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

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.
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PMID:The influence of etiology upon ictal semiology, treatment decisions and long-term outcomes in infantile spasms and West syndrome. 1682 60

We screened 165 mentally retarded patients for ARX gene 428-451 base pair (bp) duplication. Eighteen individuals from five families were found to carry the duplication, and all had intellectual impairment. Twelve presented with focal hand dystonia, while six patients had EEG abnormalities including seizures. Other symptoms included speech difficulties (4/18), testis enlargement (4/18), lower limb spasticity or foot dystonia (4/18), and facial telangiectasia (3/18). These features confirm the pleiotropic effect of the duplication.
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PMID:Genotype-phenotype associations for ARX gene duplication in X-linked mental retardation. 1708 67

X-linked lissencephaly with absent corpus callosum and abnormal genitalia (XLAG) is caused by a mutation in the ARX gene. We herein report the clinical course of siblings with XLAG with a splicing mutation in ARX. Seizures were observed in utero. Cerebral atrophy was progressive postnatally, and fetal echoencephalography indicated that the atrophy might have started in the prenatal period. They had a typical phenotype, except that the genital abnormality of the younger brother was not remarkable. A portal-systemic shunt that has not been reported in cases with XLAG was seen in the older brother. The siblings had the different complications and severity of disease in spite of possessing the same mutation.
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PMID:[X-linked lissencephaly with absent corpus callosum and abnormal genitalia: a report of siblings followed from the prenatal period]. 1751 35

The term lissencephaly covers a group of rare malformations sharing the common feature of anomalies in the appearance of brain convolutions (characterised by simplification or absence of folding) associated with abnormal organisation of the cortical layers as a result of neuronal migration defects during embryogenesis. Children with lissencephaly have feeding and swallowing problems, muscle tone anomalies (early hypotonia and subsequently limb hypertonia), seizures (in particular, infantile spasms) and severe psychomotor retardation. Multiple forms of lissencephaly have been described and their current classification is based on the associated malformations and underlying aetiology. Two large groups can be distinguished: classical lissencephaly (and its variants) and cobblestone lissencephaly. In classical lissencephaly (or type I), the cortex appears thickened, with four more or less disorganised layers rather than six normal layers. In the variants of classical lissencephaly, extra-cortical anomalies are also present (total or subtotal agenesis of the corpus callosum and/or cerebellar hypoplasia). The classical lissencephalies and the variant forms can be further divided into several subgroups. Four forms can be distinguished on the basis of their genetic aetiology: anomalies in the LIS1 gene (isolated lissencephaly and Miller-Dieker syndrome), anomalies in the TUBA3 and DCX genes, and lissencephalies caused by mutations in the ARX gene (XLAG syndrome, X-linked lissencephaly with agenesis of the corpus callosum). The incidence of all forms of type I lissencephaly is around 1 in 100,000 births. In addition to these four entities, isolated lissencephalies without a known genetic defect, lissencephalies with severe microcephaly (microlissencephaly) and lissencephalies associated with polymalformative syndromes are also included in the group of classical lissencephalies. Cobblestone lissencephaly (formally referred to as type II) is present in three entities: the Walker-Warburg, Fukuyama and MEB (Muscle-Eye-Brain) syndromes. It is characterised by global disorganisation of cerebral organogenesis with an uneven cortical surface (with a pebbled or cobblestone appearance). Microscopic examination reveals total disorganisation of the cortex and the absence of any distinguishable layers. Management is symptomatic only (swallowing problems require adapted feeding to prevent food aspiration, articular and respiratory physiotherapy to prevent orthopaedic problems resulting from hyptonia and treatment of gastrooesophageal reflux). The epilepsy is often resistant to treatment. The encephalopathy associated with lissencephaly is often very severe and affected children are completely dependent on the carer.
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PMID:[Genetic and clinical aspects of lissencephaly]. 1757 Oct 22

Early infantile epileptic encephalopathy with suppression-burst pattern (EIEE) is one of the most severe and earliest forms of epilepsy, often evolving into West syndrome; however, the pathogenesis of EIEE remains unclear. ARX is a crucial gene for the development of interneurons in the fetal brain, and a polyalanine expansion mutation of ARX causes mental retardation and seizures, including those of West syndrome, in males. We screened the ARX mutation and found a hemizygous, de novo, 33-bp duplication in exon 2, 298_330dupGCGGCA(GCG)9, in two of three unrelated male patients with EIEE. This mutation is thought to expand the original 16 alanine residues to 27 alanine residues (A110_A111insAAAAAAAAAAA) in the first polyalanine tract of the ARX protein. Although EIEE is mainly associated with brain malformations, ARX is the first gene found to be responsible for idiopathic EIEE. Our observation that EIEE had a longer expansion of the polyalanine tract than is seen in West syndrome is consistent with the findings of earlier onset and more-severe phenotypes in EIEE than in West syndrome.
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PMID:A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome). 1766 84

We report the clinical course of a case of X-linked lissencephaly with absent corpus callosum and abnormal genitalia (XLAG) exhibiting severe diarrhea. The patient demonstrated lactose intolerance and his intractable seizures were relieved with lactose-free, extensively hydrolyzed whey protein formula. At the age of 2 years while being treated with the antiallergic formula, he was affected with severe diarrhea that resembled watery diarrhea-hypokalemia-acidosis syndrome (WDHA). Administration of octreotide was effective in relieving his secretory diarrhea. Hypoglycemia without hyperinsulinemia was seen during fasting, and plasma vasoactive intestinal polypeptide was not increased when he had WDHA-like diarrhea. Although pancreas of ARX mutant mice revealed an increased number of beta and delta cells, we did not detect the cause of hypoglycemia and secretory diarrhea by pancreatic endocrinology. His urinary findings mimicked the symptoms of Fanconi syndrome, so it was possible that his hyperaldsteronemia affected not only his intestinal tract, but also his renal tubules.
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PMID:[Severe diarrhea associated with X-linked lissencephaly with absent corpus callosum and abnormal genitalia: a case report of successful treatment with the somatostatin analogue octreotide]. 1787 13

We present four patients with ARX mutations and widely variant clinical presentations. Case 1, a female with a known ARX mutation has refractory infantile spasms and severe mental retardation. Case 2, a male presented with a neurodegenerative disorder and has a known ARX mutation likely de novo as mother is not a carrier. Cases 3 and 4, two siblings with a novel variant in ARX, which is not clearly pathogenic, have developmental delay. One of the siblings had a diagnosis of autistic spectrum disorder, failure to thrive with severe feeding difficulties, intracranial hemorrhage, and seizures. There are very few affected females with ARX related infantile spasms. These cases expand the known phenotype of this emerging condition.
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PMID:Expansion of the ARX spectrum. 1846 64

Pathogenic variations of the ARX (aristaless-related homeobox) gene are associated with marked phenotypic pleiotropy. These phenotypes are X-linked neurological disorders that include brain and genital malformation and non-malformation syndromes. Typically, malformation phenotypes result from pathogenic variations that are predicted to truncate the ARX protein, or alter residues in the highly conserved homeodomain. While non-malformation phenotypes tend to be caused by pathogenic variations that are predicted to expand the first two polyalanine tracts of ARX, or alter residues outside of the homeodomain. The most common pathogenic variation of the ARX gene is a duplication of 24 bp, c.429_452 dup, which leads to an expansion of the second polyalanine tract of the ARX protein from 12 to 20 alanine residues. This pathogenic variation is associated with both sporadic and familial nonsyndromic mental retardation. Syndromic manifestations include mental retardation with hand dystonia (Partington syndrome), infantile spasms (West syndrome) and/or other epileptic seizures. Here, we report on a novel pathogenic variant of a tandem 33 bp duplication that is predicted to result in an expansion of polyalanine tract 2 in two brothers with mental retardation, epilepsy, dystonia, and the novel feature of intermittent hyperventilation. This pathogenic variation is predicted to result in a "non-homogeneous" polyalanine tract expansion that is longer than predicted expansion caused by the common 24 bp duplication. The location of the novel 33 bp duplication in the same region as the common 24 bp duplication supports this region as the ARX variation "hot spot."
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PMID:Clinical study of two brothers with a novel 33 bp duplication in the ARX gene. 1950 62

ARX (the aristaless-related homeobox gene) is a transcription factor that participates in the development of GABAergic and cholinergic neurons in the forebrain. Many ARX mutations have been identified in X-linked lissencephaly and mental retardation with epilepsy, and thus ARX is considered to be a causal gene for the two syndromes although the neurobiological functions of each mutation remain unclear. We attempted to elucidate the causal relationships between individual ARX mutations and disease phenotypes by generating a series of mutant mice. We generated three types of mice with knocked-in ARX mutations associated with X-linked lissencephaly (P353R) and mental retardation [P353L and 333ins(GCG)7]. Mice with the P355R mutation (equivalent to the human 353 position) that died after birth were significantly different in Arx transcript/protein amounts, GABAergic and cholinergic neuronal development, brain morphology and lifespan from mice with P355L and 330ins(GCG)7 but considerably similar to Arx-deficient mice with truncated ARX mutation in lissencephaly. Mice with the 330ins(GCG)7 mutation showed severe seizures and impaired learning performance, whereas mice with the P355L mutation exhibited mild seizures and only slightly impaired learning performance. Both types of mutant mice exhibited the mutation-specific lesser presence of GABAergic and cholinergic neurons in the striatum, medial septum and ventral forebrain nuclei when compared with wild-type mice. Present findings that reveal a causal relationship between ARX mutations and the pleiotropic phenotype in mice, suggest that the ARX-related syndrome, including lissencephaly or mental retardation, is caused by only the concerned ARX mutations without the involvement of other genetic factors.
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PMID:Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice. 1960 12

Autistic spectrum disorders (ASD) and epilepsies are heterogeneous disorders that have diverse etiologies and pathophysiologies. The high rate of co-occurrence of these disorders suggest potentially shared underlying mechanisms. A number of well-known genetic disorders share epilepsy and autism as prominent phenotypic features, including tuberous sclerosis, Rett syndrome, and fragile X. In addition, mutations of several genes involved in neurodevelopment, including ARX, DCX, neuroligins and neuropilin2 have been identified in children with epilepsy, ASD or often both. Finally, in animal models, early-life seizures can result in cellular and molecular changes that could contribute to learning and behavioral disabilities as seen in ASD. Increased understanding of the common genetic, molecular and cellular mechanisms of ASD and epilepsy may provide insight into their underlying pathophysiology and elucidate new therapeutic approaches of both conditions.
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PMID:Epilepsy and autism spectrum disorders: are there common developmental mechanisms? 2057 72


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