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Background: Malformations of cortical development (MCDs) are a major source of handicap. Much progress in understanding the genetic causes has been made recently. The number of affected children in whom a molecularly confirmed diagnosis can be made is unclear., Objective: To evaluate the etiology of MCDs in children and the effect of a combined radiological, clinical, and syndrome classification., Design: A case series of 113 children with a radiological diagnosis of MCD from January 1, 1992, to January 1, 2006., Setting: The Erasmus Medical Center-Sophia Children's Hospital, a secondary and tertiary referral center., Patients: Patients with MCD underwent a complete radiological, clinical, and neurological assessment and testing for known genes involved in the pathogenesis of MCD as appropriate for their phenotype., Results: We established an etiological diagnosis in 45 of 113 cases (40%). For 21 patients (19%), this included molecular and/or genetic confirmation (Miller-Dieker syndrome; LIS1, DCX, FLNA, EIF2AK3, or KIAA1279 mutations; or an inborn error of metabolism). In 17 (15%), a syndrome with an unknown genetic defect was diagnosed. In 7 patients (6%), we found evidence of a gestational insult. Of the remaining 68 patients, 34 probably have a yet-unknown genetic disorder based on the presence of multiple congenital anomalies (15 patients), a family history with multiple affected persons (12 patients), or consanguineous parents (7 patients)., Conclusions: In our cohort, combining diagnostic molecular testing with clinical, radiological, and genetic classification; syndrome identification; and family study provided a diagnosis in 40% of the cases of MCD. This contributes to the possibility of prenatal diagnosis and improved patient treatment and disease management.

Abnormal neurodevelopment in midline structures such as the adhesio interthalamica (AI) has been reported in schizophrenia, but not consistently replicated. We investigated the prevalence and anterior-posterior length of the AI in 62 schizophrenia patients (32 males, 30 females) and 63 healthy controls (35 males, 28 females) using magnetic resonance imaging. We also explored the relation between the AI and volumetric measurements for the third ventricle, medial temporal structures (amygdala, hippocampus, and parahippocampal gyrus), superior temporal sub-regions, and frontal lobe regions (prefrontal area and anterior cingulate gyrus). The AI was absent in 24.2% (15/62) of the schizophrenia patients and in 9.5% (6/63) of the controls, showing a significant group difference. For the length of the AI, schizophrenia patients had a shorter AI than controls, and males had a shorter AI than females. The subjects without an AI had a significantly larger third ventricle and smaller parahippocampal gyrus than the subjects with an AI for both groups. We found a significant diagnosis-by-AI interaction for the amygdala. The schizophrenia patients without an AI had a smaller bilateral amygdala than those with an AI, whereas the AI was not associated with the volume of the amygdala in the control subjects. These findings suggest that the absence of AI in schizophrenia could be a marker of developmental abnormalities in the neural network including the thalamus and connected amygdaloid regions, which may play an important role in the pathogenesis of schizophrenia.

We report a case of congenital brainstem disconnection including the second detailed autopsy. A full-term newborn presented with irreversible apnoea and died on the fifth day. MRI revealed disconnection of the brainstem. The autopsy included a series of transverse sections of the mesencephalon, medulla oblongata and bridging tissue fragments. A fragile tube walled by mature brainstem tissue could be reconstructed. It enveloped a cylinder of fluid within the ventral pons extending to the mesencephalon and the lower brainstem. The aqueduct was patent and outside the lesion. The basilar artery was represented by a tiny median vessel. The ventral and lateral parts of the posterior brainstem were surrounded by heterotopic glial tissue. The olivary nucleus was absent and the cerebellar dentate nucleus was dysplastic. Considering the maturity of the remaining parts of the pons, the onset of structural decline is likely to be close to the time of birth. Probable causes are progressively insufficient perfusion through an hypoplastic basilar artery, and obstructed venous drainage through an abnormal glial barrier surrounding the posterior brainstem. The morphological findings can be characterized as a syrinx, known from disorders in which brainstem or spinal cord are damaged by a combination of mechanical and circulatory factors.

Hypoxic-ischemic (HI) encephalopathy is an important neurological problem of the perinatal period. Little is known of the long-term progression of HI insults or the maladaptive changes that lead to epilepsy. Using rats with unilateral carotid occlusion followed by hypoxia at postnatal day 7, this study provides an initial analysis of the epilepsy caused by a perinatal HI insult with chronic and continuous behavioral monitoring. The histopathology was investigated at postnatal day 30 and later at > or =6 months of age using cresyl violet, Timm, and rapid Golgi staining and immunocytochemistry. The resultant epilepsy showed an increase in seizure frequency over time, with a preponderance for seizure clusters and behavioral features of an ipsilateral cerebral syndrome. In addition to parasagittal infarcts and porencephalic cysts in severe lesions, columnar neuronal death was found with cytomegaly in isolated groups of dysmorphic cortical neurons. Cortical dysgenesis was seen in the form of deep laminar cell loss, microgyri, white matter hypercellularity, and blurring of the white and gray matter junction. Mossy fiber sprouting was not only detected in the atrophied ipsilateral dorsal hippocampus of HI rats with chronic epilepsy, but was also found in comparable grades in spared ipsi- and contralateral ventral hippocampi. The cortical lesions in this animal model show histological similarities with those found in humans after perinatal HI. The occurrence of cortical abnormalities that are associated with epilepsy in humans correlates with the consequent detection of spontaneous recurrent seizures.

Background: Syndromic craniosynostoses (Saethre-Chotzen, Pfeiffer 1, 2, 3, Apert, Crouzon, mainly) are particular in this that a single gene defect (mostly fibroblast growth factor receptor [FGFR] 2) generates different clinical phenotypes that characterize these syndromes. Significant brain abnormalities have been reported in all syndromes. However, whether these abnormalities are secondary to the bone disease or primary (e.g. callosal agenesis) is still controversial. Recent evidence suggests that the white matter defect might be a primary disorder., Review of Literature: From the review of the literature and the analysis of our cases, it appears that three categories of brain abnormalities can be found. (1) The global distortion of the brain is likely mechanical and in keeping with the deformity of the skull. (2) The chronic tonsillar herniation (Chiari I deformity) is likely mechanical also and a consequence of the small size of the posterior fossa, especially after an early closure (before 24 m) of the lambdoid suture. (3) On the contrary, the constellation of abnormalities that selectively involve the white matter (non-progressive, non-destructive ventriculomegaly, callosal agenesis or thinning, agenesis of septum pellucidum, paucity of the antero-mesial temporal white matter, pyramidal hypoplasia) is much more likely to constitute a primary disorder., Conclusions: Recent neurobiological evidence supports this point of view. L1 cell adhesion molecule (L1CAM) gene plays a major role in the development of the white matter and its mutation in humans (callosal agenesis, retardation, adducted thumbs, spasticity, and hydrocephalus syndrome, Bickers-Adams syndrome) or in mice causes similar defects of the corpus callosum, septum pellucidum, centrum semi-ovale, and cortico-spinal tracts. To operate, L1CAM need interactions with FGFRs, whose defects are causal to the syndromic craniosynostoses. It seems logical to assumes that the FGFR defects generate both the skull abnormalities and, by lack of interaction with L1CAM, the primary defect of the white matter. The mental deficiency that is common in these patients therefore is likely to be part of the disease (through the L1CAM-FGFR interaction) rather than a consequence of the skull size or of the associated hydrocephalus.

We describe a patient who presented at our epilepsy-monitoring unit with myoclonic jerks, and was diagnosed with juvenile myoclonic epilepsy (JME). Imaging of his brain revealed partial agenesis of the corpus callosum (ACC). We discuss the known genetic basis of both JME and ACC, as well as the role of the corpus callosum (CC) in primary generalized epilepsy. Both JME and ACC are associated with gene loci on chromosome 15q14. Structural brain abnormalities other than ACC, such as atrophy of the corpus callosum have been reported in patients with JME. ACC has been associated with seizures, suggesting an anti-epileptogenic role of the corpus callosum. On the other hand, corpus callosotomy is used to treat refractory idiopathic generalized epilepsy, which shows that the corpus callosum may play an epileptogenic role. The occurrence of both these conditions in one patient raises the question of whether they are purely coincidental or if there is a common basis for both. Several issues need to be addressed: the mechanism of seizure generalization in the setting of partial ACC, the possible role of other structures in generalization, and whether the ACC contributes to epileptogenesis as a result of the lack of a normal CC inhibitory effect.

Background: Freezing lesions to developing rat cortex induced between postnatal day (P) one and three (P1 - 3) lead to malformations similar to human microgyria, and further correspond to reductions in brain weight and cortical volume. In contrast, comparable lesions on P5 do not produce microgyric malformations, nor the changes in brain weight seen with microgyria. However, injury occurring at all three ages does lead to rapid auditory processing deficits as measured in the juvenile period. Interestingly, these deficits persist into adulthood only in the P1 lesion case 1. Given prior evidence that early focal cortical lesions induce abnormalities in cortical morphology and connectivity 1234, we hypothesized that the differential behavioral effects of focal cortical lesions on P1, P3 or P5 may be associated with underlying neuroanatomical changes that are sensitive to timing of injury. Clinical studies indicate that humans with perinatal brain injury often show regional reductions in corpus callosum size and abnormal symmetry, which frequently correspond to learning impairments 567. Therefore, in the current study the brains of P1, 3 or 5 lesion rats, previously evaluated for brain weight, and cortical volume changes and auditory processing impairments (P21-90), were further analyzed for changes in corpus callosum volume., Results: Results showed a significant main effect of Treatment on corpus callosum volume [F (1,57) = 10.2, P < .01], with lesion subjects showing significantly smaller callosal volumes as compared to shams. An Age at Treatment x Treatment interaction [F(2,57) = 3.2, P < .05], indicated that corpus callosum size decreased as the age of injury decreased from P5 to P1. Simple effects analysis showed significant differences between P1 and P3 [F(1,28) = 8.7, P < .01], and P1 and P5 [F(1,28) = 15.1, P < .001], subjects. Rats with P1 injury resulting in microgyria had the greatest reduction in corpus callosum volume (22% reduction), followed by the P3 group (11% reduction), which showed a significant reduction in corpus callosum volume compared to shams [F(1,31) = 5.9, P < .05]. Finally, the P5 lesion group did not significantly differ from the sham subjects in callosal volume., Conclusion: Decrements in corpus callosum volume in the P1 and 3 lesion groups are consistent with the reductions in brain weight and cortical volume previously reported for microgyric rats 18. Current results suggest that disruption to the cortical plate during early postnatal development may lead to more widely dispersed neurovolumetric anomalies and subsequent behavioral impairments 1, compared with injury that occurs later in development. Further, these results suggest that in a human clinical setting decreased corpus callosum volume may represent an additional marker for long-term behavioral outcome.

Case Report: We report a case of a nonfunctioning pancreatic endocrine tumor arising from intracranial ectopic pancreatic tissue., History: An 11-year-old girl was admitted to our hospital with a brain tumor. Hydrocephalus and brain malformation were apparent at birth. We first identified a mass-like lesion in the child's brain at age 4 months. We monitored the lesion yearly by magnetic resonance imaging (MRI) until she reached age 11 years. Gadolinium-enhanced MRI showed the lesion to be a tumor, which was resected., Pathology: Examination of surgical specimens revealed a mature pancreatic tissue. We also identified monotonous neoplastic cells with round nuclei and positive immunoreactivity for synaptophysin, chromogranin A, and neurospecific enolase. However, these cells were negative for pancreatic endocrine markers. We diagnosed nonfunctioning pancreatic endocrine tumor arising from intracranial ectopic pancreatic tissue., Conclusion: Migrating pancreatic elements may have induced brain malformation during embryonic development and subsequently become malignant.

Hydrocephalus is a disabling disease for children, but current data concerning the effects of melatonin on ventricular enlargement are still limited. We have investigated the changes in the choroid plexuses (CPs) of ventricles and blood-brain barrier (BBB) of hydrocephalic rats. Forty-five Swiss Albino rats at age 2 weeks were divided into three equal groups: control, hydrocephalus, and melatonin-treated hydrocephalus groups. Hydrocephalus was induced by kaolin injection into the cisterna magna of all pups except control group and melatonin was given at a daily dose of 0.5 mg/100 g body weight for 4 weeks. At the end of the study, one animal from each group was examined using a gamma camera to study the disruption of BBB due to hydrocephalus. All animals were then killed for assay of glutathione (GSH) and nitric oxide (NO), as well as histological study of the CPs during the hydrocephalus. We observed an increased BBB activity was found in hydrocephalus group, while melatonin reversed these changes. It was found that NO concentration was elevated in hydrocephalus group and melatonin partly abolished the increased levels of NO. In contrast, GSH levels were significantly decreased in hydrocephalus group, while melatonin increased the tissue GSH level (p<0.01). Histologically, there was a significant alteration in the CPs of the ventricles of hydrocephalic animals, but it was regressed after melatonin treatment in consistent with the gross morphological changes related to hydrocephalus. In conclusion, our results clearly demonstrated for the first time the neuroprotective effects of melatonin upon hydrocephalus-induced CP changes in infantile rats, but further studies are needed to suggest melatonin as a candidate protective drug in children.

This report addresses behavioral abnormalities in children with cerebellar anomalies demonstrated on MRI scans. Published data are presented showing an interaction between cerebellar pathology and early childhood autism. The cerebellum is involved not only in movement coordination, but also in social adaptation and verbal communication. The genes expressed in the cerebellum during childhood are identical to those expressed in the hippocampus. We have observed 20 children with MRI-identified agenesis of the cerebellar vermis and behavioral abnormalities; children were aged 3-15 (mean 7.05) years and there were 12 males and eight females. A variety of autistic characteristics were identified in these children.

Improving clinical tests are allowing us to more precisely classify autism spectrum disorders and diagnose them at earlier ages. This raises the possibility of earlier and potentially more effective therapeutic interventions. To fully capitalize on this opportunity, however, will require better understanding of the neurobiological changes underlying this devastating group of developmental disorders. It is becoming clear that the normal trajectory of neurodevelopment is altered in autism, with aberrations in brain growth, neuronal patterning and cortical connectivity. Changes to the structure and function of synapses and dendrites have also been strongly implicated in the pathology of autism by morphological, genetic and animal modeling studies. Finally, environmental factors are likely to interact with the underlying genetic profile, and foster the clinical heterogeneity seen in autism spectrum disorders. In this review we attempt to link the molecular pathways altered in autism to the neurodevelopmental and clinical changes that characterize the disease. We focus on signaling molecules such as neurotrophin, Reelin, PTEN and hepatocyte growth factor, neurotransmitters such as serotonin and glutamate, and synaptic proteins such as neurexin, SHANK and neuroligin. We also discuss evidence implicating oxidative stress, neuroglial activation and neuroimmunity in autism.

Autism is a brain disorder characterized by abnormalities in how a person relates and communicates to others. Both post-mortem and neuroimaging studies indicate the presence of increased brain volume and, in some cases, an altered gray/white matter ratio. Contrary to established gross findings there is no recognized microscopic pathology to autism. Early studies provided multiple leads none of which have been validated. Clinicopathological associations have been difficult to sustain when considering possible variables such as use of medications, seizures, mental retardation and agonal/pre-agonal conditions. Research findings suggest widespread cortical abnormalities, lack of a vascular component and an intact blood-brain barrier. Many of the previously mentioned findings can be explained in terms of a mini-columnopathy. The significance of future controlled studies should be judged based on their explanatory powers; that is, how well do they relate to brain growth abnormalities and/or provide useful clinicopathological correlates.

Background: The homeodomain-containing transcription factor PITX3 was shown to be essential for normal eye development in vertebrates. Human patients with point mutations in PITX3 demonstrate congenital cataracts along with anterior segment defects in some cases when one allele is affected and microphthalmia with brain malformations when both copies are mutated. The functional consequences of these human mutations remain unknown., Results: We studied the PITX3 mutant proteins S13N and G219fs to determine the type and severity of functional defects. Our results demonstrate alterations in DNA-binding profiles and/or transactivation activities and suggest a partial loss-of-function in both mutants with the G219fs form being more severely affected. No anomalies in cellular distribution and no dominant-negative effects were discovered for these mutants. Interestingly, the impairment of the G219fs activity varied between different ocular cell lines., Conclusion: The G219fs mutation was found in multiple families affected with congenital cataracts along with anterior segment malformations in many members. Our data suggest that the presence/severity of anterior segment defects in families affected with G219fs may be determined by secondary factors that are expressed in the developing anterior segment structures and may modify the effect(s) of this mutation. The S13N mutant showed only minor alteration of transactivation ability and DNA binding pattern and may represent a rare polymorphism in the PITX3 gene. A possible contribution of this mutation to human disease needs to be further investigated.

Background: The Bosley-Salih-Alorainy syndrome (BSAS) variant of the congenital human HOXA1 syndrome results from autosomal recessive truncating HOXA1 mutations. We describe the currently recognized spectrum of ocular motility, inner ear malformations, cerebrovascular anomalies, and cognitive function., Methods: We examined nine affected individuals from five consanguineous Saudi Arabian families, all of whom harbored the same I75-I76insG homozygous mutation in the HOXA1 gene. Patients underwent complete neurologic, neuro-ophthalmologic, orthoptic, and neuropsychological examinations. Six individuals had CT, and six had MRI of the head., Results: All nine individuals had bilateral Duane retraction syndrome (DRS) type 3, but extent of abduction and adduction varied between eyes and individuals. Eight patients were deaf with the common cavity deformity of the inner ear, while one patient had normal hearing and skull base development. Six had delayed motor milestones, and two had cognitive and behavioral abnormalities meeting Diagnostic and Statistical Manual of Mental Disorders-IV criteria for autism spectrum disorder. MRI of the orbits, extraocular muscles, brainstem, and supratentorial brain appeared normal. All six appropriately studied patients had cerebrovascular malformations ranging from unilateral internal carotid artery hypoplasia to bilateral agenesis., Conclusions: This report extends the Bosley-Salih-Alorainy syndrome phenotype and documents the clinical variability resulting from identical HOXA1 mutations within an isolated ethnic population. Similarities between this syndrome and thalidomide embryopathy suggest that the teratogenic effects of early thalidomide exposure in humans may be due to interaction with the HOX cascade.

The phenotypic description of deletion 13q syndrome is dependent on the location and size of the deleted segment. At present, the syndrome is divided into 3 groups based on the deletion's location relative to chromosomal band 13q32. Groups 1 (proximal to q32) and 2 (including q32) have shown distinctive phenotypes including mental retardation and growth deficiency, whereas group 3 (q33-34 deletion) is defined by the presence of mental retardation but usually the absence of major malformations. The authors report an 8-year-old Hispanic female with dysmorphic facial features, microcephaly, moderate to severe mental retardation, and uncontrolled epilepsy associated with a terminal 13q33.3 deletion. These features expand the characterization of the phenotype associated with group 3 of the 13q deletion syndrome to include major clinical manifestations. This case report will contribute to more accurate genetic counseling as well as may help identify more individuals with this syndrome.

The objective of this article is to describe autistic spectrum disorders in children diagnosed with infantile spasms in the first year of life. The source of data was the records of all 3 pediatric departments in Iceland. Twenty children born between 1981 and 1998 who had infantile spasms were invited to participate. When appropriate, the parents of these children were asked to complete the Social Communication Questionnaire. Children scoring 10 points or higher on the questionnaire were selected for further examination using the Autism Diagnostic Interview- Revised and either the Autism Diagnostic Observation Schedule or the Childhood Autism Rating Scale. All participants were given appropriate cognitive tests or measures of adaptive behavior. The parents of 17 children (10 boys, 7 girls) agreed to participate in the study. Age at assessment ranged from 5 to 19 years with a mean age of 11 years and 6 months. Fourteen children had at least one neurodevelopmental disorder. Six (6/17), or 35.3%, were diagnosed with autism spectrum disorder (3 boys, 3 girls), five of these had a history of symptomatic infantile spasms, and four were profoundly mentally retarded (IQ/DQ<20). If the diagnosis of autism spectrum disorder was restricted to children with a developmental age of 24 months or more (3 cases), the prevalence was 17.6%. The estimates found in this study exceed the estimated prevalence of autism spectrum disorder in the general population.

Objective: This study aimed to clarify the morphology of the Martin-Gruber anastomosis (MGA) in Chinese., Methods: One hundred and five Chinese upper limbs (36 males and 20 femalese) were dissected to find the connections between medial nerve and ulnar nerve. The MGA was classified as previously described by Lee., Results: MGA was found in 24 cases (22.9%), in 11 of the 36 male and 5 of the 20 female. There was no obvious difference in the frequency of MGA in both upper limbs. Most MGA ulnar position was located at the medial and distal segment of the forearm., Conclusion: MGA anatomy could play important role in forensic diagnosis of ulnar nerve injury in Chinese population.

This review covers a fraction of the new research developments in autism but establishes the basic elements of the new neurobiologic understanding of autism. Autism is a polygenetic developmental neurobiologic disorder with multiorgan system involvement, though it predominantly involves central nervous system dysfunction. The evidence supports autism as a disorder of the association cortex, both its neurons and their projections. In particular, it is a disorder of connectivity, which appears, from current evidence, to primarily involve intrahemispheric connectivity. The focus of connectivity studies thus far has been on white matter, but alterations in functional magnetic resonance imaging activation suggest that intracortical connectivity is also likely to be disturbed. Furthermore, the disorder has a broad impact on cognitive and neurologic functioning. Deficits in high-functioning individuals occur in processing that places high demands on integration of information and coordination of multiple neural systems. Intact or enhanced abilities share a dependence on low information-processing demands and local neural connections. This multidomain model with shared characteristics predicts an underlying pathophysiologic mechanism that impacts the brain broadly, according to a common neurobiologic principle. The multiorgan system involvement and diversity of central nervous system findings suggest an epigenetic mechanism.

Prenatal exposure to low-doses of bisphenol A (BPA) has been shown to affect murine neocortical development by accelerating neuronal differentiation/migration through disrupting thyroid hormone function. We therefore studied whether prenatal exposure to low-doses of BPA affected organization of adult neocortical structures. Pregnant mice were injected with 20 microg/kg of BPA daily from embryonic day 0.5 (E0.5) and bromodeoxyuridine (BrdU) was injected at E12.5, E14.5 and at E16.5, and the fetal brains were analyzed after birth. The BrdU-positive cells labeled at E14.5 were significantly increased in the Vth and VIth cortical layers of BPA-treated mice at postnatal 3 weeks (P3W), whereas they were confined to the IVth layer of control mice, though such differences disappeared at P12W. The thalamocortical projections demonstrated by DiI-labeling were abnormal at P3W and P12W in BPA-treated mice. These results indicate that BPA might affect not only neocortical development but also thalamocortical connections.

A case of congenital bilateral perisylvian syndrome (CBPS) associated with bilateral perisylvian schizencephaly in a 24-year-old woman is reported. She presented the classical clinical triad of CBPS, which included congenital facio-masticatory diplegia, epilepsy and only mild mental retardation, despite the presence of bilateral, open-lip clefts in the perisylvian region. We hypothesize that the minimal loss of cortical tissue, along with the possible sparing of vital white matter association fibers and neuronal plasticity might have contributed to the better functional outcome in this patient.

Polymicrogyria is a malformation of cortical organization. The aim of this historic cohort study was to describe clinical and EEG features of patients with polymicrogyria. Patients underwent clinical and neurologic examination and a prolonged routine EEG to allow recording during sleep. Neuroimaging data were classified as: perisylvian polymicrogyria (subdivided into holosylvian, posterior parietal, and generalized), hemispheric polymicrogyria, and frontal polymicrogyria. Forty patients were studied: 16 with holosylvian polymicrogyria, 14 with posterior parietal polymicrogyria, 4 with generalized polymicrogyria, 3 with hemispheric polymicrogyria, and 3 with frontal polymicrogyria. Patients with polymicrogyria usually did not have epilepsy and their EEGs were mostly normal (55%); the severity of the clinical and EEG features correlated with the extent of the cortical lesion. In perisylvian polymicrogyria, epileptiform abnormalities predominated in fronto-temporal regions. Dour patients had focal electrical status (FES) in awakeness and electrical status epilepticus of sleep (ESES); these four patients had right hemispheric polymicrogyria and asymmetric bilateral perisylvian polymicrogyria, mostly on the right hemisphere. The authors conclude that the EEG is usually normal in patients with polymicrogyria, despite it being associated with FES and ESES in certain patients.

Neuronal overmigration is the underlying cellular mechanism of cerebral cortical malformations in syndromes of congenital muscular dystrophies caused by defects in O-mannosyl glycosylation. Overmigration involves multiple developmental abnormalities in the brain surface basement membrane, Cajal-Retzius cells, and radial glia. We tested the hypothesis that breaches in basement membrane and the underlying glia limitans are the key initial events of the cellular pathomechanisms by carrying out a detailed developmental study with a mouse model of muscle-eye-brain disease, mice deficient in O-mannose beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1). The pial basement membrane was normal in the knockout mouse at E11.5. It was breached during rapid cerebral cortical expansion at E13.5. Radial glial endfeet, which comprise glia limitans, grew out of the neural boundary. Neurons moved out of the neural boundary through these breaches. The overgrown radial glia and emigrated neurons disrupted the overlying pia mater. The overmigrated neurons did not participate in cortical plate (CP) development; rather they formed a diffuse cell zone (DCZ) outside the original cortical boundary. Together, the DCZ and the CP formed the knockout cerebral cortex, with disappearance of the basement membrane and the glia limitans. These results suggest that disappearance of the basement membrane and the glia limitans at the cerebral cortical surface during development underlies cortical lamination defects in congenital muscular dystrophies and a cellular mechanism of cortical malformation distinct from that of the reeler mouse, double cortex syndrome, and periventricular heterotopia.

One of the most common causes of neurological disabilities are malformations of cortical development (MCD). A useful animal model of MCD consists of prenatal exposure to methylazoxymethanol (MAM), resulting in a postnatal phenotype characterized by cytological aberrations reminiscent of human MCD. Although postnatal effects of MAM are likely a consequence of prenatal events, little is known on how the developing brain reacts to MAM. General assumption is the effects of prenatally administered MAM are short lived (24 h) and neuroblast-specific. MAM persisted for several days after exposure in utero in both maternal serum and fetal brain, but at levels lower than predicted by a neurotoxic action. MAM levels and time course were consistent with a different mechanism of indirect neuronal toxicity. The most prominent acute effects of MAM were cortical swelling associated with mild cortical disorganization and neurodegeneration occurring in absence of massive neuronal cell death. Delayed or aborted vasculogenesis was demonstrated by MAM's ability to hinder vessel formation. In vitro, MAM reduced synthesis and release of VEGF by endothelial cells. Decreased expression of VEGF, AQP1, and lectin-B was consistent with a vascular target in prenatal brain. The effects of MAM on cerebral blood vessels persisted postnatally, as indicated by capillary hypodensity in heterotopic areas of adult rat brain. In conclusion, these results show that MAM does not act only as a neurotoxin per se, but may additionally cause a short-lived toxic effect secondary to cerebrovascular dysfunction, possibly due to a direct anti-angiogenic effect of MAM itself.

Unlabelled: In fetal post-mortem examinations of the Central Nervous System, any lesions must be carefully detected and identified in order to determine their etiology. Common abnormalities found in a fetal brain can be ascribed to incomplete or defective neuronal migration, often correlated with genetic syndromes or exogenous etiological factors. Neuronal migration begins between the 7th and 8th week of gestation, whereby neuroblasts migrate along radial extensions of glial cells located in paraventricular buds. In fetuses less than 20 weeks gestational age, since myelization has not begun yet in the telencephalon, histochemical techniques such as luxol fast blue (for myelin) or Kluever-Barrera staining (for myelin and neuroblasts) cannot be employed. In order to identify the (normal or pathologic) topography of these guiding fibers and their relation with migrating neuroblasts, we are proposing here to replace luxol fast blue with PAS, thus taking advantage of PAS-positivity of glycogen contained in the guiding glial fibers. From 1984 to 2004, we performed 922 fetal-perinatal post-mortem examinations (46% before the 20th week of gestation). A double PAS-cresyl violet staining was developed on theses cases, using Kluver-Barrera staining as a basis: cresyl violet was employed to highlight neurons, and luxol fast blue for myelin was replaced with a PAS staining for glycogen., Results: PAS stains glycogen contained in glial fascicles which guide neuronal migration, highlighting migration trajectories with a Magenta red; conversely, neuroblasts are selectively blue stained by cresyl violet. Histochemical stainings normally employed to study the nervous system in adult individuals, cannot be used to investigate fetal encefalon, because there is no myelin before week 20 of gestation. The double PAS-cresyl violet staining has proved to be a valuable tool in fetal encefalon diagnosis and in the study of neuronal migration and its likely defects.

We applied novel mesh-based geometrical modeling methods to calculate and compare the thickness of the corpus callosum at high spatial resolution and to create profiles of average callosal shape in a well-matched sample (n=24) of individuals with Williams syndrome and controls. In close agreement with previous observations, superimposed surface maps indicate that the corpus callosum in Williams syndrome individuals is shorter and less curved. Moreover, we observed significantly thinner callosal regions in Williams syndrome individuals across the posterior surface, where group effects were less pronounced and spatially restricted in brain-size-adjusted data compared with native data. Circumscribed structural alterations in callosal morphology might be candidate anatomic substrates for the unique cognitive and behavioral profile associated with Williams syndrome.

In this paper, novel methods were used to map the corpus callosum morphology of children with chromosome 22q11.2 deletion syndrome in order to further investigate changes to that structure and to examine their possible effects on cognitive function. The callosal profiles were extracted from the centermost MRI midsagittal slice by supervised thresholding and the structure's boundary and midline were computed automatically. Difference analysis was based on non-rigid registration, in which a template image is warped to conform to the shape of each corpus callosum in the sample. Boundaries and midlines were registered to a template and the results used to determine the average callosal shapes for children with the deletion and for controls. Pointwise registration also enabled the detailed evaluation of callosal curvature, width, area and length. Significant differences between the two groups were found in shape, size and bending angle. Results showed group differences that were concentrated in the anterior part of the structure, more specifically in the rostrum, which was larger and longer in the group with the syndrome. Correlation analyses showed that ventricular enlargement does not fully account for callosal morphology differences in children with the deletion. However, areal measurements did reveal important relationships between changes in callosal morphology and cognitive function. These novel findings reveal intricate relationships between genetic and disease-specific factors in the callosal anatomy and the potential impact of those changes on cognitive functions.

Variations in the configuration of the bony septum found in patients with split cord malformations are rare. We report the seemingly rare occurrence of a midline bony septum that ended posteriorly as a fully formed bony spinous process. We speculate that this variation is due to misplaced mesodermal cells associated with the primitive endomesenchymal tract during approximately the third week of foetal life. The clinician that manages these patients may wish to consider this rare morphology and avoid excessive manipulation of such a process, which could potentially injure an underlying hemicord.

Objective: To determine the early outcome and the incidence of associated structural anomalies in pregnancies complicated by severe fetal ventriculomegaly (VM)., Methods: A review of cases of severe fetal VM (posterior horn of lateral ventricle > 15 mm at referral or during prenatal follow-up) referred to a fetal medicine centre in Eastern England over 4 years from 2001 was made. Results of specialist prenatal investigations including ultrasound (US), karyotype, antiplatelet antibodies and congenital infection screen were noted. Neonatal clinical and cranial US findings, autopsy findings and neurodevelopmental follow-up at 4 months were obtained., Results: Twenty cases of severe VM were identified, including 3 with spina bifida. Median gestation at diagnosis was 28 weeks (range 16-36 weeks). Twelve cases had additional intra-cranial abnormalities and two had abnormalities outside the central nervous system. One case was complicated by toxoplasmosis. There was one case of trisomy 21. Ten pregnancies were terminated. Ten babies were live born, all of whom had VM confirmed, and two of these babies died within 4 months. Of the remaining eight, seven have abnormal neurodevelopment., Conclusions: Severe VM is often diagnosed after the threshold of viability. Termination of pregnancy was requested in about half the cases owing to the risk of long-term neurodisability, and in all cases diagnosed before 24 weeks. In those live born, there was abnormal outcome in all but one., ((c) 2006 John Wiley & Sons, Ltd.)

A case of extensive bilateral frontotemporal schizencephaly is alleged - more extensively in the left hemisphere - which associated with polymicrogyria. The cortical anomaly was discovered only incidentally by MR examination in a 22 year-old man who suffered from headache due to a mild head trauma. Neurological examination proved to be negative. He had no complaints or symptoms a few weeks later. The developmental anomalies in corticalisation are shortly overviewed in this group together with the possible causing factors. It has been emphasized the importance of the precise intrauterine and/or postpartum differential diagnosis between schizencephaly, porencephaly and other failure in corticalisation.

Prenatal exposed to an anti-inflammatory drug is a major problem for the developing central nervous system. It is not well known the effect of prenatal exposed to a non-steroidal anti-inflammatory drug on the hippocampus. Total neuron number in one side of the cornu ammonis (CA) and gyrus dentatus (GD) of the hippocampal formation in control and drug-treated (diclofenac sodium, DS) groups of male rats was estimated using the optical fractionator technique. Each main group has also two subgroups that are 4 weeks old (4W-old) and 20 weeks old (20W-old). In CA, no significant difference between 4W-old DS-treated and their control was found, but a significant difference was observed between 20W-old DS-treated and their controls. A decreasing of neuron number was 12% for 20W-old DS-treated group. In GD, a decreasing of the granule cell number in 4W-old of DS-treated group was seen but an increasing of granule cell number was found in the 20W-old drug-treated rats in comparison to its control group, 7% and 9%, respectively. Although an increasing of neuron number in CA at the control group was seen with age, from 4th week to 20th week (10%), age-dependent substantial granule cell decline (17%) was observed in GD. No age effect on the total cell numbers of CA and GD of the drug-treated groups was seen in comparison to 4W-old week and 20W-old. A pronounced neuron loss observed in the drug-treated group may be attributed to the neurotoxicity of diclofenac sodium (DS) on the developing hippocampal formation. Age-dependent neuron increase in the CA of 20W-old and neuron decline in GD of 20W-old control groups may be a result of a dual effect of saline injection during the fetal life, since these animals were exposed to a stress of 15-day-period of saline injection, prenatal stress. The reason of no age effect on CA and GD cell number in the drug-treated groups may be attributed to the depletion of the progenitor cells due to neurotoxicity of DS in the fetal life of these animals.

Hemimegalencephaly is a rare brain malformation consisting of the enlargement of 1 hemisphere, often associated with abnormal cortical gyration, thick cortex, large neurons, and increased astrocytes. Cranial asymmetry is the first clinical sign usually present at birth; in the most severe cases, hemimegalencephaly may be evident during pregnancy. Hemiparesis, intractable epilepsy, and developmental delay are the typical clinical manifestations. Tuberous Sclerosis Complex is an autosomal dominant disorder affecting about 1 in 6000 live births; the number of spontaneous mutations is remarkable. It is characterized by the development of hamartias, or nongrowing lesions, and hamartomas, which grow as benign tumors and rarely progress to malignancy. These lesions most frequently involve the brain, skin, kidneys, eyes, and heart. The rare association of hemimegalencephaly and tuberous sclerosis complex has been reported in a few cases. The authors report the case of a 4-year-old boy with left hemimegalencephaly, tuberous sclerosis complex genetically confirmed, and intractable epilepsy originating from the nonhemimegalencephalic hemisphere.

We describe two male siblings affected by cardiomyopathy and genitourinary tract abnormalities. One of them also had dysgenesis of the corpus callosum. They were born to nonconsanguineous, phenotypically normal parents. This association appears to be a new entity and may suggest a new autosomal or X-linked recessive syndrome.

Pachygyria is a disorder of neuronal migration. We report an Indian family with four siblings with developmental delay, infrequent seizures, normal head size and mild to moderate mental retardation. Two of them had bilaterally symmetrical frontotemporal pachygyria. Dysmorphism and neurological signs were absent in the affected subjects. Affected male and female siblings with normal parents suggests autosomal recessive mode of inheritance. We believe these cases represent a new autosomal recessive disorder of neuronal migration. Other similar cases of lissencephaly are reviewed.

Aicardi syndrome is a cerebroretinal disorder consisting of a heterogeneous spectrum of clinical findings that includes the triad of infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae. This report describes a 6-month-old girl who has all of the essential features suggestive of Aicardi syndrome, as well as a pineal gland cyst and ventricular septal defect. Although the characteristic features of Aicardi syndrome have been described, its association with pineal gland cyst and ventricular septal defect has not been reported in the literature.

Focal cortical dysplasias (FCD) with Taylor-type balloon cells (FCD(IIb)) are frequently observed in biopsy specimens of patients with pharmacoresistant focal epilepsies. The molecular pathogenesis of FCD(IIb), which lack familial inheritance, is only poorly understood. Due to their highly differentiated, malformative nature and glioneuronal phenotype, FCD(IIb) share neuropathological characteristics with lesions observed in familial disorders such as cortical tubers present in patients with autosomal dominant tuberous sclerosis complex (TSC), related to mutations in the TSC1 or TSC2 genes, and dysplastic gangliocytomas of the cerebellum found in Cowden disease. Current data have indicated distinct allelic variants of TSC1 to accumulate in FCD(IIb). TSC1 represents a tumor suppressor operating in the phosphatidylinositol 3-kinase (PI3K)/insulin pathway. The tumor-suppressor gene PTEN is mutated in Cowden disease. Like PTEN, also carboxyl-terminal modulator protein (CTMP) modulates PI3K-pathway signaling, both via inhibition of Akt/PKB, a kinase inactivating the TSC1/TSC2 complex. Here, we have analyzed alterations of Akt, PTEN and CTMP relevant for insulin signaling upstream of TSC1/TSC2 in FCD(IIb). Immunohistochemistry with antibodies against phosphorylated Akt (phospho-Akt; Ser 473) in FCD(IIb) (n=23) showed strong phospho-Akt expression in dysplastic FCD(IIb) components. We have further studied sequence alterations of PTEN (n=34 FCD(IIb)) and CTMP (n=20 FCD(IIb)) by laser microdissection/single-strand conformation polymorphism analysis. We observed a somatic mutation in an FCD(IIb), i.e., amino-acid exchange at nucleotide position 834 (PTEN cDNA, GenBank AH007803.1) in exon 8 with replacement of phenylalanine by leucine (F278L). We also found several silent polymorphisms of PTEN in exon 2 and exon 8 as well as silent and coding polymorphisms but no mutations in CTMP. No loss of heterozygosity in FCD(IIb) (n=6) at 10q23 was observed. To our knowledge, we here report on the first somatic mutation of a tumor-suppressor gene, i.e., PTEN, in FCD(IIb). However, our study also demonstrates that mutational alterations of PTEN and CTMP do not play major pathogenetic roles for activation of Akt in FCD(IIb). Future studies need to determine the origin of insulin pathway activation upstream of TSC1/TSC2 in FCD(IIb).

Background: Homogeneous and complete trisomy 8 is extremely rare. With one recent neonatal exception, all reported cases have been mosaic, due to mitotic non-disjunction during early zygotic development. We report a case of chromosome 8 trisomy in a human embryo examined at Carnegie stage 11 (25 days post-fertilization). It presented severe cardiovascular and central nervous system malformations., Methods: The unusual bifid heart in this embryo spurred a detailed histological examination, karyotyping of a chorionic villus sample and subsequent FISH on inter-phase nuclei of intra-embryonic sections., Results: Trophoblast cells had a karyotype of 47,XX, +8. Within the embryo proper, FISH demonstrated that the trisomy 8 was homogeneous in embryonic as well as extra-embryonic tissues. FQ-PCR supports a meiosis I origin of non-disjunction. In sections, the pharyngeal arches (including cardiac outflow tract), forebrain, mesonephros and liver were absent. Somites and yolk sac blood vessels were irregularly shaped., Conclusion: We show that homogeneous, intra-embryonic trisomy 8 is compatible with implantation and early human development. Molecular pathways that may be compromised and their impact on organogenesis are discussed., (Copyright (c) 2006 John Wiley & Sons, Ltd.)

Objective: To investigate the effects of prematurity on sulcal formation., Methods: We evaluated the depth and volume of the primary olfactory sulcus (developed at 16 weeks' gestation) and the secondary orbital sulci (which start to develop at 28 weeks' gestation) in a sample of 22 adolescents with history of very-preterm birth (VPTB). We compared this preterm sample with a sample of subjects born at term and matched by age, gender, and sociocultural status. The Anatomist/BrainVISA 3.0.1 package was used to identify and quantify the sulci. In addition, voxel-based morphometry (VBM) was used to analyze possible reductions of gray and white matter in the orbitofrontal area., Results: Compared with controls, we found a significant reduction in the secondary sulci depth but not in the primary sulcus in the VPTB. VBM analysis showed reduced gray-matter volume in VPTB in the orbital region., Conclusions: Premature birth affects cerebral gyrification, and this impairment is not reversible during childhood. Identification of the specific factors involved in abnormal brain maturation may lead to effective interventions.

We report a 14-year-old boy with cavernous malformation of the optic chiasm. He had a 2-year history of gradually worsening visual disturbance. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a suprasellar mass, findings compatible with craniopharyngioma. The mass was biopsied and histological examination confirmed cavernous malformation. On the second day after the biopsy, he suffered chiasmal apoplexy due to intratumoural haemorrhage, lost visual acuity and developed a field cut. Cavernous malformations arising from the optic nerve and chiasm are extremely rare; only 29 cases have been reported to date. Most patients manifested acute visual acuity and visual field disturbances. Although MRI findings of cavernous malformations in the brain parenchyma have been reported, MRI findings on the optic nerve and chiasm may not be completely diagnostic. Of the 29 documented patients, 16 underwent total resection of the lesion without exacerbation of their preoperative symptoms; in some cases, resection was complicated by risk of damage to the surrounding neural tissue. As patients may suffer intratumoural haemorrhage after biopsy or partial removal of the lesion, the advisability of surgical treatment of cavernous malformations of the optic nerve and chiasm must be considered carefully.

Congenital bilateral perisylvian polymicrogyria syndrome (CBPS) has a cerebral cortical localization and its phenotype was thought to be purely central. This study of seven children with CBPS (five males, two females; mean age 5 y [SD 3 y 6 mo]; range 1 mo-11 y 10 mo) documents electrophysiological evidence of lower motor neuron involvement in association with congenital contractures (limb or jaw) in six of the seven children studied. This is not an expected association and does not conform to the traditional lesional classification system of the cerebral palsies. Possible pathogenic mechanisms are discussed but this association of upper and lower motor neuron involvement is likely to be a previously unsuspected part of a genetic or other pathogenic sequence.

Malformations of cortical development (MCD) result from abnormal neuronal positioning during corticogenesis. MCD are believed to be the morphological and perhaps physiological bases of several neurological diseases, spanning from mental retardation to autism and epilepsy. In view of the fact that during development, an appropriate blood supply is necessary to drive organogenesis in other organs, we hypothesized that vasculogenesis plays an important role in brain development and that E15 exposure in rats to the angiogenesis inhibitor thalidomide would cause postnatal MCD. Our results demonstrate that thalidomide inhibits angiogenesis in vitro at concentrations that result in significant morphological alterations in cortical and hippocampal regions of rats prenatally exposed to this vasculotoxin. Abnormal neuronal development was associated with vascular malformations and a leaky blood-brain barrier. Protein extravasation and uptake of fluorescent albumin by neurons, but not glia, was commonly associated with abnormal cortical development. Neuronal hyperexcitability was also a hallmark of these abnormal cortical regions. Our results suggest that prenatal vasculogenesis is required to support normal neuronal migration and maturation. Altering this process leads to failure of normal cerebrovascular development and may have a profound implication for CNS maturation.