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)

We describe clinical and neurophysiological findings in six related children with congenital microcephaly, seizures that began within the first 2-4 months of life, and severe mental retardation (MR). These affected children (five girls and one boy), born to two women who are half-sisters, inherited the disease as an autosomal recessive trait. Physical examination of these children did not show any of the anomalies in the known cortical malformation syndromes such as lissencephaly types I and II. Neuroradiological studies in these children documented microcephaly and a simplified gyral pattern with no pachygyria. Chromosomal analysis showed neither karyotypic abnormalities nor a microdeletion at 17p13.3, site of the lissencephaly type I gene locus (LIS1). Genetic studies failed to show linkage of this family to LIS1, LIS2 (a region on chromosome 2p homologous to LIS1), or MCPH1 (a locus for primary autosomal recessive microcephaly). The unique clinical and genetic findings in this family suggest that these children may be affected by an as-of-yet unmapped neuronal proliferation disorder.
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PMID:Microcephaly with simplified gyral pattern in six related children. 1032 39

Lissencephaly patients are born with severe brain malformations and suffer from recurrent seizures. LIS1, the gene mutated in isolated lissencephaly patients, is a subunit of the heterotrimeric cytosolic enzyme platelet-activating factor acetylhydrolase (PAF-AH), interacts with tubulin, and affects microtubule dynamics. In order to gain molecular insights into the possible involvement of LIS1 in seizures in lissencephaly patients, we induced seizures in rats by injection of kainate. PAF-AH activity was markedly reduced as early as 30 min following initiation of seizures, making this parameter a sensitive indicator of seizure events. PAF-AH activity returned to and surpassed control values 1 week following initiation of seizures. Expression of LIS1 in the dentate gyrus changed significantly in a manner similar to that of PAF-AH enzymatic activity. This is the first correlation found between LIS1 expression and PAF-AH activity. Furthermore, the expression of the alpha2 catalytic subunit, which is the major PAF-AH catalytic subunit in rat adult brain, changed in a dramatic fashion. An additional higher-mobility LIS1 cross-reactive band was detected in samples isolated a week following seizure occurrence. This LIS1 isoform was enriched in the microtubule-associated fraction. We propose that LIS1 expression is an important factor in regulation of PAF-AH activity. We postulate that reductions in LIS1 protein levels found in lissencephaly patients may render them more susceptible to seizures.
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PMID:Platelet-activating factor (PAF) acetylhydrolase activity, LIS1 expression, and seizures. 1039 95

Trisomy 5p and Miller-Dieker syndromes frequently are the result of unbalanced segregations of reciprocal translocations of chromosomes 5 and 17 with other autosomes. The critical regions for the expression of the mentioned syndromes have been mapped to 5p13-->pter, and 17p13.3-->pter. In this report, we describe an 8-year-old girl with mental retardation, postnatal growth deficiency, generalized muscular hypotonia, seizures, microcephaly, cortical atrophy, partial agenesis of corpus callosum, cerebral ventriculomegaly, facial anomalies, patent ductus arteriosus, pectus excavatum, long fingers, and bilateral talipes equinovarus caused by the presence of a 46,XX,der(17)t(5;17)(p13.1;p13.3)mat chromosome complement. Cytogenetic studies of the family confirmed a balanced reciprocal translocation (5;17)(p13.1;p13.3) in her mother, maternal grandfather, maternal aunt, and a female first cousin. Fluorescence in situ hybridization studies on the mother and the proposita using three probes, which map to distal 17p, confirmed the reciprocal translocation in the mother and a terminal deletion in the patient, which resulted in the retention of LIS1 and D17S379 loci and deletion of the 17p telomere. These findings and the phenotype of the proposita, strongly suggest that genes telomeric to LIS1 and locus D17S379 are involved in many clinical findings, including the minor facial anomalies of the Miller-Dieker syndrome.
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PMID:Miller-Dieker syndrome and trisomy 5p in a child carrying a derivative chromosome with a microdeletion in 17p13.3 telomeric to the LIS1 and the D17S379 loci. 1040 60

In this report, we describe a one-year-old girl of the Miller-Dieker syndrome(MDS) with lissencephaly, seizures, microcephaly and mental disorders. Cytogenetic studies of this patient confirmed the presence of a 46,XX, 17ps+ chromosome karyotype, but it could not find the microdeletion of 17p13.3. Fluorescence in situ hybridization(FISH) studies confirmed a terminal deletion in the patient using the LIS1 gene probe which mapped to 17p13.3. Further it was also found the satellite on 17p13(17ps) in the patient who was rare associated with MDS. These findings suggest that FISH analysis may be useful method to detect microdeletion of LIS1 gene as 17-specific probe in the investigation of MDS patients.
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PMID:[A case of Miller-Dieker syndrome associated with satellite on chromosome 17p]. 1130 15

Malformations of the cerebral cortex are an important cause of developmental disabilities and epilepsy. Here we review those malformations for which a genetic basis has been elucidated or is suspected and the types of associated epilepsy. Schizencephaly (cleft brain) has a wide anatomo-clinical spectrum, including partial epilepsy in most patients. Familial occurrence is rare. Heterozygous mutations in the EMX2 gene were reported in 13 patients. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of typical BPNH with epilepsy in females and prenatal lethality in males. About 88% of patients have partial epilepsy. Filamin A mutations, all leading to a truncated protein, have been reported in three families and in sporadic patients. The most frequent forms of lissencephaly (agyria-pachygyria) are caused by mutations of LIS1. XLIS mutations cause classical lissencephaly in hemizygous males and subcortical band heterotopia (SBH) in heterozygous females. The thickness of the heterotopic band and the degree of pachygyria correlate with the likelihood of developing Lennox-Gastaut syndrome. Mutations of the coding region of XLIS were found in all reported pedigrees and in 38-91% of sporadic female patients with SBH. With few exceptions, children with LIS1 mutations have isolated lissencephaly, with severe developmental delay and infantile spasms. Autosomal recessive lissencephaly with cerebellar hypoplasia, accompanied by severe developmental delay, seizures, and hypotonia has been associated with mutations of the reelin gene. Fukuyama congenital muscular dystrophy is due to mutations of the fukutin gene and is accompanied by polymicrogyria. Febrile seizures and epilepsy with generalized tonic-convulsions appear in about 50% of children but are usually not severe. Tuberous sclerosis (TS) is caused by mutations in at least two genes, TSC1 and TSC2; 75% of cases are sporadic; 60% of patients have epilepsy, manifested in 50% of them as infantile spasms. TSC1 mutations seem to cause a milder disease with fewer cortical tubers and lower frequency of seizures. Among 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 with 22q11.2 deletions. About 65% of patients have severe epilepsy, often Lennox-Gastaut syndrome.
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PMID:Epilepsy and genetic malformations of the cerebral cortex. 1157 36

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 lissencephalies. 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 2001 Oct
PMID:Epileptogenic brain malformations: clinical presentation, malformative patterns and indications for genetic testing. 1174 14

The models of cortical dysplasia discussed earlier--the Lis1 knockout, the MAM-induced cobblestone LIS, the spontaneous tish mutant, and focal freeze injury-induced PMG--illustrate several important insights into epileptogenesis in malformed brain. First, the appearance of epilepsy varies according to the pathogenesis of the dysplasia and may well depend more on the intrinsic properties of the neurons in these models rather than on the disturbed position of the cells. This is supported by models such as the reeler mouse, in which the dysfunctional extracellular matrix molecule leads to a form of lissencephaly in mouse and human, but there is a far less impressive association with seizures than for LIS1 mutations. However, Lis1 and Dex mutations that appear to affect the cytoskeleton and perhaps intracellular protein trafficking are frequently associated with infantile spasms and epilepsy. Second, the possible mechanisms of epileptogenesis in these models include (a) a loss of subsets of neurons, (b) altered neurotransmitter release, (c) differences in neurotransmitter receptor levels and changes in receptor subunit composition, (d) altered neurite density and/or synaptogenesis, (e) changed membrane properties (e.g., altered voltage-gated channels), (f) altered cell morphology (neuronal differentiation), and (g) effects on cytoskeletal function. Finally, it is important to note that the "generator" of excitability in affected brain may be within the heterotopia or in the normotopic cortex. As additional genetic models come to light and the ability to distinguish their clinical counterparts improves, more individually tailored therapies, including standards for surgical interventions, will surely evolve.
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PMID:Brain malformations, epilepsy, and infantile spasms. 1204 Sep

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

Cortical malformations are a collection of disorders affecting brain development. Mutations in the LIS1 gene lead to a disorganized and smooth cerebral cortex caused by failure in neuronal migration. Among the clinical consequences of lissencephaly are mental retardation and intractable epilepsy. It remains unclear whether the seizures result from aberrant neuronal placement, disruption of intrinsic properties of neurons, or both. The nematode Caenorhabditis elegans offers an opportunity to study such convulsions in a simple animal with a defined nervous system. Here we show that convulsions mimicking epilepsy can be induced by a mutation in a C. elegans lis-1 allele (pnm-1), in combination with a chemical antagonist of gamma-aminobutyric acid (GABA) neurotransmitter signaling. Identical convulsions were obtained using C. elegans mutants defective in GABA transmission, whereas none of these mutants or the antagonist alone caused convulsions, indicating a threshold was exceeded in response to this combination. Crosses between pnm-1 and fluorescent marker strains designed to exclusively illuminate either the processes of GABAergic neurons or synaptic vesicles surprisingly showed no deviations in neuronal architecture. Instead, presynaptic defects in GABAergic vesicle distribution were clearly evident and could be phenocopied by RNAi directed against cytoplasmic dynein, a known LIS1 interactor. Furthermore, mutations in UNC-104, a neuronal-specific kinesin, and SNB-1, a synaptic vesicle-associated protein termed synaptobrevin, exhibit similar convulsion phenotypes following chemical induction. Taken together, these studies establish C. elegans as a system to investigate subtle cytoskeletal mechanisms regulating intrinsic neuronal activity and suggest that it may be possible to dissociate the epileptic consequences of lissencephaly from the more phenotypically overt cortical defects associated with neuronal migration.
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PMID:Epileptic-like convulsions associated with LIS-1 in the cytoskeletal control of neurotransmitter signaling in Caenorhabditis elegans. 1525 12

We reviewed the epileptogenic cortical malformations for which a causative gene has been cloned or a linkage obtained. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of typical BPNH with epilepsy in female patients and prenatal lethality in most males. About 90% of patients have focal epilepsy. Filamin A mutations have been reported in all families and in approximately 20% of sporadic patients. A rare recessive form of BPNH also has been reported. Most cases of lissencephaly-pachygyria are caused by mutations of LIS1 and XLIS genes. LIS1 mutations cause a more severe malformation posteriorly. Most children have isolated lissencephaly, with severe developmental delay and infantile spasms, but milder phenotypes have been recorded. XLIS usually causes anteriorly predominant lissencephaly in male patients and subcortical band heterotopia (SBH) in female patients. Thickness of the band and severity of pachygyria correlate with the likelihood of developing Lennox-Gastaut syndrome. Mutations of the coding region of XLIS are found in all reported pedigrees and in 50% of sporadic female patients with SBH. Autosomal recessive lissencephaly with cerebellar hypoplasia; accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the RELN gene. Schizencephaly has a wide anatomoclinical spectrum, including focal epilepsy in most patients. Familial occurrence is rare. Initial reports of heterozygous mutations in the EMX2 gene need confirmation. Among several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria shows genetic heterogeneity, including linkage to Xq28 in some pedigrees, autosomal recessive inheritance in others, and association with 22q11.2 deletion in some patients. About 65% of patients have severe epilepsy, often Lennox-Gastaut syndrome. Recessive bilateral frontal polymicrogyria has been linked to chromosome 16q12.2-21.
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PMID:Genetic malformations of the cerebral cortex and epilepsy. 1581 77


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