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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

ARX mutations are associated with variable clinical phenotypes. We report a new neurodegenerative phenotype associated with a known ARX mutation and causing early abnormal neurodevelopment, a complex movement disorder, and early infantile epileptic encephalopathy with a suppression-burst pattern (Ohtahara syndrome). A male infant presented at age 5 months with a dyskinetic movement disorder, which was initially diagnosed as infantile spasms. Clinical deterioration was accompanied by progressive cortical atrophy with a reduction in white matter volume and resulting in death in the first year of life; such a rapidly progressive and severe phenotype has not previously been described. ARX mutation testing should be undertaken in children aged less than 1 year with Ohtahara syndrome and a movement disorder, and in infants with unexplained neurodegeneration, progressive white matter loss, and cortical atrophy.
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PMID:A novel ARX phenotype: rapid neurodegeneration with Ohtahara syndrome and a dyskinetic movement disorder. 1974 3

Recently, it has been reported that longer expansions of the polyalanine tract of the ARX gene could cause an early infantile encephalopathy with suppression burst pattern and that the length of this repeat region could be related to the severity of the electroclinical picture. We describe the history of two male individuals, born from monozygotic twin sisters, with Ohtahara syndrome (OS) that evolved into West syndrome phenotype and epileptic encephalopathy. In both children, we have found a previously unreported missense mutation in exon 5 of ARX gene (c.1604T>A) resulting in the substitution of a leucine with a glutamine in the aminoacid sequence. The two mothers and the maternal grandmother carry the same mutation which segregates with the disease phenotype in the family. This study confirms that ARX is involved in the pathogenesis of cryptogenic early onset epileptic encephalopathy, such as OS, and suggests that the severity of the electroclinical picture is likely to not exclusively correlate with the extent of expansions of the polyalanine tracts, but rather with the functional effect of different pathogenetic mutations.
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PMID:Familial Ohtahara syndrome due to a novel ARX gene mutation. 2110 97

Ohtahara syndrome or Early Infantile Epileptic Encephalopathy (EIEE) with Suppression-Burst, is the most severe and the earliest developing age-related epileptic encephalopathy. Clinically, the syndrome is characterized by early onset tonic spasms associated with a severe and continuous pattern of burst activity. It is a debilitating and early progressive neurological disorder, resulting in intractable seizures and severe mental retardation. Specific mutations in at least four genes (whose protein products are essential in lower brain's neuronal and interneuronal functions, including mitochondrial respiratory chains have been identified in unrelated individuals with EIEE and include: (a) the ARX (aristaless-related) homeobox gene at Xp22.13 (EIEE-1 variant); (b) the CDKL5 (SYK9) gene at Xp22 (EIEE-2 variant); (c) the SLC25A22 (GC1) gene at 11p15.5 (EIEE-3 variant); and (d) the Stxbp1 (MUNC18-1) gene at 9q34-1 (EIEE-4 variant). A yet unresolved issue involves the relationship between early myoclonic encephalopathy (EME-ErbB4 mutations) versus the EIEE spectrum of disorders.
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PMID:Ohtahara syndrome with emphasis on recent genetic discovery. 2196 65

Epilepsy accounts for a significant portion of the dis-ease burden worldwide. Research in this field is fundamental and mandatory. Animal models have played, and still play, a substantial role in understanding the patho-physiology and treatment of human epilepsies. A large number and variety of approaches are available, and they have been applied to many animals. In this chapter the in vitro and in vivo animal models are discussed,with major emphasis on the in vivo studies. Models have used phylogenetically different animals - from worms to monkeys. Our attention has been dedicated mainly to rodents.In clinical practice, developmental aspects of epilepsy often differ from those in adults. Animal models have often helped to clarify these differences. In this chapter, developmental aspects have been emphasized.Electrical stimulation and chemical-induced models of seizures have been described first, as they represent the oldest and most common models. Among these models, kindling raised great interest, especially for the study of the epileptogenesis. Acquired focal models mimic seizures and occasionally epilepsies secondary to abnormal cortical development, hypoxia, trauma, and hemorrhage.Better knowledge of epileptic syndromes will help to create new animal models. To date, absence epilepsy is one of the most common and (often) benign forms of epilepsy. There are several models, including acute pharmacological models (PTZ, penicillin, THIP, GBL) and chronic models (GAERS, WAG/Rij). Although atypical absence seizures are less benign, thus needing more investigation, only two models are so far available (AY-9944,MAM-AY). Infantile spasms are an early childhood encephalopathy that is usually associated with a poor out-come. The investigation of this syndrome in animal models is recent and fascinating. Different approaches have been used including genetic (Down syndrome,ARX mutation) and acquired (multiple hit, TTX, CRH,betamethasone-NMDA) models.An entire section has been dedicated to genetic models, from the older models obtained with spontaneous mutations (GEPRs) to the new engineered knockout, knocking, and transgenic models. Some of these models have been created based on recently recognized patho-genesis such as benign familial neonatal epilepsy, early infantile encephalopathy with suppression bursts, severe myoclonic epilepsy of infancy, the tuberous sclerosis model, and the progressive myoclonic epilepsy. The contribution of animal models to epilepsy re-search is unquestionable. The development of further strategies is necessary to find novel strategies to cure epileptic patients, and optimistically to allow scientists first and clinicians subsequently to prevent epilepsy and its consequences.
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PMID:Animal models. 2293 64

Severe early-onset epilepsy is due to a number of known causes, although a clear etiology is not identifiable in up to a third of all the cases. Pathogenic sequence variations in the ARX gene have been described almost exclusively in males, whereas heterozygous female relatives, such as mothers, sisters and even grandmothers have been largely reported as asymptomatic or mildly affected. To investigate the pathogenic role of ARX in refractory epilepsy of early onset even in females, we have screened the ARX sequence in a population of 50 female subjects affected with unexplained epileptic encephalopathy with onset in the first year of life. We report the identification of a novel truncating mutation of the coding region of the ARX gene in a girl with a structurally normal brain. Our findings confirm the role of ARX in the pathogenesis of early epilepsy and underline the importance of screening of the ARX gene in both male and female subjects with otherwise unexplained early onset epileptic encephalopathy.
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PMID:Early-onset epileptic encephalopathy in a girl carrying a truncating mutation of the ARX gene: rethinking the ARX phenotype in females. 2303 62

Early-onset epileptic encephalopathies include various diseases such as early-infantile epileptic encephalopathy with suppression burst. We experimentally investigated the unique clinicopathological features of a 28-month-old girl with early-onset epileptic encephalopathy. Her initial symptom was intractable epilepsy with a suppression-burst pattern of electroencephalography (EEG) from 7 days of age. The suppression-burst pattern was novel, appearing during sleep, but disappearing upon waking and after becoming 2 months old. The EEG showed multifocal spikes and altered with age. Her seizures demonstrated various clinical features and continued until death. She did not show any developmental features, including no social smiling or head control. Head MRI revealed progressive atrophy of the cerebral cortex and white matter after 1 month of age. (123)IMZ-SPECT demonstrated hypo-perfusion of the cerebral cortex, but normo-perfusion of the diencephalon and cerebellum. Such imaging information indicated GABA-A receptor dysfunction of the cerebral cortex. The genetic analyses of major neonatal epilepsies showed no mutation. The neuropathology revealed atrophy and severe edema of the cerebral cortex and white matter. GAD-immunohistochemistry exhibited imbalanced distribution of GABAergic interneurons between the striatum and cerebral cortex. The results were similar to those of focal cortical dysplasia with transmantle sign and X-linked lissencephaly with ARX mutation. We performed various metabolic examinations, detailed pathological investigations and genetic analyses, but could not identify the cause. To our knowledge, her clinical and pathological courses have never been described in the literature.
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PMID:A case of severe progressive early-onset epileptic encephalopathy: unique GABAergic interneuron distribution and imaging. 2342 26

The authors describe 2 patients with early infantile epileptic encephalopathy caused by 2 novel mutations involving the STXBP1 gene. The authors suggest that in spite of the rarity of STXBP1 mutations, molecular analysis of STXBP1 gene should be performed in patients with early infantile epileptic encephalopathy, after exclusion of ARX mutations in male patients and CDKL5 mutations in female patients. The potential mechanisms explaining the variable clinical phenotypes caused by STXBP1 mutations are discussed and the designation of early-onset epileptic encephalopathies, including an updated genetic classification, is proposed to encompass the epileptic encephalopathies beginning in the first 6 months of life.
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PMID:Novel STXBP1 mutations in 2 patients with early infantile epileptic encephalopathy. 2353 65

Bursts of paroxysmal activity alternating with lack of activity define the suppression-burst (SB) pattern that may be acute, in hypoxic-ischemic encephalopathy and barbiturate intoxication, or chronic in the course of early epileptic and neonatal myoclonic (NME) encephalopathies. Malformations, namely Aicardi syndrome and hemimegalencephaly, gene mutations - of ARX and MUNC18 -, and inborn errors of metabolism, namely glycine encephalopathy, are the main causes, with spasms indicating more likely a malformation whereas myoclonus indicates metabolic disorders. Although glycine encephalopathy has a very severe outcome in its classical expression, it may be transient in the neonatal period, for reasons yet not identified. Although glycine encephalopathy is the main identified cause of NME, the disorder may not cause SB, especially in cases with later onset. The biochemical bases, due to changes in one of the four proteins that compose the enzyme, are well understood, but there is no phenotype-genotype correlation. Prenatal diagnosis is based on villous biopsy. The mechanism of SB partly depends on glutamate - or glycine, the co-neurotransmitter for NMDA transmission - overflow, mainly in the immature brain but also in cases due to barbiturate intoxication. Energy supply defect may also be involved in some inborn errors of metabolism.
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PMID:Epileptic encephalopathy with suppression-bursts and nonketotic hyperglycinemia. 2362 1


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