Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014547 (focal epilepsy)
 1,627 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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.
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PMID:Epileptogenic brain malformations: clinical presentation, malformative patterns and indications for genetic testing. 1218 71

Several malformation syndromes with abnormal cortical development have been recognized. Specific causative gene defects and characteristic electroclinical patterns have been identified for some. X-linked periventricular nodular heterotopia is mainly seen in female patients and is often associated with focal epilepsy. FLN1 mutations have been reported in all familial cases and in about 25% of sporadic patients. A rare recessive form of periventricular nodular heterotopia owing to ARGEF2 gene mutations has also been reported in children with microcephaly, severe delay, and early-onset seizures. Lissencephaly-pachygyria and subcortical band heterotopia represent a malformative spectrum resulting from mutations of either the LIS1 or the DCX (XLIS) gene. LIS1 mutations cause a more severe malformation posteriorly. Most children have severe developmental delay and infantile spasms, but milder phenotypes are on record, including posterior subcortical band heterotopia owing to mosaic mutations of LIS1. DCX mutations usually cause anteriorly predominant lissencephaly in male patients and subcortical band heterotopia in female patients. Mutations of the coding region of DCX were found in all reported pedigrees and in about 50% of sporadic female patients with subcortical band heterotopia. Mutations of XLIS have also been found in male patients with anterior subcortical band heterotopia and in female patients with normal brain magnetic resonance imaging. The thickness of the band and the severity of pachygyria correlate with the likelihood of developing severe epilepsy. Autosomal recessive lissencephaly with cerebellar hypoplasia, accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the reelin (RELN) gene. X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia in genotypic males is associated with mutations of the ARX gene. Affected boys have severe delay and infantile spasms with suppression-burst electroencephalograms. Early death is frequent. Carrier female patients can have isolated corpus callosum agenesis. 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 have not been confirmed. Among several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria shows genetic heterogeneity, including linkage to chromosome Xq28 in some pedigrees, autosomal dominant or recessive inheritance in others, and an association with chromosome 22q11.2 deletion in some patients. About 65% of patients have severe epilepsy. Recessive bilateral frontoparietal polymicrogyria has been associated with mutations of the GPR56 gene.
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PMID:Neuronal migration disorders, genetics, and epileptogenesis. 1592 Dec 28

The malformations of the cerebral cortex represent a major cause of developmental disabilities, severe epilepsy and reproductive disadvantage. The advent of high-resolution MRI techniques has facilitated the in vivo identification of a large group of cortical malformation phenotypes. Several malformation syndromes caused by abnormal cortical development have been recognised and specific causative gene defects have been identified. Periventricular nodular heterotopia (PNH) is a malformation of neuronal migration in which a subset of neurons fails to migrate into the developing cerebral cortex. X-linked PNH is mainly seen in females and is often associated with focal epilepsy. FLNA mutations have been reported in all familial cases and in about 25% of sporadic patients. A rare recessive form of PNH due ARGEF2 gene mutations has also been reported in children with microcephaly, severe delay and early seizures. Lissencephaly-pachygyria and subcortical band heterotopia (SBH) are disorders of neuronal migration and represent a malformative spectrum resulting from mutations of either LIS1 or DCX genes. LIS1 mutations cause a more severe malformation in the posterior brain regions. Most children have severe developmental delay and infantile spasms, but milder phenotypes are on record, including posterior SBH owing to mosaic mutations of LIS1. DCX mutations usually cause anteriorly predominant lissencephaly in males and SBH in female patients. Mutations of DCX have also been found in male patients with anterior SBH and in female relatives with normal brain magnetic resonance imaging. Autosomal recessive lissencephaly with cerebellar hypoplasia, accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the reelin (RELN) gene. X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia in genotypic males is associated with mutations of the ARX gene. Affected boys have severe delay and seizures with suppression-burst EEG. Early death is frequent. Carrier female patients can have isolated corpus callosum agenesis. Among several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria shows genetic heterogeneity, including linkage to chromosome Xq28 in some pedigrees, autosomal dominant or recessive inheritance in others, and an association with chromosome 22q11.2 deletion in some patients. About 65% of patients have severe epilepsy. Recessive bilateral frontoparietal polymicrogyria has been associated with mutations of the GPR56 gene. Epilepsy is often present in patients with cortical malformations and tends to be severe, although its incidence and type vary in different malformations. It is estimated that up to 40% of children with drug-resistant epilepsy have a cortical malformation. However, the physiopathological mechanisms relating cortical malformations to epilepsy remain elusive.
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PMID:Genetic malformations of cortical development. 1672 81

Focal malformations of cortical development (FMCDs) account for the majority of drug-resistant pediatric epilepsy. Postzygotic somatic mutations activating the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway are found in a wide range of brain diseases, including FMCDs. It remains unclear how a mutation in a small fraction of cells disrupts the architecture of the entire hemisphere. Within human FMCD-affected brain, we found that cells showing activation of the PI3K-AKT-mTOR pathway were enriched for the AKT3(E17K) mutation. Introducing the FMCD-causing mutation into mouse brain resulted in electrographic seizures and impaired hemispheric architecture. Mutation-expressing neural progenitors showed misexpression of reelin, which led to a non-cell autonomous migration defect in neighboring cells, due at least in part to derepression of reelin transcription in a manner dependent on the forkhead box (FOX) transcription factor FOXG1. Treatments aimed at either blocking downstream AKT signaling or inactivating reelin restored migration. These findings suggest a central AKT-FOXG1-reelin signaling pathway in FMCD and support pathway inhibitors as potential treatments or therapies for some forms of focal epilepsy.
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PMID:An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development. 2652 71