Epilepsy and genetic malformations of the cerebral cortex

Abstract

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.

Correlation of Prenatal and Postnatal MRI Findings in Schizencephaly

“…10,13,21 Bilaterality of the defect is the major poor prognostic factor. 10,13 While children with unilateral schizencephaly often present with hemiparesis and mild mental delay, those with bilateral defects may be tetraparetic with severe mental deficits.…”

Aspectos clínicos em 16 pacientes com diagnóstico tomográfico de esquizencefalia

“…(1) is an extremely rare congenital disorder characterized by a fullthickness cleft within the cerebral hemispheres, delimited by an abnormal cortex (2-4) , extending from the ventricular surface to the arachnoid space (3,4) . Frequently, schizencephaly involves the perisylvian regions (2,5) and large portions of the cerebral hemispheres may be absent and replaced by fluid (2) .…”

Molecular genetic decoding of malformations of cortical development

“…Development of the cerebral cortex is complex and involves proliferation, migration, and organization of neural progenitor cells [2,3]. Abnormalities at any stage during cerebral cortex development could result in a wide range of phenotypes, ranging from focal cortical dysplasia to hemimegalencephaly (HME) which show the enlargement of one hemisphere of brain (Fig.…”