Article

Agyria-Pachygyria (Lissencephaly Syndrome)

Authors:
  • Institute of Clinical Neurobiology
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Abstract

A clinico-pathological report is given on 4 cases of agyria (premature neonate to age 13 months), 3 cases of pachygyria (aged 2,5 to 4,3 years) and a boy aged 4,5 years with temporal pachygyria and frontal microgyrias. Clinical features, more pronounced in agyria than in pachygyria, were microcephaly, frequent facial anomalies, neonatal feeding difficulties, hypotonia with subsequent seizures, hypsarrhythmic EEG pattern in 3 children, arrest of psychomotor development and signs of decerebration. One case of agyria occurred with familial faciorenal dysplasia, two were associated with congenital heart disease, and the fourth with chromosomal abnormality. Morphologically, the colpocephalic brain showed a four-layered agyric pallium with radially aligned cell columns and periventricular heterotopias, lacking differentiation of the claustra, olivary heterotopias and cerebellar dysgenesias in the 4 younger infants. In the agyric neonate additional agenesis of corpus callosum was present. Pachygyric brains showed a six-layered cortex, periventricular heterotopias, lacking differentiation of the claustra, but no cerebello-olivary anomalies. Cytoarchitectonic analysis of the agyric cortex suggests a disorder of neuronal migration during stage III of neocortex formation (Rakic and Sidman) between the 11th and 13th fetal week, while the pachygyric cortex showing the later formed layers II and IV presumable is caused by an attenuated and later disorder acting in early stage IV of neocortex formation, i. e. around or after the 13th fetal week. Additional insula-claustrum dysplasia, olivary and cerebellar anomalies are due to concomittent migration disorders between the 11th and 14th week. Along this period there is a gradient from agyric to normal six-layered cortex, whereas microgyria presumably results from an event occurring after migration has terminated (after the 16th fetal week). Etiological factors of agyria-pachygyria may be both hereditary (familial lissencephaly-syndrome) and environmental ones (prenatal drug application or intrauterine perfusion disorders).

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... It rallies a spectrum of gyral malformations from a complete absence of gyri to regional pachygyria (an area with broad and shallow gyri formation) (Jellinger and Rett, 1976). ...
... This malformation is also combined with demyelination, dysplasic cerebellum with cysts and brainstem hypoplasia (Devisme et al., 2012). Some phenotypes that were described in lissencephaly can be explained by neuronal migration defects (Francis et al., 2006;Jellinger and Rett, 1976;Kato, 2003). Moreover, the genes mutated in lissencephaly, such as LIS1 (lissencephaly 1) or DCX (doublecortin), encodes proteins that are crucial for proper neuronal migration (see more in detail in part cyclic saltatory neuronal migration, McManus et al., 2004;Ocbina et al., 2006;Toriyama et al., 2012;Tsai et al., 2007)). ...
Thesis
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CAMP is crucially involved in brain development. However, the role of cAMP during neuronal migration is still largely unexplored. To analyze cAMP dynamics in migrating neurons, we performed live imaging of a cAMP specific FRET-based biosensor in newly formed migrating neurons of the postnatal Rostral Migratory Stream (RMS). These cells display a cyclic saltatory mode of migration with alternations of nucleokinesis (NK) and pauses, along with stereotypical movement of the centrosome (CTR). We discovered a cAMP-rich dynamic hotspot surrounding the CTR during NK. The CTR is located at the basis of the primary cilium (PC). Genetic ablation of the PC in migrating cells slows-down migration and triggers defects in CTR movements, as well as disappearance of the cAMP-rich hotspot. Adenylyl Cyclase 3 (AC3) is localized in the PC and its downregulation by RNA interference leads to similar migration defects as PC ablation as well as hotspot disappearance, suggesting the importance of ciliary cAMP production for normal migration. Protein Kinase A (PKA) is located at the CTR of migrating cells. To test whether the cAMP-rich hotspot could act on PKA, we expressed a non-centrosomally located dominant-negative PKA, which led to the same migration defects as PC ablation and AC3 knock-down. Our data unveil a new mechanism regulating neuronal saltatory migration through ciliary production of cAMP diffusing to the centrosome, and locally activating PKA. The cAMP hotspot is also present during adult tangential migration along the RMS, in postnatal radial migration in the olfactory bulb and in embryonic radial migration, suggesting its general importance for neuronal migration. Fragile X syndrome (FXS) is a neurodevelopmental disorder and the most common inherited form of intellectual disability. We discovered that migrating neurons of FXS mice display multiple, deregulated cAMP hotspots along with abnormal migration. FXS neurons migrate slower and pause more than the control. More investigation on the molecular mechanism underlying these phenotypes are needed to determine how and if neuronal migration defects are linked to cAMP deregulation. This could highlight a new neurodevelopmental phenotype of FXS.
... Gyration is physiologically accomplished by approximately the 32nd fetal week. The critical time window for lissencephalic aberrations to initiate is between fetal weeks 11-13 (113). Lissencephaly/agyria and pachygyria, that is, cortical architecture somewhat more advanced, represent a spectrum of cortical aberrations. ...
... The claustrum is frequently absent and respective differences can be distinguished frequently by MRI (118). In the medulla and cerebellum, aberrant cerebellar cortex architecture and heterotopias of the nucleus olivaris can be observed (113). At the transition zone of the pachygyric to normal cortical areas, the outer neural layer continues into the normal cortex, whereas the inner neural layer does not continue in the normal cortex. ...
Article
Structural abnormalities of the brain are increasingly recognized in patients that suffer from pharmacoresistant focal epilepsies by applying high-resolution imaging techniques. In many of these patients, epilepsy surgery results in control of seizures. Neuropathologically, a broad spectrum of malformations of cortical development (MCD) is observed in respective surgical brain samples. These samples provide a unique basis to further understand underlying pathomechanisms by molecular approaches and develop improved diagnostics and entirely new therapeutic perspectives. Here we provide a comprehensive description of neuropathological findings, available classification systems as well as molecular mechanisms of MCDs. We emphasize the recently published ILEA classification system for focal cortical dysplasias (FCDs), which are now histopathologically distinguished as types I to III. However, this revised classification system represents a major challenge for molecular neuropathologists, as the underlying pathomechanisms in virtually all FCD entities will need to be specified in detail. The fact that only recently, the mammalian target of rapamycin (mTOR)-antagonist Everolimus has been introduced as a treatment of epilepsies in the context of tuberous sclerosis-associated brain lesions is a striking example of a successful translational "bedside to bench and back" approach. Hopefully, the exciting clinico-pathological developments in the field of MCDs will in short term foster further therapeutic breakthroughs for the frequently associated medically refractory epilepsies.
... Patients with lissencephaly often have an associated microcephaly indicating defects in neural progenitor proliferation (Lee et al., 2010;Pramparo et al., 2010). Furthermore, the 'smooth' brain is the result of abnormal neuronal migration, which causes an abnormally thick fourlayered cortex (Dobyns et al., 1984;Jellinger and Rett, 1976), and many patients with lissencephaly also have a reduction or absence of major axon tracts, indicating problems with axon guidance or outgrowth (Kappeler et al., 2007). Thus, causative genes for lissencephaly encode proteins with critical roles in each of these steps in development: neural progenitor proliferation, neuronal migration, and axon outgrowth. ...
Article
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Mutations in the microtubule (MT)-binding protein doublecortin (DCX) or in the MT-based molecular motor dynein result in lissencephaly. However, a functional link between DCX and dynein has not been defined. Here, we demonstrate that DCX negatively regulates dynein-mediated retrograde transport in neurons from Dcx -/y or Dcx -/y ;Dclk1 -/- mice by reducing dynein's association with MTs and by disrupting the composition of the dynein motor complex. Previous work showed an increased binding of the adaptor protein C-Jun-amino-terminal kinase-interacting protein 3 (JIP3) to dynein in the absence of DCX. Using purified components, we demonstrate that JIP3 forms an active motor complex with dynein and its cofactor dynactin with two dyneins per complex. DCX competes with the binding of the second dynein, resulting in a velocity reduction of the complex. We conclude that DCX negatively regulates dynein-mediated retrograde transport through two critical interactions by regulating dynein binding to MTs and by regulating the composition of the dynein motor complex.
... Polymicrogyria presumably results from events after the 16th fetal week when the migration has terminated. [9] The possible causes of neuronal migration disorders may be acquired or genetic. The acquired etiologies include viral infections such as varicella, cytomegalovirus and toxoplasmosis infections, exposure to toxins such as ethanol, carbon monoxide, isotretinoic acid and cytotoxic drugs, effects of ionizing radiation and intrauterine circulatory disturbances. ...
Article
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Lissencephaly means smooth brain, i.e., brain without convolutions or gyri, rare and severe cortical malformation. It results from a defect in neuronal migration with four rather than six layers in cortex and the onset of this disorder is presumed to be before 9 weeks of gestation The spectrum ranges from complete absence of gyri (agyria) to broad gyri with reduced sulci (pachygyria), with an abnormally thick cortex. [1] Here, we report a 11 months old male babywith failure to thrive, spasticity, global developmental delay, microcephaly and cortical visual impairment. MRI brain was done which was suggestive of diffuse gyral thickening involving bilateral cerebral hemispheres with broad flat gyri and shallow sulci suggestive of Agyria-Pachygyria complex (Lissencephaly) and mild dilatation of bilateral lateral ventricles and widening of bilateral sylvian fissures.
... Finally, specific branches and segments of the primary axon are selectively eliminated to yield mature projections that are functionally appropriate for the area of the cortex in question. Histologically, classic lissencephaly is characterized by four abnormal cortical layers: Neurofilament staining highlights a scarcity of cells in layer I; large and disorganized pyramidal neurons in layer II; a relatively hypocellular layer III, which becomes myelinated; and a thick layer IV composed of medium and small neurons [22,23]. As novel LIS-related genes have been discovered, microscopic presentation variations have been reported due to genetic pathogenesis. ...
Article
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Purpose To clarify brain abnormalities on magnetic resonance imaging (MRI) and its clinical implications in lissencephaly/subcortical band heterotopia (LIS/SBH) spectrum patients. Methods The clinical severity and classification according to Di Donato were retrospectively reviewed in 23 LIS/SBH spectrum patients. The morphological and signal abnormalities of the brainstem, corpus callosum, and basal ganglia were also assessed. The brainstem distribution pattern of the corticospinal tract (CST) was analyzed by diffusion tensor imaging (DTI) and categorized into two types: normal pattern, in which the CST and medial lemniscus (ML) are separated by the dorsal portion of the transverse pontine fiber, and the abnormal pattern, in which the CST and ML are juxtaposed on the dorsal portion of a single transverse pontine fiber. Correlations between MR grading score and potential additional malformative findings of the brain and clinical symptoms were investigated. Results All patients with grade 3 (n = 5) showed brainstem deformities, signal abnormalities of pontine surface and had a tendency of basal ganglia deformity and callosal hypoplasia whereas those abnormalities were rarely seen in patients with grade 1 and 2 (n = 18). For DTI analysis, the patients with grade 3 LIS/SBH had typically abnormal CST, whereas the patients with grade 1 and 2 LIS/SBH had normal CST. The classification was well correlated with CST and brainstem abnormalities and clinical severity. Conclusion MR assessment including DTI analysis may be useful in assessing the clinical severity in LIS/BH spectrum and may provide insight into its developmental pathology.
... The neuropathological features of classic or thick LIS are well known, and include a thick and poorly organized 4-layered cortex with (1) molecular, (2) superficial cellular (pyramidal cell), (3) cell sparse, and (4) deep cellular layers (Crome, 1956;Jellinger & Rett, 1976). Several descriptions of the brain in Miller-Dieker syndrome due to deletion 17p13.3 and LIS1 match this pattern (Miller, 1963 have 4-layered thick LIS with a posterior more severe than anterior gradient, relatively thick superficial cellular layer (layer 2) and blurred cortical-white matter margin, designated LIS-4LP (Forman et al., 2005). ...
Article
Lissencephaly ("smooth brain," LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The LIS spectrum includes agyria, pachygyria, and subcortical band heterotopia. Our first classification of LIS and subcortical band heterotopia (SBH) was developed to distinguish between the first two genetic causes of LIS-LIS1 (PAFAH1B1) and DCX. However, progress in molecular genetics has led to identification of 19 LIS-associated genes, leaving the existing classification system insufficient to distinguish the increasingly diverse patterns of LIS. To address this challenge, we reviewed clinical, imaging and molecular data on 188 patients with LIS-SBH ascertained during the last 5 years, and reviewed selected archival data on another ∼1,400 patients. Using these data plus published reports, we constructed a new imaging based classification system with 21 recognizable patterns that reliably predict the most likely causative genes. These patterns do not correlate consistently with the clinical outcome, leading us to also develop a new scale useful for predicting clinical severity and outcome. Taken together, our work provides new tools that should prove useful for clinical management and genetic counselling of patients with LIS-SBH (imaging and severity based classifications), and guidance for prioritizing and interpreting genetic testing results (imaging based- classification).
... In lissencephaly, the cortex histologically consists of four layers (from pia to ventricle) ( Figure 2D see part indicated by b): (1) below the pia is a molecular layer, followed by a thin (2) pyramidal layer (undeveloped and displaced layers V and VI), then cell-sparse layer (3), and finally, a thick inner cell layer (4) presumably consisting of neurons, which did not completed migration (63). Molecular genetic studies have shown that there are both autosomal and X-linked lissencephaly due to the mutations in LIS1 and DCX genes respectively. ...
Article
In this review we outline the neurobiological basis for classification of cortical migratory disorders. Neurons of the human cortex are born in the ventricular and subventricular zone and migrate for a long distance to reach their final point of destination in the cortex, using two types of migratory routes and mechanisms: (1) radial migration along radial glia and (2) tangential, presumably "neurophilic" migration. The process of migration is complex and may be disturbed by various genetic and extrinsic factors. The disturbances of proliferation in the ventricular zone result in major malformations such as schizencephaly, while the failure of onset of migration results in periventricular nodular heterotopia with characteristic abnormalities in magnetic resonance imaging (MRI) and with genetic aberration in the background (FILAMIN1 gene mutation). The typical migratory disorder is lissencephaly type I caused by defect of ongoing migration. The lissencephaly type I is currently included in agyria-pachigyria band spectrum disorders. This group of disorders is caused by mutations of LIS1 and DCX (XLIS) gene mutations associated with Miller-Dieker syndrome, Lennox-Gastaut syndrome and epilepsy. The defects of late phases of migration cause lissencephaly type II, cobblestone complex, which is associated with Walker-Warburg syndrome, macrocephaly, retinal malformation, muscle-eye-brain disease and Fukuyama congenital muscular dystrophy. Zellweger syndrome is morphologically characterized by polymicrogyria and biochemically by defects of the mitochondrial desaturation pathway. The disorders with later migration failure show abnormal MRI restricted to the cortex. Another migratory disorder, focal cortical dysplasia, is a frequent cause of drug resistant epilepsy. An especially helpful diagnostic tool for migratory disorders is high resolution (3T) MRI. Genetic testing together with detailed MRI of migratory disorders opens new perspectives for early detection and improved treatment of migratory disorders.
... Pachygyria, in which there are focal thickening and convolution of gyri, is a type of neuronal migration disorder (NMD) closely resembles lissencephaly type 1, others in this entity being pachygyria, agyria, porencephaly, lissencephaly or schizencephaly, the most severe form. [2] The lissencephaly-pachygyria spectrum is useful in describing the spectrum of diseases that cause relative smoothness of the brain surface and includes agyria (no gyri), pachygyria (broad gyri) and lissencephaly (smooth brain surface). It is a basket term for a number of congenital cortical malformations characterised by absent or minimal sulcation. ...
Article
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Psychiatric manifestation of pachygyria, a neuronal migration disorder is rare in literature; rarer if it is bipolar disorder specifically. Here, we report a case of mania and seizure who subsequently diagnosed as pachygyria. Proper literature about pathophysiology is discussed and recently discovered putative genetic role in bipolar disorder explained. This case also emphasis the importance of detailed history taking and imaging investigation even in a pure psychiatric presentation.
... Pachygyria, in which there are focal thickening and convolution of gyri, is a type of neuronal migration disorder (NMD) closely resembles lissencephaly type 1, others in this entity being pachygyria, agyria, porencephaly, lissencephaly or schizencephaly, the most severe form. [2] The lissencephaly-pachygyria spectrum is useful in describing the spectrum of diseases that cause relative smoothness of the brain surface and includes agyria (no gyri), pachygyria (broad gyri) and lissencephaly (smooth brain surface). It is a basket term for a number of congenital cortical malformations characterised by absent or minimal sulcation. ...
Article
Full-text available
Psychiatric manifestation of pachygyria, a neuronal migration disorder is rare in literature; rarer if it is bipolar disorder specifically. Here, we report a case of mania and seizure who subsequently diagnosed as pachygyria. Proper literature about pathophysiology is discussed and recently discovered putative genetic role in bipolar disorder explained. This case also emphasis the importance of detailed history taking and imaging investigation even in a pure psychiatric presentation.
Chapter
The cerebral cortex can be divided into a large isocortex, a much smaller allocortex (the hippocampal formation and the olfactory cortex), and a transition zone (the mesocortex) in between. Although many individual variations exist in the sulcal pattern and in the extent of the various cortical areas, the remarkable conservation of the pattern of areal divisions within the human brain suggests the existence of a highly conserved and rather rigidly regulated regional specification programme that controls their development. Histogenesis of the cerebral cortex progresses through three major phases: cell production, cell migration, and cortical differentiation and maturation. Migrating cells from the ventricular zone to the cortical plate form ontogenetic radial cell columns. An important role in neurogenesis for the outer part of the subventricular zone became evident.During the last decades, analysis of the genetic control of cortical development became possible. Mechanisms for induction and regionalization of the cerebral cortex are being unravelled and genes that are implicated in controlling regionalization, arealization, and differentiation have been discovered in the mouse brain. This neurogenetic approach has given a great impetus to the study of neuronal migration disorders (NMDs). Advances in neurogenetics and the increasing application of magnetic resonance imaging (MRI) resulted in the distinction of a growing number of NMDs, of many of which the gene involved has been discovered. In this chapter, after a brief overview of the cerebral cortex (► Sect. 10.2) and its main connections (► Sect. 10.3), the development of the isocortex (► Sect. 10.4), the hippocampus (► Sect. 10.5), and their main fibre systems, including diffusion tensor imaging data in the fetal brain (► Sect. 10.6), are discussed, followed by an overview of developmental disorders of the cerebral cortex. Malformations of cortical development (MCDs) include malformations due to abnormal cell production (► Sect. 10.7.1), abnormal migration (► Sect. 10.7.2), abnormal cortical organization (► Sect. 10.7.3), vascular disorders (► Sect. 10.7.5), and disorders of cortical connectivity (► Sect. 10.7.6). Many of these result in epilepsy (► Sect. 10.7.4) and/or intellectual disability (► Sect. 10.7.7). In ► Sect. 10.7.8, some neurobehavioural disorders are briefly reviewed, followed by a brief discussion of the development of language and some congenital language disorders (► Sect. 10.8). Throughout the chapter, clinical cases are presented and illustrated with MRI and autopsy data.KeywordsDevelopment cerebral cortexDevelopment isocortexSubventricular zoneRegionalization cerebral cortexDevelopment hippocampusDevelopment main fibre connectionsNeuronal migration disordersMalformations of cortical developmentEpilepsyIntellectual disabilityNeurobehavioural disordersDevelopment of languageCongenital language disorders
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Prenatal diagnosis of brainstem anomalies is important due to the usually associated neurodevelopmental impairment and genetic implications. The extreme developmental changes that the brainstem and cerebellum undergo during fetal life pose a challenge for the characterization and definition of the different malformations. The present review aims to demonstrate the normal development of the fetal brainstem and to present the main features required for diagnosis of its anomalies according to available data in the medical literature.
Chapter
Discovery of nearly 200 genes implicated in epilepsy and insights into the molecular and cellular pathways involved are transforming our knowledge of the causes, classifications, diagnosis, and in some cases, treatments for individuals with chronic seizure disorders. Numerous disorders once considered "idiopathic" are now recognized as genetic conditions. Despite these remarkable advances, the cause of epilepsy for most individuals is unknown. We present a clinical approach to patients with epilepsy, presenting an algorithm for clinical and genetic testing, and review genes implicated in epilepsy and their associated syndromes.
Article
Lissencephaly (agyria) is a rare congenital brain anomaly characterized by a lack of apparent gyri formation. We reported previously a case of the lissencephaly syndrome. This paper presented a comparison between CT findings at the age of 5 months and neuropathological findings at 19 months. The macroscopical examination showed smooth surface without cerebral convolution, incomplete sylvian fissure formation without operculum insulae, cavum septi pellucidi, enlargement of the lateral ventricles especially in the posterior portion, thicker white matter of frontal lobe than that of occipital lobe, thick cortex with poor demarcation between gray and white matter. These changes corresponded well to the findings in CT previously done; Therefore CT scan is useful for the diagonsis of this disease. Golgi study revealed that there was a disorganization of neuronal disposition and developmental retardation or arrest of neurons, in addition to a maldevelopment of cortical cellular layers. In the patient there was a history of acute exanthematous disease of her mother at 2 months of pregnancy. The patient showed hepatosplenomegaly with elevation of IgM and cytomegalovirus CF titer at 5 months, and chronic nonspecific infectious lesions with necrosis in lymphnodes, liver and submandibular glands at autopsy. These clinical and pathological findings may be considered to suggest that the intrauterine infection had caused the syndrome in this patient.
Chapter
A malformation is defined as a morphological defect of an organ, part of an organ, or a larger region of the body resulting from an intrinsically abnormal developmental process [1].
Chapter
Das Zentralnervensystem ist das am frühesten angelegte Organ des Organismus. Seine Entwicklung beginnt mit der Bildung der Neuralplatte. Die vor diesem Zeitpunkt während der Gameto- bzw. Blastogenese erfolgenden Entwicklungsstörungen sind in der Regel mit dem weiteren Überleben nicht vereinbar.
Chapter
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Chapter
Die Darstellung der Neuropathologie ist im Vergleich mit der Behandlung der Pathologie der übrigen Körperorgane ausführlicher sowohl im Hinblick auf den Umfang als auch auf die Zahl der aufgenommenen Literaturhinweise. Begründet wird dies damit, daß — von Handbuch-ähnlichen Publikationen abgesehen — die Darstellung der Neuropathologie in den meisten übrigen Lehrbüchern der Allgemeinen und Speziellen Pathologie ebenso wie die Darstellung der Muskelpathologie stiefmütterlich ist und nicht diejenige Information erlaubt, die nötig ist, um auch dem nicht primär neuropathologisch Arbeitenden einen ausreichenden Einblick in die Sachlage und die Problematik bestimmter Befunde zu geben.
Chapter
Neuropsychologists frequently work with patients who have specified brain lesions that produce well-documented cognitive or behavioral effects. However, for those clinicians working with children or adolescents who suffer developmental disorders, the pathogenesis of cognitive and behavioral deficits may be poorly understood. This chapter reviews the anomalies of neurological development that not infrequently are seen in children and adolescents with developmental disorders. Most typically the neuropsychological manifestations of these anomalies impact on widely distributed functional systems, thus producing generalized and severe impairment. However, there are exceptions, especially with regard to anomalies of neuronal migration. Some basic understanding of these effects should aid neuropsychologists in a better conceptualization of how disorders of neurological development produce different effects than do discrete lesions of the central nervous system.
Chapter
The mammalian cerebral cortex is composed of the neural networks responsible for the behavioral diversity of mammals and intellectual life of humans. The formation of the neural networks that perform these tasks requires the creation, migration, and proper connections of neurons of different physiological types. In addition to the neurons of these networks, there are a number of other cell types required for the creation of a functional cerebral cortex. These include cells that support the function of neurons in the adult, such as astrocytes and oligodendrocytes, and cells that are required only during development, such as radial glia. The adult cerebral cortex is organized horizontally into functional areas and vertically into cortical layers, or lamina. Vertically, each layer consists of different neuronal types that make characteristic connections to other neurons locally within the cortex, to distant sites within the cortex, and/or to sites outside the cerebral cortex. Different functional areas of the cortex have the same basic laminar structure, but differ in the number of neurons within each layer and thickness of each layer. Also, neurons in different functional areas make connections that reflect their functional specification.
Article
Objective. To show the disorders of the brain cortical development and the possible origin in base to a large series studied in a Pediatric Neurology service. Patients and methods. A series of 144 children with ages ranging between newborn and 12 years was studied from the clinic, image (MR, 3DMR) and evolutive point of views. Results. The diagnosis was: polymicrogyria in 61 cases, lissencephaly in 22, eschizencephaly in 16, heterotopia in 16, cortical dysplasia in 9, hemimegalencephaly in 8, cobblestone in 7, sublobar dysplasia in 3, and 'double cortex' in 2. Mental retardation, motor disorders and epilepsy were the most important anomalies. Conclusions. Actually, the image is the most important study to make the diagnosis of every type of cerebral malformation. However, to know the specific gene that origin every disorder seems to be the most important thing to make the classification of every malformative type and the possible prevention of this pathology.
Chapter
The cerebral cortex can be divided into a large isocortex, a much smaller allocortex (the hippocampal formation and the olfactory cortex) and a transition zone (the mesocortex) in between. Although many individual variations exist in the sulcal pattern and in the extent of the various cortical areas, the remarkable conservation of the pattern of areal divisions within the human brain suggests the existence of a highly conserved and rather rigidly regulated regional specification programme that controls their development. Histogenesis of the cerebral cortex progresses through three major phases: cell production, cell migration, and cortical differentiation and maturation. Migrating cells from the ventricular zone to the cortical plate form ontogenetic radial cell columns. Recently, an important role in neurogenesis for the outer part of the subventricular zone became evident.
Article
We present the results of a collaborative study on the association of congenital muscular dystrophy with central nervous system anomalies revealed by CT scan investigation of 10 patients. In seven children, an abnormal hypodensity of the cerebral white matter is found; in four of these patients, this radiological anomaly is either isolated, or associated with a moderate intellectual impairment; in one case, severe mental retardation and ocular changes had occurred; in the other two cases, the muscular disease was progressing slowly, in association with microcephaly, epilepsy, and moderate mental retardation. Three children were afflicted with a severe early encephalopathy and congenital muscular dystrophy, and presented signs of cortical and subcortical atrophy on CT scan. Two of these patients corresponded to different types of cerebro-ocular dysplasia-muscular dystrophy syndromes, and the third patient of Fukuyama's congenital muscular dystrophy. These observations are discussed and compared with those reported in the literature. The authors emphasize the need to investigate possible cerebral CT scan anomalies in congenital muscular dystrophies, and to look for muscular changes in some prenatal encephalopathies.
Article
The migrational disorders are a rare group of congenital malformations of the brain. They consist of the following entities — lissencephaly (agyria — pachygyria), pachygyria, schizencephaly, heterotopia and polymicrogyria. We studied 40 children with migrational disorders radiologically with CT and MR. This article (Part II) deals with our patients with schizencephaly, heterotopia and polymicrogyria. These patients presented clinically with a variety of symptoms. The most common were seizures, delayed development, failure to thrive and hydrocephalus. CT and MR both demonstrated the characteristic findings in all of our patients except the polymicrogyria group. The gray matter and cleft abnormalities seen in these disorders were demonstrated with CT and MR. However, MR provided better delineation of these disorders than CT. Because some forms of migrational disorders can be inherited, it is extremely important for the radiologist to understand the characteristic findings for correct diagnosis which is essential for parental counseling.
Article
Cerebral abnormalities are considered an obligatory manifestation of the Neu-Laxova syndrome and include lissencephaly, severe microcephaly, aplasia of the corpus callosum, hypoplasia of the cerebellum, and other pathological changes. We present data on 3 cases with central nervous system anomalies, two of which have not been described previously, and summarize the literature on the subject. The problem of distinguishing type III lissencephaly is discussed.
Article
A case of lissencephaly (agyria) is reported in which the Golgi stain was used to study the fronto-parietal cortex. The external cellular layer, the so-called true cortex, was shown to be made up of neurons from the 5th and 6th layers of the normal cortex. The neurons in the much less cellular layer were shown to be large pyramidal cells with well-developed dendritic branching and spines. The deeper cellular layer was a neuronal pool without well-defined layering. All the neural forms from the normal cortex were represented. In this layer the inner neurons showed a less advanced stage of development than did those in the outer groups.
Article
The Snell dwarf mouse (Pit1dw-J homozygote) has a mutation in the Pit1 gene that prevents the normal formation of the anterior pituitary. In neonates and adults there is almost complete absence of growth hormone (GH), prolactin (PRL), thyroxin (T4), and thyroid-stimulating hormone (TSH). Since these hormones have been suggested to play a role in normal development of the central nervous system (CNS), we have investigated the effects of the Pit1dw-J mutation on the cerebellum and hippocampal formation. In the cerebellum, there were abnormalities of both foliation and lamination. The major foliation anomalies were 1) changes in the relative size of specific folia and also the proportional sizes of the anterior vs posterior cerebellum; and 2) the presence of between one and three microfolia per half cerebellum. The microfolia were all in the medial portion of the hemisphere in the caudal part of the cerebellum. Each microfolium was just rostral to a normal fissure and interposed between the fissure and a normal gyrus. Lamination abnormalities included an increase in the number of single ectopic granule cells in the molecular layer in both cerebellar vermis (86%) and hemisphere (40%) in comparison with the wild-type mouse. In the hippocampus of the Pit1dw-J homozygote mouse, the number of pyramidal cells was decreased, although the width of the pyramidal cell layer throughout areas CA1–CA3 appeared to be normal, but less densely populated than in the wild-type mouse. Moreover, the number of granule cells that form the granule cell layer was decreased from the wild-type mouse and some ectopic granule cells (occurring both as single cells and as small clusters) were observed in the innermost portion of the molecular layer. The abnormalities observed in the Pit1dw-J homozygote mouse seem to be caused by both direct and indirect effects of the deficiency of TSH (or T4), PRL, or GH rather than by a direct effect of the deletion of Pit1. J. Comp. Neurol. 400:363–374, 1998.
Article
Two siblings are reported who appear to have an autosomal recessive disorder of eye and centralnervous sytem anomalies. The findings in fourteen previously described and similarly affected patients are summarized. Ocular anomalies include microphthalmos, megalocornea, the Peter anomaly, cataract, coloboma, persistent hyperplastic primary vitreous, and retinal detachment with retinal dysplasia. Central nervous system malformations include agyria-pachygyria, cerebellar dysplasia, encephalocele, Dandy-Walker cyst, and hydrocephalus. We suggest that this disorder be known as Warburg syndrome. ( J Pediatr 102 :542, 1983)
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10 Kinder im Alter von 1 bis 16 Jahren mit verschiedenartigen computertomographisch nachweisbaren Migrationsstörungen werden vorgestellt. Das klinische Korrelat einer zirkumskripten Pachygyrie sind fokale kontralaterale Anfälle (n = 5). Globale Rindenfehlbildungen gehen mit schweren psycho-neurologischen Folgesymptomen einher (n = 3). Zwei Patienten mit paraventrikulären Heterotopien haben nur gelegentliche Krampfanfälle.
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The most striking, interesting, yet poorly understood gross morphological features of the cerebral hemispheres in mammals are the diverse and complex arrangements of their cortical gyri and sulci (Fig. 1). Among mammals, the spinal cord and brain-stem nuclei are morphologically quite similar, despite variations in size. However, during evolution, the cerebrum and cerebellum have undergone marked variations in size, shape, and convolutional complexity (Fig. 2). External morphological features of mammalian brains have long been utilized to judge not only the degree of phylogenetic development, but also the nature and level of complexity of brain functions. The great variety of living mammals exhibit a corresponding variety of brain shapes, sizes, and patterns of fissuration and convolution of the cerebral neocortex. The view has consistently been expressed that animals with brains having greater amounts of convoluted cerebral neocortex were more intelligent as well as perceptually and behaviorally more complex.
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Miller-Dieker syndrome, which includes lissencephaly and a characteristic phenotypic appearance, has been reported to have an autosomal recessive pattern of inheritance. However, we have found abnormalities of chromosome 17 in two of three unrelated patients with this syndrome, one with a ring chromosome 17 and the other with an unbalanced translocation resulting in partial monosomy of 17p13. A review of the literature revealed five additional patients in three families, who had Miller-Dieker syndrome and an abnormality of 17p. Thus, we propose that monosomy of distal 17p may be the cause of Miller-Dieker syndrome in some patients.
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The preoperative study of patients who are candidates for epilepsy surgery often classifies their epileptic foci as "lesional" or "non-lesional" based upon evidence from neuroimaging. Many lesions not detected by MRI are found by microscopic examination of the resected tissue. Advances have been made in neuropathological techniques to study resected brain tissue and to specify the types of focal cortical dysgeneses and other lesions by extending microscopic findings by applying immunocytochemical markers that identify specific types and distributions of neurons and glial cells that denote tissue architecture. There may be etiological differences between focal and extensive cortical dysplasias involving many gyri or entire lobes of cerebral cortex. Of additional importance in pediatric brain resections is that these modern techniques also denote cellular maturation and can identify abnormal cells with mixed lineage. α-B-crystallin can serve as a metabolic tissue marker of epileptic activity, regardless of the presence or absence of a "structural" lesion by MRI or by conventional histopathology. Satellitosis may contribute to epileptogenic neurons and later to death of those neurons. The classification of malformations of the brain is a process requiring continuous updates that include genetics, neuroimaging, and neuropathology as new data emerge, but should not be exclusive to one region of the brain, such as cerebral cortex or cerebellum. Standardization in neuropathological terminology enhances scientific communication. The ILAE recently published a useful consensus classification of focal cortical dysplasias that is flexible to enable future revisions and changes as new data become available.
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Imaging studies, particularly magnetic resonance (MR) imaging, can be extremely helpful in cerebral palsy. Both the cause of insult and the age of the fetus at the time of the insult are important factors in determining the signal intensity and pattern of abnormality detected on MR imaging. As a result, MR studies can provide information regarding both the cause and timing of the cerebral damage or malformation. Additionally, MR studies are capable of determining the extent or severity of cerebral involvement, which can affect prognosis. This article presents imaging findings associated with the most common causes of cerebral palsy. MRDD Research Reviews 3:118-128, 1997. © 1997 Wiley-Liss, Inc.
Article
Lissencephaly (smooth-brain) is an abnormality of brain development characterized by incomplete neuronal migration and a smooth cerebral surface. At least 2, and possibly more, distinct pathological types occur, each associated with several distinct syndromes. In this paper, the manifestations of 3 disorders associated with type I (classical) lissencephaly are discussed, including the Miller-Dieker syndrome with or without deficiency of 17p13, Norman-Roberts syndrome, and isolated lissencephaly sequence.
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Four infants had agyria confirmed by CT scan. All were mentally retarded, microcephalic, 3 of them having characteristic facial dysmorphy and 2 infantile spasms. EEG was characterized by very high amplitude rhythms in the alpha range, associated with delta waves and with infrequent spikes. The tracing was poorly modified by sleep. Drugs reduced its amplitude and rapid rhythms appeared with benzodiazepines. The authors point to the usefulness of the EEG in suggesting diagnosis before the CT scan, as was the case in 2 patients. They point to the urgent need of studying infantile epilepsies according to etiology, and not only to seizure types.RésuméQuatre enfants présentant une agyrie confirmée par le CT scan étaient retardés mentaux, microcéphales, 3 d'entre-eux présentant une dysmorphie faciale caractéristique et 2 des spasmes infantiles. L'EEG était caractérisé par des rythmes de la bande alpha de très grande amplitude associés à des ondes delta et à de rares pointes. Le tracé était peu modifié par le sommeil. Les drogues diminuaient son amplitude et les benzodiazépines faisaient apparaître des rythmes rapides. Les auteurs soulignent l'utilité de l'EEG pour suggérer le diagnostic avant le CT scan comme ce fut le cas chez 2 enfants. Ils soulignent la nécessité d'étudier les épilepsies du nourrisson en fonction de l'étiologie et non seulement du type de crises.
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X-linked lissencephaly with absent corpus callosum and ambiguous genitalia is a newly recognized syndrome responsible for a severe neurological disorder of neonatal onset in boys. Based on the observations of 3 new cases, we confirm the phenotype in affected boys, describe additional MRI findings, report the neuropathological data, and show that carrier females may exhibit neurological and magnetic resonance imaging abnormalities. In affected boys, consistent clinical features of X-linked lissencephaly with absent corpus callosum and ambiguous genitalia are intractable epilepsy of neonatal onset, severe hypotonia, poor responsiveness, genital abnormalities, and early death. On magnetic resonance imaging, a gyration defect consisting of anterior pachygyria and posterior agyria with a moderately thickened brain cortex, dysplastic basal ganglia and complete agenesis of the corpus callosum are consistently found. Neuropathological examination of the brain shows a trilayered cortex containing exclusively pyramidal neurons, a neuronal migration defect, a disorganization of the basal ganglia, and gliotic and spongy white matter. Finally, females related to affected boys may have mental retardation and epilepsy, and they often display agenesis of the corpus callosum. These findings expand the phenotype of X-linked lissencephaly with absent corpus callosum and ambiguous genitalia, may help in the detection of carrier females in affected families, and give arguments for a semidominant X-linked mode of inheritance.
Chapter
Neuropsychologists frequently work with patients who have specified brain lesions that produce well-documented cognitive or behavioral effects. However, for those clinicians working with school-age children or adolescents who suffer developmental disorders, the pathogenesis of cognitive and behavioral deficits may be poorly understood.
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An anatomoclinical observation of agyria is reported. The karyotype revealed a partial deletion of the short arm of chromosome 17. The etiology of agyria is reviewed in the light of this chromosomal abnormality. In addition we describe the peculiar pattern of neurons in the cortex: Golgi stain demonstrated many inverted pyramidal cells in the superficial part of the cortical layer. The mechanism of this abnormality is discussed.
Chapter
Nach einer Darstellung der normalen Entwicklung des Nervensystems werden spezielle Fehlbildungen ausführlich besprochen, insbesondere Neuralrohrdefekte, Dysraphien des Kleinhirns, Störungen der Seitendifferenzierung und Kommissuren, kortikale Anomalien, Anomalien des Ventrikelsystems, Schädelanomalien und toxisch sowie durch Chromosomenanomalien bedingte Fehlbildungen.
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The Miller-Dieker Syndrome (MDS) consists of lissencephaly, characteristic facies, pre- and postnatal growth retardation, plus various other birth defects. Autosomal recessive inheritance has been presumed based on four reported families with two or more affected siblings. We present substantial evidence that monosomy 17p13.3 causes the MDS phenotype. This includes two patients with ring chromosome 17, one patient with a de novo 17p13 deletion, and one patient with monosomy 17p due to an unbalanced 7p; 17p translocation. We report the first prenatal diagnosis of MDS in a 20-week fetus from this latter family. Additionally, we report a balanced translocation between chromosome 17 and different autosomes (8, 12, and 15) in three of the four familial cases of lissencephaly. The finding of a chromosomal basis for this presumed autosomal recessive disorder significantly alters genetic counseling and makes prenatal diagnosis possible in some families.
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Focal aseptic necrosis of the cerebral cortex was induced in newborn rats by focal contact freezing. In the region of freezing the following changes took place: necrosis of the pia mater, total necrosis of the differentiating Ist–IVth layers of the cortex and partial necrosis of the Vth and VIth layers of the cortex. The VIth-b layer was mostly preserved. In partial necrosis the differentiating neuroblasts died. The capillaries and migrating neuroblasts destined for the Ist, IInd, and IIIrd cortex layer survived. They stopped only at the periphery of total necrosis and continued to differentiate. After healing, an atypical cortex, consisting of four layers, was formed in the necrotic region, quite similar to the microgyric cortex of four layers known in the human. After deeper necrosis a cortical microsulcus developed, also formed by a cortex of four layers. The newly formed first microgyric (molecular) layer had its histologic structure homologous to the molecular layer of the surrounding cortex. The second microgyric layer (outer, cellular one) was formed by neuroblasts assigned to the IInd and IIIrd normal layers, which migrated through partial necrosis and took up their final position at the periphery of total necrosis. The third microgyric (light) layer was formed by the original Vth layer destroyed by partial necrosis, and it contained single neurons and glial cells. The fourth microgyric layer was formed by the persistent deep part of the VIth layer. The four layered cortex was formed only during the time of neuroblastic migration. The findings are discussed in relation to the normal pathogenesis of cortical microgyria in children. The experimental findings show that the microgyric cortex is formed only during the course of neuroblastic migration.
Article
Full-text available
Cobblestone lissencephaly represents a peculiar brain malformation with characteristic radiological anomalies, defined as cortical dysplasia combined with dysmyelination, dysplastic cerebellum with cysts and brainstem hypoplasia. Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or 'cobblestone' brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker-Warburg syndrome, muscle-eye-brain and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN and FKRP genes attributed these diseases to α-dystroglycanopathies. However, studies have not been able to identify causal mutations in the majority of patients and to establish a clear phenotype/genotype correlation. Therefore, we decided to perform a detailed neuropathological survey and molecular screenings in 65 foetal cases selected on the basis of histopathological criteria. After sequencing the six genes of α-dystroglycanopathies, a causal mutation was observed in 66% of cases. On the basis of a ratio of severity, three subtypes clearly emerged. The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 (8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%). An intermediary type, cobblestone lissencephaly B, was linked to LARGE mutations (4.5%) identified for the first time in foetuses. We conclude that cobblestone lissencephaly encompasses three distinct subtypes of cortical malformations with different degrees of neuroglial ectopia into the arachnoid space and cortical plate disorganization regardless of gestational age. In the cerebellum, histopathological changes support the novel hypothesis that abnormal lamination arises from a deficiency in granule cells. Our studies demonstrate the positive impact of histoneuropathology on the identification of α-dystroglycanopathies found in 66% of cases, while with neuroimaging criteria and biological values, mutations are found in 32-50% of patients. Interestingly, our morphological classification was central in the orientation of genetic screening of POMT1, POMT2, POMGNT1, LARGE and FKRP. Despite intensive research, one-third of our cases remained unexplained; suggesting that other genes and/or pathways may be involved. This material offers a rich resource for studies on the affected neurodevelopmental processes of cobblestone lissencephaly and on the identification of other responsible gene(s)/pathway(s).
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