Neuroradiologic features in NMDs
Cortical malformations from abnormal migration are increasingly recognized as a cause of both epilepsy and developmental disabilities. Neuronal migration disorders (NMDs) represent one of the conditions associated with intractable epilepsy; particularly, histologically proven developmental brain abnormalities are observed in up to 25% of children with intractable seizures (14). Most of such abnormalities may now be detected with magnetic resonance imaging (MRI), although some cortical malformations remain undetectable even with the best imaging techniques. Sometimes, we can use a specific term in case of suggestive (or even pathognomonic) MRI pattern, but neuroradiological investigations do not always provide a precise indication of the pathological nature of the lesion.
Abnormalities of the cerebral cortex may be diffuse or they may involve discrete cortical areas. Certain NMDs are genetically determined and, for others, a genetic origin has been hypothesized; however, some may be linked to prenatal insult (environmental, chemical or iatrogenic) with a precise gestational age timing-related.
Recognizing in every single patient the type of NMDs represent a very important challenge. It can allow us to formulate more accurate prognostic evaluations, considering that some malformations are more epileptogenic than others, as they occur in specific forms (showing a well-known neuroradiological pattern) in which the epileptogenesis appears to originate from the intrinsic properties of the dysplastic tissue (15).
Most NMDs affected patients, can be well identified by MRI techniques, structural and functional.
To best classify NMDs in these children, imaging studies should be optimized and, as a rule, thin-section T1- and T2-weighted MRI images should be acquired. For T1-weighted images, a volumetric spoiled gradient echo sequence should be acquired with partition size of 1–1.5 mm to allow the data to be reformatted in any plane. At a minimum, sagittal, coronal and axial images are necessary. For T2-weighted images, contrast between grey and WM is best using conventional spin echo images. In neonates and infants less than 10-month olds (before myelination), thin-section (1.5–3 mm) heavily T2-weighted spin echo images are optimal, whereas between the ages of 10 and 24 months, thin partitions of T1-weighted volumetric spoiled gradient echo images with heavy T1 weighting are best. Beyond the age of two years, standard adult protocols should be used.
The imaging findings of lissencephaly vary with the severity of the mutation (16). When very severe, the cortex is markedly thickened and almost no sulci are formed (Fig. 3); when less severe, the cortex is less thickened and a variable number of shallow sulci separate broad gyri. In some cases, a ‘cell-sparse zone’ is identified between the thin outer cortical layer and the thicker inner cortical layer of neurons whose migration has been arrested (17).
Figure 3. Brain MRI: lissencephaly type I. T1 weighed axial view: slight hypoplasia of the corpus callosum and a small cyst of the septum pellucidum and a cavum vergae (pentagon); agyria in the parietal lobes (arrows); some gyri and sulci in frontal and occipital lobes (arrowheads), colpocephaly (horizontal and bidirectional arrow) and beginning of the silvian fissures.
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The imaging characteristics of bilateral frontoparietal polymicrogyria (BFPP) (myelination defects, cerebellar cortical dysplasia with cysts, frequent involvement of the medial aspects of the cerebral hemispheres) resemble more those of the so-called cobblestone malformations (muscle–eye–brain disease and Fukuyama congenital muscular dystrophy) that are also associated with N-glycosylation defects in the developing brain. Therefore, this disorder might be best classified as a cobblestone malformation. The imaging appearance of polymicrogyria varies with the age of the patient (18). In newborns and young infants, the polymicrogyric cortex is very thin, with multiple, very small undulations. After myelination, polymicrogyria appears as slightly thick cortex with a slightly irregular cortex-WM junction. The pial surface might appear paradoxically smooth, as a result of fusion of the molecular layer (cortical layer 1) across adjacent microgyri. Polymicrogyria can be localized to a single gyrus, involve portions of a hemisphere, be bilateral and asymmetrical, bilateral and symmetrical or diffuse (Fig. 4). Sometimes, it is associated with deep clefts that might extend through the entire cerebral mantle to communicate with the lateral ventricle (schizencephaly).
Single photon emission computed tomography (SPECT) (ictal and interictal) and positron emission tomography (PET) give additional information about metabolic correlations (19); in specific condition MRI-spectroscopy may give crucial metabolic information too.
Previous studies have shown that interictal and postictal SPECT are well correlated with EEG in partial epilepsy in terms of focal decreasing in cerebral blood flow (rCBF) (19). However, decreased rCBF can be present in cortical dysplasia in both ictal and interictal phases (20).
Functional studies have suggested that NMDs can present with either hypometabolism or preserved perfusion of heterotopia, the so-called ‘displaced grey matter activity (21)’.
In NMDs, the observation of preserved perfusion by SPECT studies in heterotopia has been related to the microscopic finding of a normal six-layered cortex in laminar heterotopia (22), while cerebellar hemispheric hypoperfusion, contralateral to the epileptic focus, has been reported in a variety of unilateral cerebral lesions in patient with focal epilepsy (23). These cerebellar modifications cannot be interpreted as the result of a complication of repetitive seizures, nor the expression of lesions at the ‘morphologic’ level; they are most likely the result of altered corticopontocerebellar input from the contralateral cerebral hemisphere (cerebellar diaschisis) (24).
In addition to MRI and PET/SPECT studies, Proton MRI spectroscopy (MRS) should add information for the identification and characterization of abnormal brain tissue of NMDs. In general N-acetylaspartate (NAA), choline-containing compounds (Cho) and creatine-phosphocreatine (Cr) are expressed in a various concentration throughout the brain, depending on tissue degree of maturation. Furthermore, neuronal tissue may have different spectra profiles depending on technology (single or multiple voxel) (Fig. 5). In fact, giant grey matter heterotopia have been reported to be characterized by normal NAA, Cho, Cr spectra or by increased Cho, Cr peaks and a normal NAA signal. By means of proton MRS at 4.1 T it has been demonstrated that focal cortical dysplasia revealed metabolic abnormalities consistent with the structural lesions, whereas in focal heterotopia and polymicrogyria biochemical abnormalities have not been demonstrated (25).
Figure 5. (A,B): A: MRI (coronal view-T2 weighted) in the left frontal lobe a diffuse cortical hyperintensity (arrow) with absence of the normal cortical blurring between white and grey matter compatible with cortical dysplasia. B: MRI spectroscopy (single voxel) notes the augmentation of the myoinositol and the marked depletion of the N-acetyl-aspartate in the cortical dysplasia.
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Among new neurodevelopmental technologies, functional magnetic resonance imaging (fMRI) is a recent method to study the sensorimotor cortex in healthy subjects and in patients (7). Bilateral and symmetric band heterotopia have been studied with this methodology in only one child (6); in this patient a bilateral activation of both normal cortical mantle and band heterotopia was observed during a finger-tapping test. In our patient, activation of the normal left sensorymotor cortex together with the facing band heterotopia was observed. In the right hemisphere only the sensorymotor cortex was activated; no involvement of the right band heterotopic tissue was observed (25) (Fig. 6).
Figure 6. (A, B): A: MRI scan (axial view: IR sequence; TR = 2000 ms, TE = 20 ms). Normal overlying cortical mantle; bilateral band heterotopia (arrows) characterized by a greater thickness in the left hemisphere especially at frontal and occipital levels (arrowheads). B: fMRI activation of both the left band heterotopia (arrow) and the overlying cortex (arrowhead) when right hand is activated.
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Schizencephaly is characterized by full thickness cleft of the cerebral hemisphere from the ependyma to the pial surface of the brain. The cleft is located everywhere, but it is more frequent in the perisylvian regions. (Fig. 7). This malformation can be unilateral or bilateral, symmetric or asymmetric and divided in two types: closed or fused lips, type I (if the cleft walls are in apposition) and open lips, type II (if the cleft walls are separated). Schizencephaly type II is more common than type I (11).
Figure 7. MRI (IR sequence SE 200 – 38 coronal view) show large left open lip frontotemporoparietal schizencephaly (arrowheads), with a polymicrogyric cortex lining the cleft. On the right-hand side a polymicrogyric opercular malformation is also present (arrows).
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NMDs genetic aspects
NMDs are frequently caused by defects in molecules that are essential for neuronal migration (26). For example, among the identified genes currently associated with PH, the most cited are ARFGEF2 and FLNa (8). FLNa is tightly regulated both temporally and spatially during cortical development, where normal expression appears to be low in the VZ and is higher in the IZ and CP. This reflects enrichment of FLNa in post-mitotic migrating neurons, an expression pattern that might be maintained in part by FILIP (Filamin-A-interacting protein), a potent degrader of FLNa (27). Although FILIP is expressed in the developing forebrain, whether it is present and active in both neurons and radial glia is unknown. It is conceivable that FILIP activity is high in neuronal progenitors and is subsequently lost or inactivated in post-mitotic neurons, allowing FLNa to initiate migration.
FLNa is believed to drive migration by reorganizing the actin cytoskeleton to generate the forces necessary for cell mobility (28). This is supported by the finding that in mice, expression of FLNa lacking the actin-binding domain (FLNa-actin binding domain [ABD]) arrests the migration of post-mitotic neurons, albeit in the IZ. FLNa mutations resulting in PH often involve truncation or disruption of the actin-binding domain, indicating that FLNa's ability to cross-link actin may be necessary for migration. Nevertheless, FLNa might play additional developmental roles during corticogenesis.
Genetics in lissencephaly
Lissencephaly (including both agyria and pachygyria) is the most severe of the known malformations from abnormal neuronal migration. Most cases of lissencephaly occur without any associated malformation outside the brain (isolated lissencephaly sequence – ILS), and some belong to more complex malformation syndromes, explaining the difficulty in Lissencephaly classification (Table 1).
Table 1. Types of lissencephaly classification (new proposed 2008 classification is based on the gradient [anterior/posterior] and size of the altered cerebral structure and on the association with anomalies of extra-cerebral structures; this classification in not completely defined)
|Types of lissencephaly classification||Lissencephaly groups||Sub-groups|
|Dobyns and Leventer 2003 (43)||Classic (or Type I)||Isolated lissencephaly sequence (ILS)|
|Subcortical band heterotopia (SBH)|
|Miller–Dieker syndrome (MDS)|
|Isolated lissencephaly without known genetic defects|
|Cobblestone (or Type II)||Walker–Warburg syndrome (WWS)|
|Muscle–eye–brain disease (MEB)|
|Fukuyama type congenital muscolar dystrophy|
|Lissencephaly (mild) with cerebellar hypoplasia ‘GROUP B’ (LCH) or Disequilibrium syndrome|| |
|X-linked lissencephaly with abnormal genitalia (XLAG)|| |
|New (2008) proposed lissencephaly classification (8,44)||Lissencephaly variants 4,3,2 layers||Variant 4 layers (classical lissencephaly; Miller–Dieker syndrome):|
|1. Isolated lissencephaly sequence (ILS);|
|2. Subcortical band heterotopia (SBH);|
|3. Lissencephaly with cerebellar hypoplasia (LCH) ‘group A’;|
|4. Baraitser–Winter syndrome|
|Variant 3 layers: XLAG|
|Variant 2 layers: lissencephaly with cerebellar hypoplasia (LCH) ‘group C’;|
|Other lissencephalies (autosomal recessive)||1. Lis with mild frontal pachygyria;|
|2. Lissencephaly with cerebellar hypoplasia (LCH) ‘group B’;|
|Microlissencephaly spectrum (severe congenital microcephaly with lis)||1. Barth microlissencephaly syndrome;|
|2. Norman–Roberts syndrome (NRS);|
|3. Microcephalic osteodysplastic primordial dwarfism I (MOPD 1);|
|Cobblestone cortical malformation||1. Walker–Warburg syndrome (WWS);|
|2. Muscle-eye-brain disease (MEB);|
|3. Fukuyama type congenital muscolar dystrophy;|
|4. Gpr56-related bilateral fronto-parietal cobblestone-like malformation;|
|5. Debre' type cutis laxa with cgd type II glycosylation defect and cobblestone-like dysgenesis|
Less severe defects in the same genes and developmental processes result in subcortical band heterotopia. In this group of malformations, neurons begin migration but are unable to complete it. To date, mutations of six genes have been associated with lissencephaly including LIS1, DCX, TUBA1A, RELN, VLDLR and ARX, whereas co-deletion of YWHAE with LIS1 appears to act as a modifier locus. The associated phenotypes include isolated lissencephaly sequence (DCX in males, LIS1 and rarely TUBA1A), subcortical band heterotopia (DCX in females and rare males, and LIS1), Miller–Dieker syndrome (co-deletion of LIS1 and YWHAE), mild lissencephaly with cerebellar hypoplasia ‘group b’ or the ‘disequilibrium syndrome’ (RELN and VLDLR) and X-linked lissencephaly with abnormal genitalia (ARX) (Table 2). Mutations of LIS1 (including deletions), DCX and TUBA1A account for 65%, 12% and an unknown but small percent of patients with lissencephaly. In contrast to previous reports, recent data suggest that neither type nor position of intragenic mutations in the LIS1 gene allows an unambiguous prediction of the phenotypic severity (29). The proteins coded by these genes all regulate microtubule and cytoplasmic dynein function and – at least for LIS1– interfere with neuronal migration by blocking microtubule-directed nuclear movement in VZ neuroblasts, conversion of nascent post-mitotic neurons to multipolar pre-migratory cells and conversion of multipolar to bipolar migratory cells. Mutations of these three genes lead to the classic form of lissencephaly in which cortical thickness is increased fourfold (3.5–4 mm to 12–20 mm) and produce a recognizable gradient in which the malformation is more severe anteriorly (DCX) or posteriorly (LIS1 and TUBA1A).
Table 2. Classic Lissencephaly (type I): involved genes with protein products, functions and associated phenotipes (8)
|Gene||Full name/protein product||Locus||Protein function||Associated phenotype|
|LIS1 or PAFAH1B1||Alpha subunit of the intracellular 1b isoform of the platelet activating factor acetylhydrolase||17 p13.3||Initiation and progression of neuronal movement through regulation of microtubule and dynein function||Isolated Lissencephaly Sequence (ILS) (OMIM #607432)|
|DCX or XLIS||Doublecortin||Xq22.3q23||Initiation and progression of neuronal movement through regulation of microtubule and dynein function||X-Linked Lissencephaly (in males); Subcortical Band Heterotopia (in females); (OMIM #300067)|
|TUBA1A||Alpha 1a tubulin||12q12-q14||Initiation and progression of neuronal movement through regulation of microtubule and dynein function||Isolated Lissencephaly Sequence (ILS) (OMIM #611603)|
|VLDLR||Very low density lipo-protein receptor||9p24||Part of the reelin signalling pathway||Lissencephaly with cerebellar hypoplasia "group b" (LCH) (OMIM #224050)|
|RELN||Reeler mutant mouse/Reelin||7q22||Cell–cell interactions and neuronal migration (secreted by Cajal–Retzius cell 1)||Lissencephaly with cerebellar hypoplasia "group b" (LCH) (OMIM #257320)|
|ARX||Aristaless related homeobox (trascription factor)||Xp22.13||Proliferation/development of neuronal precursor; tangential migration of interneurons||X-linked Lissencephaly with Abnormal Genitalia (XLAG) (OMIM #300215)|
|YWHAE (with LIS1)||Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein||17p13.3||14-3-3 family of proteins; mediate signal transduction by binding to phosphoserine-containing proteins||Miller–Dieker syndrome (MDS) (OMIM #247200)|
Other patients with classical ILS or subcortical band heterotopia (SBH) (about 20%) have mutations of the DCX gene (Xq22.3), resulting in X-linked lissencephaly (LISX1) or double cortex (DC) syndrome; mutations of DCX gene and is its product, doublecortin, a cytoplasmic protein which appears to direct neuronal migration by regulating the organization and stability of microtubules, cause a complete lissencephaly in males and a double cortex syndrome in females; this difference is caused by the physiological random inactivation of the X chromosome (lyonization) occurring in females. If the abnormal DCX gene is not compensated by its normal homologous copy, a normal neuronal migration is prevented: consequently, the mutated neurons in the non-inactivated X chromosome are unable to complete the migration and reach their final destination; in reverse, the neurons with a normal copy of the gene (whose abnormal counterpart is contained in the inactivated X-chromosome) can normally migrate to the brain cortical surface. The above reported mutations in females result in two bands of cortex separated by a layer of WM (double cortex), while in males it results in a complete lissencephalic phenotype (30).
Mutations of ARX are a rare cause of lissencephaly (16) although less severe mutations result in a more common developmental disorder, cryptogenic infantile spasms. This gene is a transcription factor expressed in forebrain that regulates non-radial migration of interneurons from ventral regions (ganglionic eminence) to the developing cortex (31) and has other unknown functions in the dorsal cortex. Severe seizures are presumably related to a severe deficiency of inhibitory interneurons and suggest a novel developmental mechanism for some forms of early onset severe epilepsy. Patients with ARX mutations have abnormalities of the basal ganglia and absence of the corpus callosum, whereas those with RELN and VLDLR mutations have less cortical thickening, absence of a cell-sparse zone and profound cerebellar hypoplasia (32). The cerebral cortex of the newly described two-layered lissencephaly (17) has only a slightly thickened cortex with few sulci, thinning of the cerebral WM and, often, absence of the corpus callosum.
ARX's role in nervous system development is confirmed by numerous syndromes genetically related: X-linked infantile spasms (West syndrome), X-linked myoclonic epilepsy with spasticity and mental retardation, X-linked mental retardation, Partington syndrome (mental retardation, dystonic movements of the hands and dysarthria), Proud syndrome (acquired microcephaly, mental retardation, agenesis of the corpus callosum and peculiar facies), hydranencephaly with ambiguous genitalia, XLAG syndrome. XLAG is a syndrome described in 1999, presenting with lissencephaly (more severe than LIS1 or DCX-related lissencephaly), agenesis of the corpus callosum, refractory epilepsy (with tonic, multifocal myoclonic or generalized tonic–clonic seizures) of neonatal onset, acquired microcephaly and male genotype with ambiguous genitalia; all patients show intractable epilepsy and lacked psychomotor development, and the most of cases die before the age of 18 months (33).
The main genes involved in Lissencephaly type II are summarized in Table 3.
Table 3. Cobblestone Lissencephaly (type II): involved genes with protein products, functions and associated phenotypes (8)
|Gene||Full name/protein product||Locus||Protein function||Associated phenotypes|
|POMT1||Protein-O-mannosyltransferase 1||9q34||Cell integrity and cell wall rigidity||Walker–Warburg syndrome (WWS) (OMIM #236670)|
|Muscle-eye-brain disease (MEB) (OMIM #253280)|
|POMT2||Protein-O-mannosyltransferase 2||14q24.3||Interaction with the product of the POMT1 gene for enzymatic function||MEB WWS|
|FKTN (or FCMD)||Fukutin||9q31–33||Glycosilation of alpha–destro-glycan carbohydrates in the skeletal muscle||Fukuyama type congenital muscular dystrophy (FCMD) (OMIM #253800)|
|FKRP||Fukutin related protein||19q13.32||Co-operates with Fukutin||MEB|
|POMGnT1||Protein O-linked mannose beta1, 2-N-acetylglucosaminyltransferase||1p34||Conversion of the mannose beta 1–2 acetylate||MEB|
|LARGE||Acetylglucosaminyltransferase-like protein||22q-12.3–13.1||Glycosilation of the alpha-destro-glycans||MEB|
Genetics in heterotopia
Heterotopia are clusters of normal neurons in abnormal locations. The most common type, periventricular nodular heterotopia (PNH), are the neurons that never begin migration, remaining adjacent to the lateral ventricles. To date, 15 distinct PNH syndromes have been described (34). The most common of these is classic bilateral PNH, which is much more frequent in females; more than 50% have mutations of the X-linked FLNA gene. Autosomal recessive microcephaly with PNH is a very rare phenotype caused by mutations of ARFGEF2. PNH has also been associated with copy number variations including duplication 5p15.1 or 5p15.33 (35) and deletion 6q26-q27 or 7q11.33 (36).
Some patients with PNH have also been described with Chiari I and Amniotic Band Syndrome (37,38). No genetic insights into other forms of heterotopia have been gleaned. Heterotopia are divided into three main groups, PNH, subcortical heterotopia and leptomeningeal heterotopia, but only the first two can be detected by imaging (so called subcortical band heterotopia or ‘double cortex’ is a mild form of lissencephaly and classified in that group). PNH might be isolated – usually presenting with seizures – or part of a multiple congenital anomaly syndrome. When isolated they are often X-linked, and affected patients develop normally until the onset of epilepsy, which appears in 72% and at variable ages. Subcortical heterotopia are sporadic, irregular, curvilinear accumulations of grey matter nodules that course from the ventricular surface to the cortex, which is often thin and microgyric. The ipsilateral hemisphere is typically small and the basal ganglia are small and irregular. Affected patients have epilepsy and might have accompanying neurologic signs/symptoms.
Genetics in polymicrogyria
The term polymicrogyria defines an excessive number of abnormally small gyri that produce an irregular cortical surface. It is a very common cortical malformation and is associated with a dizzying array of patterns and syndromes (Table 4).
Table 4. Polymicrogyric syndromes (45)
|Polymicrogyric syndromes||Clinical signs/symptoms||Cerebral or other associated malformation||Inheritance|
|Bilateral generalized polymicrogyria (BGP)||Motor and cognitive delay; spastic haemi- or quadriparesis; Seizures||Ventriculomegaly and reduced WMvolume; macrocephaly, scalp and limb defects, low set ears, macrostomia, hypothyroidism and sensorineural hearing loss||AR|
|Bilateral frontal polymicrogyria (BFP)||Motor and language delay; spastic haemi- or quadriparesis; Mild/moderate mental retardation; seizures (38%)||Undefined||AR|
|Bilateral perisylvian polymicrogyria (BPP) (4 grades) (OMIM #300388)||Pseudo-bulbar palsy (facio-pharyngo-glosso-masticatory paresis) and dysarthria (100%); seizures (85%); piramidal signs; mental delay (50–80%)||Arthrogryposis, club feet and micrognathia||AR or AD Xq28 (X-linked)|
|Bilateral fronto-parietal polymicrogyria (BFPP) (OMIM #606854)||Motor and mental delay; dysconjugate gaze (esotropia); seizures (>90%); cerebellar and piramidal signs;||Bilateral WM abnormalities atrophy of the brain stem and cerebellum||16q12.2-21 (GPR56 gene) AR|
|Bilateral parasagittal parieto-occipital polymicrogyria (BPOP)||Seizures; mild/moderate mental retardation||Undefined||Undefined|
|Unilateral polymicrogyria (OMIM%610031)||Spastic haemiparesis; mental delay; seizures; electrical status epilepticus during sleep (ESES)||Undefined||AR or AD or X-linked|
Extent and location of the polymicrogyric abnormality influence the severity of neurologic manifestations. Polymicrogyric cortex in language-related areas, around the left perisylvian fissure, was identified by means of autopsy in individuals with developmental dysphasia or dyslexia (39) and is considered to be an important cause of the developmental language disorder. Mutations of the SRPX2 gene have been associated with bilateral perisylvian polymicrogyria, which is regularly accompanied by oral and speech dyspraxia, but also with oral and speech dyspraxia and seizures in individuals with normal brain MRI. These observations, and the finding that the orthologous gene SRPX2 is not detected during murine embryogenesis, suggest a major role for SRPX2 in the development and functioning of language-related areas in humans.
Polymicrogyria pathogenesis is not understood; brain pathology demonstrates abnormal development or loss of neurons in middle and deep cortical layers (40), variably associated with an unlayered cortical structure. Today, polymicrogyria has been associated with mutations of only a few genes including (8) SRPX2, PAX6, TBR2, KIAA1279, RAB3GAP1 and COL18A1, with all but SRPX2 found in rare syndromes (Table 5). Developmental studies are available for only PAX6 and TBR2, but these suggest one potentially interesting mechanism. The SRPX2 gene maps to band Xq23, and does not account for X-linked forms of perisylvian polymicrogyria that map to Xq27 and Xq28.
Table 5. Polymicrogyria:involved genes with protein products, functions and associated phenotipes (45)
|Gene||Full name/protein product||Location||Protein function||Associated phenotype|
|SRPX2||Sushi-repeat-containing protein, X-linked 2||Xq21.33-q23||Involved in the proteolytic remodeling of the extracellular matrix (partner of uPAR, ADAMTS4, CTSB*) in the development and functioning of the speech cortex||Bilateral Perisylvian Polymicrogyria (BPP)|
|PAX6||Paired box 6||11p13||DNA binding protein and regulator of gene transcription, expressed in the developing nervous system||Unilateral Polymicrogyria|
|TBR2||Eomesodermin homolog (EOMES)||3p21.3-p21.2||Conserved protein family that shares a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes||Undefined|
|KIAA1279||Kinesis like family 1 protein (KIF1) binding protein||10q21.3||KIF1 is an axonal transporter of synaptic vesicles||Bilateral Generalized Polymicrogyria|
|RAB3GAP1||RAB3 GTPase activating protein subunit 1 (catalytic)||2q21.3||Involved in regulation of RAB3 protein family, implicated in regulated exocytosis of neurotransmitters and hormones||Undefined|
|COL18A1||Alpha 1 type XVIII collagen||21q22.3||Extracellular matrix proteins with an important role in neural tube closure||Undefined|
|GPR56||G protein-coupled receptor 56||16q12.2-q21||Expressed in neuronal progenitor cells of the ventricular and subventricular germinal zones during neurogenesis||Bilateral Fronto-Parietal Polymicrogyria (BPFF)|
BFPP is associated with mutations of a gene named GPR56. GPR56 codes for a G-protein-coupled receptor that is expressed in neuronal progenitor cells of the ventricular and subventricular germinal zones during periods of neurogenesis. It appears that mutations in GPR56 result in impaired trafficking of the mutant protein to the plasma membrane.
Genetics in schizencephaly
To date the etiology of this disorder is not established because it is associated with several causes that include genetic, vascular, toxic, metabolic and infectious factors. It is supposed that a focal ischemic necrosis or focal damage can destroy radial glial fibres during the early development of the cerebral cortex (6).
Another hypothesized cause is that CMV infection during third and fourth month of gestation can involve disruption the radial glial cells guide (41).
An important role in the genesis of schizencephaly is played by mutation in the omeobox gene EMX2, a gene encoding for a transcription factor involved in the expression of the gene. Several studies evidenced data suggesting that EMX2 gene may be involved in the modulation of cell proliferation of cortical neuroblasts and/or cell migration of postmitotic neurons, as it is known that these cells reach their final destination in the mature cortex according to their generation date. On the other hand recent data demonstrate that EMX2 gene has no major role in schizencephaly (42).