Bilateral Frontoparietal Polymicrogyria Research Articles

A Novel GPR56 Mutation Causes Bilateral Frontoparietal Polymicrogyria

Bilateral frontoparietal polymicrogyria is an autosomal recessive inherited human brain malformation with abnormal cortical lamination. The affected cortex appears to consist of numerous small gyri, with scalloping of the cortical-white matter junction. There are associated white matter, brain stem, and cerebellar changes. Affected individuals manifest mental retardation, language impairment, motor developmental delay, and seizure disorder. GPR56 is the causative gene. Here we report a novel missense mutation of GPR56, E496K, identified in a consanguineous pedigree with bilateral frontoparietal polymicrogyria. GPR56 protein is cleaved at the G-protein-coupled receptor proteolytic site into an N-and a C-terminal fragment, named GPR56(N) and GPR56(C), respectively. E496K is located in GPR56(C). Further biochemical studies reveal that this mutation affects GPR56(C) cell surface expression similar to the effect of a previously reported mutation, R565W. These results provide further insights into how GPR56 mutation causes neurologic disease.

Disease-associated GPR56 Mutations Cause Bilateral Frontoparietal Polymicrogyria via Multiple Mechanisms

Loss-of-function mutations in the gene encoding G protein-coupled receptor 56 (GPR56) lead to bilateral frontoparietal polymicrogyria (BFPP), an autosomal recessive disorder affecting brain development. The GPR56 receptor is a member of the adhesion-GPCR family characterized by the chimeric composition of a long ectodomain (ECD), a GPCR proteolysis site (GPS), and a seven-pass transmembrane (7TM) moiety. Interestingly, all identified BFPP-associated missense mutations are located within the extracellular region of GPR56 including the ECD, GPS, and the extracellular loops of 7TM. In the present study, a detailed molecular and functional analysis of the wild-type GPR56 and BFPP-associated point mutants shows that individual GPR56 mutants most likely cause BFPP via different combination of multiple mechanisms. These include reduced surface receptor expression, loss of GPS proteolysis, reduced receptor shedding, inability to interact with a novel protein ligand, and differential distribution of the 7TM moiety in lipid rafts. These results provide novel insights into the cellular functions of GPR56 receptor and reveal molecular mechanisms whereby GPR56 mutations induce BFPP.

Comparative domain modeling of human EGF-like module EMR2 and study of interaction of the fourth domain of EGF with chondroitin 4-sulphate

EMR2 is an EGF-like module containing mucin-like hormone receptor-2 precursor, a G-protein coupled receptor (G-PCR). Mutation in EMR2 causes complicated disorders like polycystic kidney disease (PKD). The structure of EMR2 shows that the fifth domain is comprised of EGF-TM7 helices. Functional assignment of EMR2 by support vector machine (SVM) revealed that along with transporter activity, several novel functions are predicted. A twenty amino acid sequence “MGGRVFLVFLAFCVWLTLPG” acts as the signal peptide responsible for posttranslational transport. Eight amino acids are involved in N-glycosylation sites and two cleavage sites are Leu517 and Ser518 in EMR2. The residue Arg241 is responsible for interaction with glycosaminoglycan and chondroitin sulfate. On the basis of structure, function and ligand binding sites, competitive EMR2 inhibitors designed may decrease the rate of human diseases like Usher's syndrome, bilateral frontoparietal polymicrogyria and PKD.

The Orphan Adhesion-GPCR GPR126 Is Required for Embryonic Development in the Mouse

Adhesion-GPCRs provide essential cell-cell and cell-matrix interactions in development, and have been implicated in inherited human diseases like Usher Syndrome and bilateral frontoparietal polymicrogyria. They are the second largest subfamily of seven-transmembrane spanning proteins in vertebrates, but the function of most of these receptors is still not understood. The orphan Adhesion-GPCR GPR126 has recently been shown to play an essential role in the myelination of peripheral nerves in zebrafish. In parallel, whole-genome association studies have implicated variation at the GPR126 locus as a determinant of body height in the human population. The physiological function of GPR126 in mammals is still unknown. We describe a targeted mutation of GPR126 in the mouse, and show that GPR126 is required for embryonic viability and cardiovascular development.

GPR56-related bilateral frontoparietal polymicrogyria: further evidence for an overlap with the cobblestone complex

GPR56 mutations cause an autosomal recessive polymicrogyria syndrome that has distinctive radiological features combining bilateral frontoparietal polymicrogyria, white matter abnormalities and cerebellar hypoplasia. Recent investigations of a GPR56 knockout mouse model suggest that bilateral bifrontoparietal polymicrogyria shares some features of the cobblestone brain malformation and demonstrate that loss of GPR56 leads to a dysregulation of the maintenance of the pial basement membrane integrity in the forebrain and the rostral cerebellum. In light of these findings and other data in the literature, this study aimed to refine the clinical features with the first description of a foetopathological case and to define the range of cobblestone-like features in GPR56 bilateral bifrontoparietal polymicrogyria in a sample of 14 patients. We identified homozygous GPR56 mutations in 14 patients from eight consanguineous families with typical bilateral bifrontoparietal polymicrogyria and in one foetal case, out of 30 patients with bifrontoparietal polymicrogyria referred for molecular screening. The foetal case, which was terminated at 35 weeks of gestation in view of suspicion of Walker Warburg syndrome, showed a cobblestone-like lissencephaly with a succession of normal, polymicrogyric and 'cobblestone-like' cortex with ectopic neuronal overmigration, agenesis of the cerebellar vermis and hypoplastic cerebellar hemispheres with additional neuronal overmigration in the pons and the cerebellar cortex. The 14 patients with GPR56 mutations (median 8.25 years, range 1.5-33 years) were phenotypically homogeneous with a distinctive clinical course characterized by pseudomyopathic behaviour at onset that subsequently evolved into severe mental and motor retardation. Generalized seizures (12/14) occurred later with onset ranging from 2.5 to 10 years with consistent electroencephalogram findings of predominantly anterior bursts of low amplitude α-like activity. Neuroimaging demonstrated a common phenotype with bilateral frontoparietally predominant polymicrogyria (13/13), cerebellar dysplasia with cysts mainly affecting the superior vermis (11/13) and patchy to diffuse myelination abnormalities (13/13). Additionally, the white matter abnormalities showed a peculiar evolution from severe hypomyelination at 4 months to patchy lesions later in childhood. Taken as a whole, these observations collectively demonstrate that GPR56 bilateral bifrontoparietal polymicrogyria combines all the features of a cobblestone-like lissencephaly and also suggest that GRP56-related defects produce a phenotypic continuum ranging from bilateral bifrontoparietal polymicrogyria to cobblestone-like lissencephaly.

Genetic malformations of the human frontal lobe.

Interest in genetic malformations of the frontal lobe has grown from the recognition that certain brain malformations have a predilection for the frontal lobes or are more severe in the anterior brain. These malformations can be deleterious, as the frontal lobes in humans are particularly large in comparison with those of other species and play an important role in cognitive developmental functions.

Bilateral frontoparietal polymicrogyria (BFPP) syndrome secondary to a 16q12.1‐q21 chromosome deletion involving GPR56 gene

Bilateral frontoparietal polymicrogyria (BFPP) syndrome secondary to a 16q12.1‐q21 chromosome deletion involving GPR56 gene

Mutation of the Variant α-Tubulin TUBA8 Results in Polymicrogyria with Optic Nerve Hypoplasia

The critical importance of cytoskeletal function for correct neuronal migration during development of the cerebral cortex has been underscored by the identities of germline mutations underlying a number of human neurodevelopmental disorders. The proteins affected include TUBA1A, a major alpha-tubulin isoform, and microtubule-associated components such as doublecortin, and LIS1. Mutations in these genes are associated with the anatomical abnormality lissencephaly, which is believed to reflect failure of neuronal migration. An important recent observation has been the dependence of cortical neuronal migration upon acetylation of alpha-tubulin at lysine 40 by the histone acetyltransferase Elongator complex. Here, we describe a recognizable autosomal recessive syndrome, characterized by generalized polymicrogyria in association with optic nerve hypoplasia (PMGOH). By autozygosity mapping, we show that the molecular basis for this condition is mutation of the TUBA8 gene, encoding a variant alpha-tubulin of unknown function that is not susceptible to the lysine 40 acetylation that regulates microtubule function during cortical neuron migration. Together with the unique expression pattern of TUBA8 within the developing cerebral cortex, these observations suggest a role for this atypical microtubule component in regulating mammalian brain development.

Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations.

Bilateral frontoparietal polymicrogyria (BFPP) has been reported in sporadic patients and in recessive pedigrees. Eleven mutations in GPR56, a gene encoding an evolutionarily dynamic G-protein-coupled receptor, have been identified in 29 patients from 18 families. The clinical features of BFPP include severe mental retardation, motor and language impairment, and epilepsy. No detailed description of the epilepsy is available for the patients reported to date. We report three consanguineous families in which four affected individuals with BFPP and GPR56 mutations had Lennox-Gastaut syndrome. Family studies, brain magnetic resonance imaging (MRI), electroencephalography (EEG)-video recordings, and mutation analysis. In Family 1, with one affected proband, we found an R565W change in the second extracellular loop of GPR56, involving a highly conserved aminoacidic residue. In Family 2, with one affected proband, we found an R79X change affecting the protein N-terminus and predicted to cause a premature truncation with loss of the G-protein-coupled receptor proteolytic site. In family 3, with two affected siblings, we found an R33P substitution in the protein N-terminus, involving a highly conserved aminoacidic residue. Epilepsy, present in all four patients, had started between ages 1 and 8 years, with infantile spasms in one patient and with de novo Lennox-Gastaut syndrome in the remaining three. All patients had Lennox-Gastaut syndrome when last observed, at ages 13 to 32 years. Several genes, when mutated, can cause malformations of cortical development that have been associated with the Lennox-Gastaut syndrome. BFPP caused by GPR56 mutations represents an additional, although rare, genetically determined cause of Lennox-Gastaut syndrome.

Structural and functional analysis of GPR56 protein in human frontal cortex developmental disease BFPP: The role of disease‐associated mutations on receptor trafficking and functions

G protein‐coupled receptor 56 (GPR56) plays a role in the development of neural progenitor cells and has been linked to the developmental malformations of human brain. Similar to other adhesion GPCRs, GPR56 contains a GPCR proteolytic site (GPS) motif. Genetic mutations in GPR56 cause a human brain cortical malformation called bilateral frontoparietal polymicrogyria (BFPP). However, it remains unclear how these mutations affect GPR56 function. We cloned the wild type GPR56 cDNA and disease‐associated point mutants, including R38W, Y88C, and C91S in the N terminal domain, two mutations (R565W, L640R) in the extracellular loop domain, and the two mutations in the GPS domain (C346S and W349S). We aim to investigate how the BFPP‐associated mutations affect the intracellular trafficking and cell surface expression of GPR56. We found that disease‐associated GPR56 missense mutations produce proteins with reduced intracellular trafficking and poor cell surface expression or impaired GPS cleavage that fail to traffic beyond the ER. Furthermore, we has produced recombinant GPR56 extracellular domain as a protein probe for ligand search on various cell lines. We have identified a potential novel cellular ligand for GPR56. NSC97‐2628‐B‐182‐030‐MY2

GPR56 Regulates Pial Basement Membrane Integrity and Cortical Lamination

GPR56 is a member of the family of adhesion G-protein-coupled receptors that have a large extracellular region containing a GPS (G-protein proteolytic site) domain. Loss-of-function mutations in the GPR56 gene cause a specific human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). BFPP is a radiological diagnosis and its histopathology remains unclear. This study demonstrates that loss of the mouse Gpr56 gene leads to neuronal ectopia in the cerebral cortex, a cobblestone-like cortical malformation. There are four crucial events in the development of cobblestone cortex, namely defective pial basement membrane (BM), abnormal anchorage of radial glial endfeet, mislocalized Cajal-Retzius cells, and neuronal overmigration. By detailed time course analysis, we reveal that the leading causal events are likely the breaches in the pial BM. We show further that GPR56 is present in abundance in radial glial endfeet. Furthermore, a putative ligand of GPR56 is localized in the marginal zone or overlying extracellular matrix. These observations provide compelling evidence that GPR56 functions in regulating pial BM integrity during cortical development.

Orphan G Protein-coupled Receptor GPR56 Regulates Neural Progenitor Cell Migration via a Gα12/13 and Rho Pathway

In the developing forebrain, the migration and positioning of neural progenitor cells (NPCs) are regulated coordinately by various molecules. Mutation of these molecules, therefore, causes cortical malformation. GPR56 has been reported as a cortical malformation-related gene that is mutated in patients with bilateral frontoparietal polymicrogyria. GPR56 encodes an orphan G protein-coupled receptor, and its mutations reduce the cell surface expression. It has also been reported that the expression level of GPR56 is involved in cancer cell adhesion and metastasis. However, it remains to be clarified how GPR56 functions in brain development and which signaling pathways are activated by GPR56. In this study, we showed that GPR56 is highly expressed in NPCs and has the ability to inhibit NPC migration. We found that GPR56 coupled with Galpha(12/13) and induced Rho-dependent activation of the transcription mediated through a serum-responsive element and NF-kappaB-responsive element and actin fiber reorganization. The transcriptional activation and actin reorganization were inhibited by an RGS domain of the p115 Rho-specific guanine nucleotide exchange factor (p115 RhoGEF RGS) and dominant negative form of Rho. Moreover, we have demonstrated that a functional anti-GPR56 antibody, which has an agonistic activity, inhibited NPC migration. This inhibition was attenuated by p115 RhoGEF RGS, C3 exoenzyme, and GPR56 knockdown. These results indicate that GPR56 participates in the regulation of NPC movement through the Galpha(12/13) and Rho signaling pathway, suggesting its important role in the development of the central nervous system.

Three Patients With Severe Bilateral Frontoparietal Polymicrogyria

The bilateral frontoparietal polymicrogyria syndrome is characterized anatomically by predominantly frontoparietal diffuse polymicrogyria and clinically by generalized tonic-clonic seizures and mental retardation developing in early childhood. Despite the diffuse nature of the cortical involvement, patients do gain the ability to speak and to walk. In addition, epilepsy can be relatively well controlled with antiepileptic drugs. In three cases of bilateral frontoparietal polymicrogyria, the patients demonstrated consistently similar clinical and neuroimaging characteristics, with more severe structural and developmental abnormalities than those reported previously. The designation proposed here recognizes such cases as a severe form of bilateral frontoparietal polymicrogyria. An ethnic difference or a causal gene other than GPR56 might be responsible for the difference in severity between the classical and the more severe forms of bilateral frontoparietal polymicrogyria.

Biochemical characterization of genetic mutations of GPR56 in patients with bilateral frontoparietal polymicrogyria (BFPP)

Bilateral frontoparietal polymicrogyria (BFPP) is a rare genetic disease characterized by cortical malformation associated with GPR56 mutations of frameshift, splicing, and point mutations (Science 303:2033). All the missense point mutations are located in the regions predicted to be exposed at the cell surface, e.g. the N-terminal extracellular domain (ECD), the proteolytic site (GPS), and the extracellular loops of transmembrane domain (TM), implying functionally important interaction among these domains. Wild type GPR56 protein is cleaved at the GPCR protein cleavage site (GPS) and gives rise to two subunits (ECD and TM), which are transported to cell surface. We have shown that GPR56 GPS mutant protein is defective in cleavage and surface localization, while non-GPS mutant proteins are cleaved normally but still defective in surface localization. Furthermore, all the mutant proteins demonstrated different glycosylation pattern from that of wild-type protein. PNGase F and Endo H sensitivity assays suggests that the mutant proteins are trapped in endoplasmic reticulum (ER), preventing them from trafficking to Golgi where further glycosylation modification usually occurs before destination to cell surface. Therefore, the loss-of-function of all these missense mutations is primarily caused by their failure to localize to cell surface.

Disease-associated mutations affect GPR56 protein trafficking and cell surface expression

Bilateral frontoparietal polymicrogyria (BFPP) is a congenital brain malformation resulting in irregularities on the surface of the cortex, where normally convoluted gyri are replaced by numerous (poly) and noticeably smaller (micro) gyri. Individuals with BFPP suffer from epilepsy, mental retardation, language impairment and motor developmental delay. Mutations in the gene-encoding G protein-coupled receptor 56 (GPR56) cause BFPP; however, it remains unclear how these mutations affect GPR56 function. Here, we examine the biochemical properties and protein trafficking of wild-type and mutant GPR56. We demonstrate that GPR56 protein undergoes two major modifications, GPS domain-mediated protein cleavage and N-glycosylation, and that the N-terminal fragment can be released from the cell surface. In contrast to the wild-type protein, disease-associated GPR56 missense mutations in the tip of the N-terminal domain (R38Q, R38W, Y88C and C91S) produce proteins with reduced intracellular trafficking and poor cell surface expression, whereas the two mutations in the GPS domain (C346S and W349S) produce proteins with dramatically impaired cleavage that fail to traffic beyond the endoplasmic reticulum. Cell-trafficking impairments are abrogated in part by pharmacological chaperones that can partially rescue mutant GPR56 cell surface expression. These data demonstrate that some BFPP-associated mutations in GPR56 impair trafficking of the mutant protein to the plasma membrane, thus providing insights into how BFPP-associated mutations affect GPR56 function.

Orphan G protein–coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway

GPR56 is an orphan G protein - coupled receptor, mutations of which have recently been associated with bilateral frontoparietal polymicrogyria, a rare neurologic disease that has implications in brain development. However, no phenotype beyond central nervous system has yet been described for the GPR56-null mutations despite abundant GPR56 expression in many non - central nervous system adult tissues. In the present study, we show that higher GPR56 expression is correlated with the cellular transformation phenotypes of several cancer tissues compared with their normal counterparts, implying a potential oncogenic function. RNA interference-mediated GPR56 silencing results in apoptosis induction and reduced anchorage-independent growth of cancer cells via increased anoikis, whereas cDNA overexpression resulted in increased foci formation in mouse fibroblast NIH3T3 cell line. When GPR56 silencing was induced in vivo in several xenograft tumor models, significant tumor responses (including regression) were observed, suggesting the potential of targeting GPR56 in the development of tumor therapies. The expression profiling of GPR56-silenced A2058 melanoma cell line revealed several genes whose expression was affected by GPR56 silencing, particularly those in the integrin-mediated signaling and cell adhesion pathways. The potential role of GPR56 in cancer cell adhesion was further confirmed by the observation that GPR56 silencing also reduced cell adhesion to the extracellular matrix, which is consistent with the observed increase in anoikis and reduction in anchorage-independent growth phenotypes. The oncogenic potential and apparent absence of physiologic defects in adult human tissues lacking GPR56, as well as the targetable nature of G protein - coupled receptor by small molecule or antibody, make GPR56 an attractive drug target for the development of cancer therapies.

Genetic malformations of cortical development

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.

Genotype–phenotype analysis of human frontoparietal polymicrogyria syndromes

Human cerebral cortical polymicrogyria is a heterogeneous disorder, with only one known gene (GPR56) associated with an apparently distinctive phenotype, termed bilateral frontoparietal polymicrogyria (BFPP). To define the range of abnormalities that could be caused by human GPR56 mutations and to establish diagnostic criteria for BFPP, we analyzed the GPR56 gene in a cohort of 29 patients with typical BFPP. We identified homozygous GPR56 mutations in all 29 patients with typical BFPP. The total of 11 GPR56 mutations found represented a variety of distinct founder mutations in various populations throughout the world. In addition, we analyzed five patients with BFPP who did not show GPR56 mutation and found that they define a clinically, radiographically, and genetically distinct syndrome that we termed BFPP2. Finally, we studied seven patients with a variety of other polymicrogyria syndromes including bilateral frontal polymicrogyria, bilateral perisylvian polymicrogyria, and bilateral generalized polymicrogyria. No GPR56 mutation was found in these patients. This study provides a molecular confirmation of the BFPP phenotype and provides the wherewithal for diagnostic screening.

Topical Review: Cortical Malformation and Pediatric Epilepsy: A Molecular Genetic Approach

Genetic malformations of the cerebral cortex are important causes of neurologic morbidity in children because they are often associated with developmental delay, motor disturbances (cerebral palsy), and epilepsy. Primary autosomal recessive microcephaly is a cortical malformation with a low incidence of epilepsy. One of its causative genes, ASPM, might play an important role in regulating proliferation of neuronal progenitor cells. Mutations in ASPM do not seem to affect later stages of cortical development, such as neuronal migration, and this might be responsible for the low epileptogenicity of this malformation. ASPM might also have played an important role in the evolutionary expansion of the human brain. Bilateral frontoparietal polymicrogyria, on the other hand, is a highly epileptogenic malformation. Its causative gene, GPR56, is also expressed in the neurogenic regions of the cortex, but its primary function might be in the determination of cell fate and/or cortical patterning. Further studies of these genes will likely lead to a better understanding of human brain development and epilepsy.

Topical Review: Neuronal Migration Disorders, Genetics, and Epileptogenesis

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.