selective cellular dysfunction and disease.
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PMID:Calcium channels and channelopathies of the central nervous system. 1189 Apr 56

A family with X-linked mental retardation characterized by severe mental retardation, speech and behavioral abnormalities, and seizures in affected male patients has been found to have a G1141C transversion in the creatine-transporter gene SLC6A8. This mutation results in a glycine being replaced by an arginine (G381R) and alternative splicing, since the G-->C transversion occurs at the -1 position of the 5' splice junction of intron 7. Two female relatives who are heterozygous for the SLC6A8 mutation also exhibit mild mental retardation with behavior and learning problems. Male patients with the mutation have highly elevated creatine in their urine and have decreased creatine uptake in fibroblasts, which reflects the deficiency in creatine transport. The ability to measure elevated creatine in urine makes it possible to diagnose SLC6A8 deficiency in male patients with mental retardation of unknown etiology.
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PMID:X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28. 1189 26

This is the first report of benign adult familial myoclonic epilepsy (BAFME) with night blindness. Our cases of BAFME (mother, son, and daughter) demonstrated night blindness with a reduced b-wave response on electroretinography (ERG) suggesting an alteration in calcium-mediated neurotransmitter release from photoreceptors in response to light. Several familial epilepsies have been shown to be due to a channelopathy. On the other hand, the mutation of a calcium-channel gene in Xp11.23 was recently reported in incomplete X-linked congenital stationary night blindness (CSNB). Although the gene locus of BAFME was recently assigned to 8q23.3-q24.1, the causative gene has yet to be identified. The present familial case suggests that BAFME may also be a disease of the calcium channel that is present in the retina and the central nervous system (CNS).
Seizure 2002 Jun
PMID:Benign adult familial myoclonic epilepsy (BAFME) with night blindness. 1202 75

MEHMO (Mental retardation, Epileptic seizures, Hypogenitalism, Microcephaly and Obesity) is an X-linked disorder characterised by mental retardation, epileptic seizures, hypogenitalism, microcephaly and obesity. It was recently assigned to the locus Xp21.1-p22.13. We describe a child with MEHMO and lactic acidosis whose muscle biopsy revealed markedly reduced activities of complexes 1,3 and 4 of the mitochondrial electron transport chain. Histological staining showed mitochondrial proliferation and lipid storage. Electron microscopy revealed abnormal and enlarged mitochondria with concentric cristae and electron dense bodies. This is the first identification of MEHMO as a mitochondrial disorder and one of the very few X-linked mitochondrial syndromes.
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PMID:MEHMO (Mental retardation, Epileptic seizures, Hypogenitalism, Microcephaly, Obesity): a new X-linked mitochondrial disorder. 1203 29

Clinical data from 50 mentally retarded (MR) males in nine X-linked MR families, syndromic and non-specific, with mutations (duplication, expansion, missense, and deletion mutations) in the Aristaless related homeobox gene, ARX, were analysed. Seizures were observed with all mutations and occurred in 29 patients, including one family with a novel myoclonic epilepsy syndrome associated with the missense mutation. Seventeen patients had infantile spasms. Other phenotypes included mild to moderate MR alone, or with combinations of dystonia, ataxia or autism. These data suggest that mutations in the ARX gene are important causes of MR, often associated with diverse neurological manifestations.
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PMID:Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. 1214 61

The term acanthocytosis is derived from the Greek for "thorn" and is used to describe a peculiar spiky appearance of erythrocytes. Acanthocytosis is found to be associated with at least three hereditary neurological disorders that are generally referred to as neuroacanthocytosis. Abetalipoproteinaemia is an autosomal recessive condition, characterised by absence of serum apolipoprotein B containing lipoproteins leading to fat intolerance and fat-soluble vitamin deficiency. This results in a progressive spinocerebellar ataxia with peripheral neuropathy and retinitis pigmentosa. Chorea-acanthocytosis is also an autosomal recessive condition and is characterised by chorea, orofaciolingual dyskinesia, dysphagia, dysarthria, areflexia, seizures and dementia. Some of its features, including choreic movements, peripheral neuropathy with areflexia, elevated serum creatine kinase levels and myopathy are shared by another form of neuroacanthocytosis, McLeod syndrome. Patients affected by this X-linked disorder also show abnormal expression of Kell blood group antigens and a permanent haemolytic state. In addition to these cases, acanthocytosis is occasionally associated with other neurological disorders, such as Hallervorden-Spatz disease. For each of the neuroacanthocytosis syndromes we review the main clinical features and their molecular bases. The recent molecular genetics findings are the first step towards the understanding of the pathogenetic mechanisms and eventually the search for effective treatments.
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PMID:Clinical features and molecular bases of neuroacanthocytosis. 1218 48

We review here those malformations of the cerebral cortex which are most often observed in epilepsy patients, for which a genetic basis has been elucidated or is suspected and give indications for genetic testing. There are three forms of lissencephaly (agyria-pachygyria) resulting from mutations of known genes, which can be distinguished because of their distinctive imaging features. They account for about 85% of all licence-phalies. Lissencephaly with posteriorly predominant gyral abnormality is caused by mutations of the LIS1 gene on chromosome 17. Anteriorly predominant lissencephaly in hemizygous males and subcortical band heterotopia (SBH) in heterozygous females are caused by mutations of the XLIS (or DCX) gene. Mutations of the coding region of XLIS were found in all reported pedigrees, and in most sporadic female patients with SBH. Missense mutations of both LIS1 and XLIS genes have been observed in some of the rare male patients with SBH. Autosomal recessive lissencephaly with cerebellar hypoplasia has been associated with mutations of the reelin gene. With few exceptions, children with lissencephaly have severe developmental delay and infantile spasms early in life. Patients with SBH have a mild to severe mental retardation with epilepsy of variable severity and type. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of typical BPNH with focal epilepsy in females and prenatal lethality in males. About 88% of patients have focal epilepsy. Filamin A (FLNA) mutations have been reported in some families and in sporadic patients. Additional, possibly autosomal recessive gene(s) are likely to be involved in causing BPNH non-linked to FLN1. Tuberous sclerosis (TS) is a dominant disorder caused by mutations in at lest two genes, TSC1 and TSC2. 75% of cases are sporadic. Most patients with TS have epilepsy. Infantile spasms are a frequent early manifestation of TS. Schizencephaly (cleft brain) has a wide anatomo-clinical spectrum, including focal epilepsy in most patients. Familial occurrence is rare. Heterozygous mutations in the EMX2 gene have been reported in some patients. However, at present, there is no clear indication on the possible pattern of inheritance and on the practical usefulness that mutation detection in an individual with schizencephaly would carry in terms of genetic counselling. Amongst several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria had familial occurrence on several occasions. Genetic heterogeneity is likely, including autosomal recessive, X-linked dominant, X-linked recessive inheritance and association to 22q11.2 deletions. FISH analysis for 22q11.2 is advisable in all patients with perisylvian polymicrogyria. Parents of an affected child with normal karyotype should be given up to a 25% recurrence risk.
Seizure 2002 Apr
PMID:Epileptogenic brain malformations: clinical presentation, malformative patterns and indications for genetic testing. 1218 71

X-linked forms of non-specific mental retardation are complex disorders, for which mutations in several genes have recently been identified. These include OPHN1, GDI1, PAK3, IL1RAPL, TM4SF2, FMR2 and RSK2. To investigate the mechanisms through which alterations of these gene products could result in cognitive impairment, we analyzed their expression using quantitative PCR technique in two in vitro models of activity-dependent gene regulation: kainate-induced seizures and long-term synaptic potentiation (LTP). We found that the level of expression of four genes, PAK3, IL1RAPL, RSK2 and TM4SF2, was significantly up-regulated following kainate treatment. Furthermore we observed a significant increase in mRNA levels of PAK3 and IL1RAPL following LTP induction. These results suggest a possible role for these four genes in activity-dependent brain plasticity.
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PMID:Activity-dependent regulation of genes implicated in X-linked non-specific mental retardation. 1220 50


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