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Genetic factors represent an important etiologic group in the causation of intellectual disability. We describe a Saudi Arabian family with closley related parents in which four of six children were affected by a congenital cognitive disturbance. The four individuals (aged 18, 16, 13, and 2 years when last examined) had motor and cognitive delay with seizures in early childhood, and three of the four (sparing only the youngest child) had progressive, severe cognitive decline with spasticity. Two affected children had ocular malformations, and the three older children had progressive visual loss. The youngest had normal globes with good functional vision when last examined but exhibited the oculodigital sign, which may signify a subclinical visual deficit. A potentially deleterious nucleotide change (c.1A>G; p.Met1Val) in the C12orf57 gene was homozygous in all affected individuals, heterozygous in the parents, and absent in an unaffected sibling and >350 normal individuals. This gene has no known function. This family manifests a autosomal recessive syndrome with some phenotypic variability that includes abnormal development of brain and eyes, delayed cognitive and motor milestones, seizures, and a severe cognitive and visual decline that is associated with a homozygous variant in a newly identified gene. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: We describe two Finnish brothers with frontotemporal pachygyria, intellectual deficiency and mild dysmorphisms. Previously, only a few cases of similar frontotemporal pachygyria have been reported. This report provides further evidence about frontotemporal pachygyria being a distinct genetic entity inherited as an autosomal recessive trait. [Copyright &y& Elsevier]

A midline brain-in-brain malformation was recently reported, but appropriate classification of this malformation remains uncertain. We describe a child with a complex brain malformation that was not restricted to the midline structures, enlarging the neuroanatomical spectrum of this pseudotumoral midline dysplasia associated with corpus callosum dysgenesis, azygos anterior cerebral artery, absent septum pellucidum and bilateral perirolandic cortical abnormalities. The spectrum of fusion of the cerebral hemispheres and associated brain hemispherical abnormalities is not completely understood. Our data are in line with previous arguments that this malformation could be an additional variant in the spectrum of holoprosencephaly. [ABSTRACT FROM AUTHOR]

Hemimegalencephaly (HME) is a rare congenital malformation of the brain, grossly characterized by enlargement and overdevelopment of one cerebral hemisphere. We describe a 16-month-old patient with facial asymmetry caused by congenital infiltrating lipomatosis of the face (CILF) associated with ipsilateral HME. Although HME has been described as part of different syndromic diseases, the association of HME with CILF has been rarely reported. Our case and literature review suggest that when the diagnosis of CILF is suspected or established, the possible presence of associated HME has to be considered and a magnetic resonance imaging (MRI) must be performed even in absence of neurological features, not always present in early stages. MRI also demonstrates the involvement of intracranial structures outside the affected cerebral hemisphere, such as brain stem, cerebellum, cranial nerves, and blood vessels. In our patient, computed tomography of the brain provided detailed information on osseous hypertrophy and skull-base foramina enlargement. [ABSTRACT FROM AUTHOR]

The term twin spotting refers to phenotypes characterized by the spatial and temporal co-occurrence of two (or more) different nevi arranged in variable cutaneous patterns, and can be associated with extra-cutaneous anomalies. Several examples of twin spotting have been described in humans including nevus vascularis mixtus, cutis tricolor, lesions of overgrowth, and deficient growth in Proteus and Elattoproteus syndromes, epidermolytic hyperkeratosis of Brocq, and the so-called phacomatoses pigmentovascularis and pigmentokeratotica. We report on a 28-year-old man and a 15-year-old girl, who presented with a previously unrecognized association of paired cutaneous vascular nevi of the telangiectaticus and anemicus types ( naevus vascularis mixtus) distributed in a mosaic pattern on the face (in both patients) and over the entire body (in the man) and a complex brain malformation (in both patients) consisting of cerebral hemiatrophy, hypoplasia of the cerebral vessels and homolateral hypertrophy of the skull and sinuses (known as Dyke-Davidoff-Masson malformation). Both patients had facial asymmetry and the young man had facial dysmorphism, seizures with EEG anomalies, hemiplegia, insulin-dependent diabetes mellitus (IDDM), autoimmune thyroiditis, a large hepatic cavernous vascular malformation, and left Legg-Calvé-Perthes disease (LCPD) [LCPD-like presentation]. Array-CGH analysis and mutation analysis of the RASA1 gene were normal in both patients. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging ( MRI) features of brain lesions in 5 dogs and 2 cats characterized by extensive cystic changes of the cerebral hemispheres in terms of a porencephaly are presented. Age at diagnosis ranged from 12 weeks to 7 years. MRI findings were confined to the forebrain. Porencephalic lesions appeared as wedge-shaped parenchymal defects connecting the ventricular system and the subarachnoid space or as large cystic defects in the cerebral hemispheres. Although in two adult dogs the porencephalic lesions were asymptomatic, the other animals showed clinical symptoms depending on the affected cerebral area. Three animals had seizures. Interestingly, four animals showed neurological signs normally not localized to the forebrain (nystagmus, hypermetria, ataxia). Whether these clinical signs are related to impaired function of the cerebral cortex or to not recognizable lesions in the cerebello-vestibular system could not be further clarified. Although the defects develop intrauterine or postnatal, the clinical symptoms can occur later in life. The definition of porencephaly as well as its subclassification is not uniform in veterinary medicine. We suggest the term encephaloclastic porencephaly unregarding the underlying cause of the defect, which cannot be further specified by diagnostic imaging. [ABSTRACT FROM AUTHOR]

Since the neuroradiological features of patients with 2211.2 deletion syndrome are not well-understood, examinations using functional imaging were performed in this study. Brain magnetic resonance imaging (MRI) and 1 H-magnetic resonance spectroscopy (MRS) were performed using a clinical 3-Tesla MR imager in 4 patients with 2211.2 deletion syndrome (2 boys and 2 girls; aged 2-6 years.) and 20 age- and sex-matched healthy control subjects. Furthermore, interictal 123 I-iomazenil (IMZ) single photon emission computed tomography (SPECT) was examined in 2 of the 4 patients. Among the 4 patients with 2211.2 deletion syndrome, 2 patients showed polymicrogyria and 1 patient showed agyria. Those patients with brain malformations also showed abnormal brain artery patterns and decreased accumulation of IMZ in 123 I-IMZ SPECT. Although all 4 patients showed epileptic discharges in their electroencephalograms (EEG), one patient with polymicrogyria had no seizure episodes. Decreases in γ-aminobutyric acid (GABA) corresponding to the areas of polymicrogyria and/or epileptic discharges in EEG were shown in all patients except for the patient with agyria. Although consistent evidence was not seen in patients with 2211.2 deletion syndrome in this study, brain malformations and disturbances of the GABAergic nervous system would be underlying mechanisms of the neurodevelop-mental abnormalities in this syndrome. [ABSTRACT FROM AUTHOR]

A retrospective population based survey of patients born with holoprosencephaly in South-Eastern Hungary between July 1, 1992 and June 30, 2006 was performed. All live birth cases with craniofacial and non-craniofacial abnormalities were included in the study. A total of 9 patients (5 boys and 4 girls) were found with holoprosencephaly among 185 486 live births, which correspond to a birth prevalence of 0.49 per 10 000 live births (95% confidence interval [CI]: 0.17-0.80). These figures were similar to those ones found in New York State and several European regions. In our series one newborn had trisomy 13. Eight patients did not have chromosomal abnormalities on routine testing, 4 of them had craniofacial abnormalities only and another 4 showed non-craniofacial anomalies as well. Three patients died in the neonatal period and another one in childhood. Patients surviving the neonatal period had intellectual and motor handicap, and epilepsy. [ABSTRACT FROM PUBLISHER]

GPR56, an orphan G protein-coupled receptor (GPCR) from the family of adhesion GPCRs, plays an indispensable role in cortical development and lamination. Mutations in the GPR56 gene cause a malformed cerebral cortex in both humans and mice that resembles cobblestone lissencephaly, which is characterized by overmigration of neurons beyond the pial basement membrane. However, the molecular mechanisms through which GPR56 regulates cortical development remain elusive due to the unknown status of its ligand. Here we identify collagen, type III, alpha-1 (gene symbol Col3a1) as the ligand of GPR56 through an in vitro biotinylation/proteomics approach. Further studies demonstrated that Col3a1 null mutant mice exhibit overmigration of neurons beyond the pial basement membrane and a cobblestone-like cortical malformation similar to the phenotype seen in Gpr56 null mutant mice. Functional studies suggest that the interaction of collagen III with its receptor GPR56 inhibits neural migration in vitro. As for intracellular signaling, GPR56 couples to the Ga12/13 family of G proteins and activates RhoA pathway upon ligand binding. Thus, collagen III regulates the proper lamination of the cerebral cortex by acting as the major ligand of GPR56 in the developing brain. [ABSTRACT FROM AUTHOR]

Microcephalic osteodysplastic primordial dwarfism (MOPD) is a rare microlissencephaly syndrome, with at least two distinct phenotypic and genetic types. MOPD type II is caused by pericentrin mutations, while types I and III appear to represent a distinct entity (MOPD I/III) with variably penetrant phenotypes and unknown genetic basis. The neuropathology of MOPD I/III is little understood, especially in comparison to other forms of lissencephaly. Here, we report postmortem brain findings in an 11-month-old female infant with MOPD I/III. The cerebral cortex was diffusely pachygyric, with a right parietal porencephalic lesion. Histologically, the cortex was abnormally thick and disorganized. Distinct malformations were observed in different cerebral lobes, as characterized using layer-specific neuronal markers. Frontal cortex was severely disorganized and coated with extensive leptomeningeal glioneuronal heterotopia. Temporal cortex had a relatively normal 6-layered pattern, despite cortical thickening. Occipital cortex was variably affected. The corpus callosum was extremely hypoplastic. Brainstem and cerebellar malformations were also present, as well as old necrotic foci. Findings in this case suggest that the cortical malformation in MOPD I/III is distinct from other forms of pachygyria-lissencephaly. [ABSTRACT FROM AUTHOR]

We present a case in which the unusual cerebral malformations of thanatophoric dysplasia (TD) were identified on a 21-week fetal US and confirmed by antenatal MRI, postmortem imaging and autopsy. TD is the most common lethal skeletal dysplasia and is characterized by short long bones, which are often bowed (type 1), a small thorax, and skull deformities. There is also a recognised constellation of abnormalities of the brain primarily affecting the temporal lobes that, although well described in the postmortem setting, are not widely recognized in fetal imaging. Familiarity with this appearance will facilitate accurate antenatal diagnosis. [ABSTRACT FROM AUTHOR]

An Arab child is presented herein with a phenotype that fits the rare Baraitser-Winter syndrome. Her clinical features included a unilateral iris coloboma, ptosis, hypertelorism, epicanthic folds, broad nasal bridge, full cheeks, pointed chin, low set abnormal ears and short neck. In addition, she had cardiac defect, previously undescribed brain anomaly, seizures, hypotonia and developmental delay. Chromosomal analysis of the peripheral lymphocytes and FISH study revealed a normal 46, XX karyotype. To date, Baraitser-Winter syndrome has only been reported in 19 patients of different ethnic families. The present case adds a new finding to the spectrum of malformations published before. [ABSTRACT FROM AUTHOR]

Lennox-Gastaut syndrome (LGS) has numerous causes, but only rarely has familial recurrence been observed. We studied a family in which three male members had severe epilepsy and intellectual disability. The proband had seizure onset at 7 years of age with atonic, myoclonic, atypical absence, and tonic seizures with slow spike-wave on electroencephalography (EEG). One living sibling had a similar clinical pattern. One deceased sibling was known to have had seizures with intellectual disability. Neuroimaging revealed anterior predominant pachygyria. DNA sequencing of the gene doublecortin ( DCX) on the X chromosome revealed a novel missense mutation in the two living affected male siblings. The occurrence of three affected male family members with proven or suspected LGS in this family was puzzling and only solved by a combination of magnetic resonance (MR) and molecular genetics evaluations. This finding provided essential information for genetic counseling. [ABSTRACT FROM AUTHOR]

Abstract: Coffin–Siris syndrome or “fifth digit” syndrome is a multiple congenital anomaly-mental retardation syndrome with severe developmental delay, coarse facial features, hirsutism and absent fifth fingernails or toenails or fifth distal phalanges. The etiology of this syndrome remains uncertain. Here we report a stillborn male baby born from consanguineous parents who might represent a very severe form of Coffin–Siris syndrome with cardiac defect and multiple brain malformations including corpus callosum agenesis and Dandy Walker malformation. To the best of our knowledge, it is the first case leading to intrauterine death. Karyotype and array comparative genomic hybridization were normal; these results give additional support to mendelian inheritance for this syndrome. In our family, the most likely mode of inheritance is autosomal recessive and the recurrence is probably as high as 25%. [ABSTRACT FROM AUTHOR]

Holoprosencephaly is a congenital abnormality of the prosencephalon associated with median facial defects. Its frequency is 1 in 250 pregnancies and 1 in 16,000 live births. The degree of facial deformity usually correlates with the severity of brain malformation. Early mortality is prevalent in severe forms. This report presents a child with lobar holoprosencephaly accompanied by median cleft lip and palate. The treatment and 9 months' follow-up are presented. This unique case shows that holoprosencephaly may present different manifestations of craniofacial malformations, which are not always parallel to the severity of brain abnormalities. Patients with mild to moderate brain abnormalities may survive into childhood and beyond. [ABSTRACT FROM AUTHOR]

Abstract: Related transcription factors of the POU protein family show extensive overlap of expression in vivo and exhibit very similar biochemical properties in vitro. To study functional equivalence of class III POU proteins in vivo, we exchanged the Oct-6 gene by Brn-1 in the mouse. Brn-1 can fully replace Oct-6 in Schwann cells and rescue peripheral nervous system development in these mice. The same mice, however, exhibit severe defects in forebrain development arguing that Oct-6 and Brn-1 are not functionally equivalent in the central nervous system. The cause of the observed forebrain phenotype is complex, but anteriorly expanded Wnt1 expression contributes. Oct-6 normally represses Wnt1 expression in the early diencephalon and replacement by Brn-1 as a weaker inhibitor is no longer sufficient to maintain the necessary level of repression in the mouse mutant. The extent of functional equivalence between related transcription factors is thus strongly dependent on the analyzed tissue. [Copyright &y& Elsevier]

Abstract: Members of the zic family of transcription factors are widely understood to act during neural patterning and neural crest development. In particular, studies in mice and humans have shown that Zic2 has a role in forebrain patterning, while studies in Xenopus and zebrafish have shown that Zic2 acts during gastrulation. Expression of Zic2 prior to gastrulation has not been reported in the mouse. In the adult, Zic2 is known to be strongly expressed in cerebellar granule cells, but expression elsewhere in the adult brain has not been reported. We present data showing that Zic2 is expressed in pluripotent cells during very early mouse development. Further, in the adult brain, Zic2 expression is broad and overlaps with markers of neurogenesis. The presence of Zic2 in pluripotent cells of the embryo as well as in dividing neural cells in the adult suggests that this transcription factor may have a role in maintaining pluripotency. [Copyright &y& Elsevier]

Ultrasound examination remains the gold standard for fetal imaging. MRI is a second-line investigation following a screening reference ultrasound. Gyration, patterns of 'stratified' parenchyma and brain stem are better imaged by MRI. The optimum time to perform MRI scans depends on the indications. Mutliplanar studies are required using T1-weighted sequences to analyze the myelination process and T2-weighted sequences to provide details of the gyration and posterior fossa structures. For accurate interpretation, it is necessary to have knowledge about the stages of brain development, the malformations and the limits of MRI scans. However, together with the probability of finding a fetal abnormality, ordering the use of an impressive MRI machine generates a high level of parental anxiety. The main features of this review are focused on prenatal imaging issues as they increase in France, considering that termination of pregnancy is authorized as late as the end of pregnancy. [ABSTRACT FROM AUTHOR]

We report on an Italian boy, born to normal and nonconsanguineous parents with a prenatal diagnosis of ventriculomegaly and subependymal glial heterotopias. At birth bilateral macrostomia was diagnosed without other evident facial anomalies. Magnetic resonance imaging (MRI) showed triventricular hydrocephalus and aqueductal stenosis and confirmed the nodules of glial heterotopia. The bilateral macrostomia was surgically corrected with the vermilion square flap method and W-plasty technique and follow up MRI at 6 months showed mild increase of ventricular dilatation without signs of active hydrocephalus. The association between macrostomia and hydrocephalus has been reported only in rare cases of complex malformative syndromes but never with isolated macrostomia. [ABSTRACT FROM AUTHOR]

Abstract: Aicardi syndrome is a congenital disorder characterized by severe psychomotor retardation, corpus callosum agenesis, chorioretinal lacunae, and early-onset infantile spasms. The prognosis is generally poor for children with the classical form. We report a peculiar case of Aicardi syndrome characterized by corpus callosum hypoplasia, brain malformations with subependymal heterotopias, extensive chorioretinal lacunae, seizures, and normal cognitive functions. Therefore, the clinical picture of the syndrome is broader than originally described. Cognitive disorders should not be considered inevitable and the prognosis not ineludibly poor. [Copyright &y& Elsevier]

Abstract: We present the case of a three-year-old boy who suffered from intractable epilepsy from birth, and who displayed microcephaly and severe developmental delay. Neuroradiological examination revealed the presence of simplified gyri of the cerebral cortex, and increased signal intensity changes in the cerebral white matter on T2-weighted magnetic resonance imaging. A tentative diagnosis of congenital cortical malformation was made, but unexpectedly, the cerebrum, cerebellum, and pons showed a progressive atrophy during the follow-up period. The basal ganglia and thalamus were relatively spared. Investigations could find no evidence of leukodystrophies, metabolic disorders, hereditary brain anomalies, or congenital central nervous infections. This case may represent a novel type of neurodegenerative disease with malformation of cortical development. [Copyright &y& Elsevier]

Abstract: Aicardi syndrome (AS) is a rare disorder which includes the triad of total or partial agenesis of the corpus callosum, infantile spasms, and chorioretinal anomalies. Seizures and electroencephalogram findings observed in AS are polymorphic with both focal and generalized seizures. We first report on a patient affected by AS who presented with reflex audiogenic seizures specifically triggered by the starting tune of a popular television news. No other type of stimuli, either simple or complex, were able to precipitate the seizures in the patient. The severe cortical-subcortical lesions commonly observed in AS are associated with hyperexcitability of the cortices and may well account for the broad electroclinical patterns noted in this group of patients. From our report, the context of these patterns should be extended to include reflex audiogenic seizures. [Copyright &y& Elsevier]

The authors report the case of a surviving twin patient with severe brain malformation due to intrauterine fetal demise of the other twin. The patient was a boy with 37 weeks of gestational age. Intrauterine death of the co-twin was discovered at 18 weeks of gestation. No major anomalies were recognized at birth except for microcephalus. Magnetic resonance imaging demonstrated wide sylvian fissures, bilateral ventriculomegaly, and smooth brain surface of the temporoparieto-occipital lobes. He had spastic quadriplegia and severe mental retardation. Brief tonic seizures appeared at 7 months of age. Clonazepam was administered, and seizures disappeared at 24 months of age. Complex partial seizures began at 8 years of age. Seizures were observed weekly despite treatment with carbamazepine. The malformation of our patient was considered to be a result of a mixture of destructive process and disorders of neuronal proliferation and migration. [ABSTRACT FROM AUTHOR]

When pregnant women abuse methamphetamine, the foremost concern is the potential adverse effect of this substance on fetal development. Clinical studies in humans have found that exposure to methamphetamine during brain development can cause neurobehavioral abnormalities, such as aggressive behavior, learning problems, and poor social adaptation. In the present study, we examined the effects of prenatal methamphetamine exposure on brain development in rats. The first group of pregnant rats was administered methamphetamine at a dose of 5 mg/kg/day during gestational day (GD 10 to GD 20 [MA]. The second group of pregnant rats was injected with saline vehicle only [SAL]. On GD 21 their fetuses were removed and fetal brains were observed. We found various types of morphological damage in MA fetal brains, including microgyria, ectopia, and hemorrhage. In some cases, abnormal distribution of the leptomeninx, such as breach or accumulation, was observed in addition to these histological abnormalities. Therefore, we examined the expression of laminin, which is an important component of the pia mater, in the fetal brains. However, Western blot analysis revealed that there was no difference in expression amount of laminin in whole fetal brain between the MA and SAL groups. We concluded that methamphetamine use during pregnancy can cause histological brain alterations in fetuses. Morphological alterations of brain seen in the present study and previous human studies following prenatal exposure to methamphetamine might be related to the neurobehavioral abnormalities seen in patients who had been exposed to methamphetamine in utero. [ABSTRACT FROM AUTHOR]

Abstract: We present a 14-year-old boy with Fukuyama-type congenital muscular dystrophy (FCMD) who shows the mildest muscle weakness ever reported with this affliction and exceptionally mild mental retardation, but who has intractable epilepsy. Magnetic resonance imaging showed the typical abnormalities of FCMD. Molecular genetic analyses revealed a 3kb insertion mutation in the fukutin gene heterozygously. We could find no mutation in the coding region of the fukutin gene in the chromosome without a 3kb insertion. The most probable mechanism of clinical manifestation in this patient could be either a mutation in the noncoding regions of the fukutin gene on the chromosome without the ancestral founder haplotype of FCMD, or an error in the process of transcription or translation. Another possibility is the abnormalities in other genes involved in the glycosylation of α-dystroglycan, such as Fukutin-related protein and LARGE genes. [Copyright &y& Elsevier]

Abstract: The objective of this study is to better understand the relationship between neuroradiologic and clinical characteristics in holoprosencephaly (HPE) using the multivariate analysis called factor analysis. HPE is a brain malformation characterized by incomplete cleavage of the cerebral hemispheres and deep gray structures. We performed evaluations on 89 children with HPE that included their history, developmental assessment, and physical examination. Ten clinical variables included in factor analysis were the grade of spasticity, dystonia, choreoathetosis, hypotonia, mobility, upper extremity/hand function, expressive language, feeding/swallowing difficulty, endocrinopathies, and temperature dysregulation. Five neuroimaging variables graded by pediatric neuroradiologists were the grade of HPE (from least to most severe: lobar, semilobar, and alobar) and the degree of non-separation of caudate, lentiform, thalamic, and hypothalamic nuclei. Factor analysis using principle component extraction and varimax rotation was utilized. Four significant factors were identified: (1) neuroimaging/developmental factor, (2) motor factor, (3) hypothalamic/oromotor factor, and (4) hypotonia factor. These four factors accounted for 65.2% of the variance. In this factor analysis of HPE patients, we were able to reduce the large number of clinical and radiological variables into four factors. These factors and the constructs underlying them provide structure to the data and provide key parameters for future studies involving neurodevelopmental outcomes in HPE. [Copyright &y& Elsevier]

Background: Corpus callosum is the largest cerebral commissure that connects neocortical areas. Agenesis of corpus callosum (ACC) can be partial or complete, isolated or associated with other malformations. Its prenatal diagnosis creates problems within parental counselling due to its uncertain prognosis. The aim of this study was to correlate the neurodevelopmental outcome with both the clinical picture and the neuroradiological features, in order to improve prenatal parental counselling in a group of nine children with ACC, prenatally diagnosed by ultrasound and then confirmed by postnatal magnetic resonance imaging (MRI). Methods: In all patients, cerebral ultrasound scans, electroencephalogram (EEG) examinations, cerebral MRI, cytogenetic analysis, general physical evaluation, neurological examination and neuropsychological assessment (Griffiths Scale, Wechsler Primary and Preschool Scale of Intelligence, Wechsler Intelligence Scale for Children) were carried out. Results: In six patients the callosal agenesis was isolated, while in 3/9 it was associated with other cerebral malformations. Children with isolated callosal agenesis were asymptomatic or presented a mild hypotonia and the EEG was normal in five of them. All children with other associated brain malformations presented epilepsy, poor psychomotor development and cerebral palsy. Conclusion: The prenatal suspicion of ACC needs an accurate diagnostic approach, in order to well determine its isolated or associated nature, linked to different neurodevelopmental outcome. [ABSTRACT FROM AUTHOR]

The Dandy-Walker (DW) complex is a rare posterior fossa malformation, usually observed during the prenatal period or the early infancy. Clinically, it is characterized by mental retardation, seizures, cerebellar ataxia as well as symptoms of hydrocephalus. Structural imaging reveal a hypoplasia or agenesis of the cerebellar vermis, enlargement of the fourth ventricle with a posterior fossa cyst. Additional neurodevelopmental changes such as agenesis of the corpus callosum, lissencephaly and cortical dysplasia are also present. We report the first neuropathological analysis of an adult asymptomatic DW case. Brain computerized tomography showed a massive posterior fossa cyst and hypoplasia of the cerebellum. An Ehlers-Danlos syndrome type IV characterized by repetitive intestinal perforations and a saccular aneurysm on the left posterior communicating artery was also present. Macroscopic brain examination revealed hypoplasia of both cerebellar hemispheres and posterior part of the vermis, as well as dilatation of the fourth ventricle without hydrocephalus. The posterior fossa cyst wall was formed by an external arachnoid layer, middle layer with loose connective tissue and an internal layer of ependymal cells. There were two foci of cerebellar cortical dysplasia but no ectopic neurons, neuronal loss or gliosis in both cerebellum and cerebral cortex. No vascular or significant neurodegenerative lesions were observed. In comparison with previous reports in DW infants, this adult case displayed milder brain abnormalities compatible with a diagnosis of DW variant. The preservation of the cortical cytoarchitecture as well as the paucity of additional neurodevelopmental changes may explain the absence of clinical expression. [ABSTRACT FROM AUTHOR]

Purpose: Seizures are noted in a significant proportion of cases of de novo, heterozygous, loss-of-function mutations in SOX2, ascertained because of severe bilateral eye malformations. We wished to determine the underlying cerebral phenotype in SOX2 mutation and to test the candidacy of SOX2 as a gene contributing to human epilepsies. Methods: We examined high-resolution MRI scans in four patients with SOX2 mutations, two of whom had seizures. We determined the Sox2 expression pattern in developing murine brain. We searched for SOX2 mutation in 24 patients with typical hippocampal sclerosis and for common variations in SOX2 in 655 patients without eye disease but with epilepsy, including 91 patients with febrile seizures, 93 with hippocampal sclerosis, and 258 with temporal lobe epilepsy. Results: Striking hippocampal and parahippocampal malformations were seen in all cases, with a history of febrile seizures or epilepsy in two of four cases. The Sox2 expression pattern in developing mouse brain supports the pattern of malformations observed. Mutation screening in patients with epilepsy did not reveal any abnormalities in SOX2. No associations were found between any clinical epilepsy phenotype and common variation in SOX2. Conclusions: SOX2 haploinsufficiency causes mesial temporal malformation in humans, making SOX2 dysfunction a candidate mechanism for mesial temporal abnormalities associated with chronic epilepsy. However, although mutation of SOX2 in humans causes hippocampal malformation, SOX2 mutation or variation is unlikely to contribute commonly to mesial temporal lobe epilepsy or its structural (hippocampal sclerosis) or historic (febrile seizures) associations in humans. [ABSTRACT FROM AUTHOR]

Recent genetic insight into the mechanisms of human brain malformation have allowed one to consider a classification of these disorders by the genetic disruption. In this article an attempt is made to classify human cortical dysplasias by the known genetic disruptions or insults that lead to them. The discussion of malformation is within the context of the embryologic processes that have thought to have gone awry. Human disorders of segmentation, cell proliferation, telencephalic cleavage, differentiation, and neuronal migration are discussed. As this is a rapidly changing area, the reader is encouraged to check online databases for updates on the genetic insights that have been gained since the publication of this article. [Copyright &y& Elsevier]

Lissencephaly with cerebellar hypoplasia has been recently reported as different group of lissencephaly, which is not included in either classical or cobblestone types. We described magnetic resonance imaging findings of a 8-year-old boy with lissencephaly with cerebellar hypoplasia, to distinguish it from other forms of lissencephaly. [Copyright &y& Elsevier]

Objective: To evaluate the electroencephalographic characteristics of patients with holoprosencephaly (HPE) without epilepsy.Methods: We evaluated the electroencephalograms (EEGs) of 18 children with HPE who lacked a history of seizures. Neuroimaging studies were assessed for severity of HPE and thalamic non-separation and the presence of dorsal cysts and cortical malformations.Results: Hypersynchronous theta activity occurred in 50 and 60% of EEGs during wakefulness or drowsiness/sleep, respectively, and correlated with the grade of thalamic non-separation (p<0.05). Hypersynchronous beta activity during sleep occurred in 41% of EEGs. Posterior amplitude attenuation occurred in 33% of EEGs and correlated with the presence of a dorsal cyst (p≤0.0004). Photic driving responses were seen in 50% of the EEGs. If a dorsal cyst was present, the responses were anteriorly displaced. Epileptiform activity was noted in EEGs of 5 patients and did not correlate with the incidence of clinical seizures.Conclusions: Hypersynchronous activity was present frequently in EEGs of HPE patients, possibly attributable to incomplete separation of the thalami and hemispheres. Dorsal cysts were associated with posterior amplitude attenuation and anterior displacement of the photic response. In this selective cohort, the presence of epileptiform activity was not a risk factor for seizures.Significance: To date, this is the largest study of EEGs in children diagnosed with HPE without seizures. This study complements our earlier clinical and neuroradiologic studies by providing neurophysiologic data that serves to enhance our understanding of this complex, rare disorder. [Copyright &y& Elsevier]

Prenatal ultrasonography is the primary screening modality for the evaluation of fetal pathology. Ultrafast fetal MRI is a recent development that examines the fetus in utero. The short acquisition times (as short as 400 ms/slice) allow to picture freeze the fetus without the need for fetal sedation. The high spatial resolution, good contrast-to-noise ratio, and the multiplanar capabilities are especially advantageous in pathologies of the fetal central nervous system (CNS). Fetal MRI currently serves as a second-line imaging tool for complex fetal cerebral malformations and pathologies. Fetal ventriculomegaly, lesions within the posterior fossa, and abnormalities in cerebral myelination, migration, and sulcation are particularly well identified. [ABSTRACT FROM AUTHOR]

Objective: We describe the case of a boy with a TUBA1A mutation presenting with microphthalmia and congenital cataracts in addition to microcephaly and severe brain malformation.Methods: A boy presented in early infancy with microphthalmia, congenital cataracts, and microcephaly. His neurological course included severe hypotonia and drug-resistant epilepsy. Magnetic resonance imaging of the brain revealed a complex malformation that included agenesis of the corpus callosum, severely hypoplastic cerebellar vermis, mildly hypoplastic and dysplastic cerebellar hemispheres, mildly hypoplastic brainstem, mild posterior simplified cerebral gyral pattern, dysplastic basal ganglia and thalami, hypoplastic optic nerves, and absent olfactory bulbs.Results: TUBA1A genetic testing was conducted and revealed a previously unreported heterozygous 808G>T missense mutation. Parental genetic testing was negative, indicating that the child's mutation was de novo.Conclusion: The TUBA1A gene encodes tubulin alpha-1A, a protein with an important role in microtubule function and stability. Human mutations can result in a wide spectrum of brain malformations including lissencephaly, microlissencephaly, cerebellar hypoplasia, agenesis of the corpus callosum, pachygyria and polymicrogyria. Although TUBA1A is expressed in both developing brain and retinal tissue, there are no reported cases of TUBA1A mutations in association with major developmental ophthalmologic abnormalities. [ABSTRACT FROM AUTHOR]

We describe a 6-month-old boy suffering from motor and mental retardation. All radiological features were suggestive of holoprosencephaly with no identifiable lateral or third ventricles and fusion of the thalami. [ABSTRACT FROM AUTHOR]

Abstract Hemi-hydranencephaly is a very rare condition characterized by complete or almost near-complete unilateral absence of the cortical cortex, which is filled by a sac of cerebrospinal fluid. Prenatal vascular disruption with occlusion of the carotid artery territories ipsilateral to the damaged brain is the presumed pathogenesis. We have selected nine cases that fit the clinical and pathologic characteristics of hemi-hydranencephaly, demonstrating that destruction of one hemisphere may be not always associated with severe neurologic impairment and may allow an almost normal life. This disorder is an example of a possible prenatal re-organization in which the right and left cerebral hemispheres present functional potentiality to make up the damaged brain. The cases reported in the literature are discussed, including a patient previously reported and followed-up for 10 years. A review of the cases is performed with an evaluation of the most important aspect of this rare and mysterious disorder.

Lissencephaly (smooth brain) is a severe malformation of neuronal migration with a relatively smooth cerebral surface, thick and poorly organized cortex, and clinical signs of severe neurologic dysfunction. Subcortical band heterotopia is part of the lissencephaly malformation spectrum now referred to as The agyria-pachygyria-band spectrum. Chromosome 17-linked lissencephaly (patients with MiIIer-Dieker syndrome) have classical lissencephaly, characteristic facial features, and perhaps other associated birth defects. The critical region for the lissencephaly phenotype has been mapped to 17p 13.3, but the identity of th. chromosome 17 lissencephaly gene remains unknown. The gene responsible to X-linked lissencephaty has been mapped to Xq22.3. Autosomal recessive classical lissincephaly is thought to exist, although it is considered rate. [ABSTRACT FROM AUTHOR]

Ectopic neuronal masses below the subcortical white matter were seen in the brains of postnatal rats after 200 cGy irradiation at embryonic day 14. In contrast with the laminated organisation of the cortex located above the subcortical white matter, the ectopic masses were formed of confluent nodules composed of pyramidal and non-pyramidal neurons distributed at random, with no laminar organisation. Afferent and efferent fibres to/from the ectopic masses running together with fibres passing the subcortical white matter indicated that the ectopic masses were heavily connected to neighbouring structures. Examination of irradiated embryos revealed that the ectopic masses originated from ectopic periventricular rosettes, composed of germinal cells, which were formed shortly after irradiation. Neuronogenesis in these rosettes did not follow an inside-out gradient, as seen in the laminated cortex; however, early-generated neurons predominated in the external regions, whereas late-generated neurons were mainly located in the middle and internal regions of the ectopic masses. [ABSTRACT FROM AUTHOR]

Lissencephaly ('smooth brain') is a brain malformation characterized by a smooth cerebral surface, incomplete neuronal migration, and secondary abnormalities such as mental retardation, seizures, and minor facial dysmorphisms. Recent reports have produced evidence supporting several different causes including submicroscopic deletions in chromosome band 17p13.3, autosomal recessive inheritance, intrauterine infection, and intrauterine perfusion failure. We describe the clinical manifestations in seven patients with lissencephaly, and review pertinent studies regarding possible causes. The clinical manifestations were uniformly severe. All patients had severe mental retardation, hypotonia, often combined with spastic paralysis, and infantile spasms which did not respond to treatment. Most had poor growth, postnatal microcephaly, feeding problems, and frequent respiratory infections including pneumonia. None had other significant birth defects. Appropriate studies include computed tomography or magnetic resonance imaging (sometimes both), chromosome analysis, DNA analysis of the lissencephaly region on chromosome 17, electroencephalography and sometimes metabolic studies. [ABSTRACT FROM AUTHOR]

Hemimegalencephaly is a rare sporadic brain malformation characterized by enlargement of one cerebral hemisphere. The classical clinical triad consists of intractable epilepsy, severe psychomotor delay and hemiparesis. In this report, we describe a case of a 3-year-old girl, with all the radiological features of severe hemimegalencephaly but with a comparatively benign clinical course. She had no hemiparesis, mild delay and no seizures. An extensive literature review reveals only one previously reported case of hemimegalencephaly with the absence of seizures, as part of case series. This is the first dedicated case report, with clinical description and radiological images, of this entity. [ABSTRACT FROM AUTHOR]

SMG8 (MIM *617315) is a regulatory subunit involved in nonsense-mediated mRNA decay (NMD), a cellular protective pathway that regulates mRNA transcription, transcript stability, and degrades transcripts containing premature stop codons. SMG8 binds SMG9 and SMG1 to form the SMG1C complex and inhibit the kinase activity of SMG1. Biallelic deleterious variants in SMG9 are known to cause a heart and brain malformation syndrome (HBMS; MIM #616920), whereas biallelic deleterious variants in SMG8 were recently described to cause a novel neurodevelopmental disorder (NDD) with dysmorphic facies and cataracts, now defined as Alzahrani-Kuwahara syndrome (ALKUS: MIM #619268). Only eight subjects from four families with ALKUS have been described to date. Through research reanalysis of a nondiagnostic clinical exome, we identified a subject from a fifth unrelated family with a homozygous deleterious variant in SMG8 and features consistent with ALKUS. Interestingly, the subject also had unilateral microphthalmia, a clinical feature that has been described in SMG9-related disorder. Our study expands the phenotypic spectrum of SMG8-related disorder, demonstrates an overlapping phenotype between SMG8- and SMG9-related rare disease traits, provides further evidence for the SMG8 and SMG9 protein interactions, and highlights the importance of revisiting nondiagnostic exome data to identify and affirm emerging novel genes for rare disease traits., (© 2021 Wiley Periodicals LLC.)

Structural brain anomalies are relatively common and may be detected either prenatally or postnatally. Brain malformations can be characterized based on the developmental processes that have been perturbed, either by environmental, infectious, disruptive or genetic causes. Fetuses and neonates with brain malformations should be thoroughly surveilled for potential other anomalies, and depending on the nature of the brain malformation, may require additional investigations such as genetic testing, ophthalmological examinations, cardiorespiratory monitoring, and screening laboratory studies., (© 2022. The Author(s).)

PCDH12 is a member of the non-clustered protocadherin family of calcium-dependent cell adhesion proteins, which are involved in the regulation of brain development and endothelial adhesion. To date, only 15 families have been reported with PCDH12 associated disease. The main features previously associated with PCDH12 deficiency are developmental delay, movement disorder, epilepsy, microcephaly, visual impairment, midbrain malformations, and intracranial calcifications. Here, we report novel clinical features such as onset of epilepsy after infancy, episodes of transient developmental regression, and dysplasia of the medulla oblongata associated with three different novel truncating PCDH12 mutations in five cases (three children, two adults) from three unrelated families. Interestingly, our data suggests a clinical overlap with interferonopathies, and we show an elevated interferon score in two pediatric patients. This case series expands the genetic and phenotypic spectrum of PCDH12 associated diseases and highlights the broad clinical variability., Competing Interests: Declaration of competing interest The authors have no potential conflicts of interest to disclose., (Copyright © 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

During neocortical development, neural stem cells (NSCs) divide symmetrically to self-renew at the early stage and then divide asymmetrically to generate post-mitotic neurons. The molecular mechanisms regulating the balance between NSC self-renewal and neurogenesis are not fully understood. Using mouse in utero electroporation (IUE) technique and in vitro human NSC differentiation models including cerebral organoids (hCOs), we show here that regulator of cell cycle (RGCC) modulates NSC self-renewal and neuronal differentiation by affecting cell cycle regulation and spindle orientation. RGCC deficiency hampers normal cell cycle process and dysregulates the mitotic spindle, thus driving more cells to divide asymmetrically. These modulations diminish the NSC population and cause NSC pre-differentiation that eventually leads to brain developmental malformation in hCOs. We further show that RGCC might regulate NSC spindle orientation by affecting the organization of centrosome and microtubules. Our results demonstrate that RGCC is essential to maintain the NSC pool during cortical development and suggest that RGCC defects could have etiological roles in human brain malformations., (© 2021 The Authors.)

In this review, we explore evidence that hypoxia in the developing human fetus can lead not only to the more commonly accepted disruptive-type defects, but also patterns of anomalies that suggest that hypoxia can exert a more classic teratogenic effect, using the brain as one example. We review neuropathology in the context of intrauterine hypoxia, particularly as it relates to carbon monoxide poisoning, in utero strokes, and homozygous alpha-thalassemia. In general, the associated brain injuries resemble those seen with other causes of hypoxic-ischemic injury. Fetal strokes during development usually lead to loss of brain tissue in areas that do not follow a typical embryologic pattern, and therefore are considered disruptions. However, there is also evidence that fetal brain ischemia can cause more classically recognized patterns of abnormal embryonic neuronal migration and organization such as polymicrogyria, cortical dysplasia, or dysgenesis, including select types of focal cortical dysplasia. This study summarizes available literature and evidence to raise clinicians' awareness regarding the association between hypoxia and congenital anomalies, including brain malformations., (© 2021 Wiley Periodicals LLC.)