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Background. Lissencephaly (LIS) is a spectrum of malformations of the cerebral cortex that occur as a result of impaired migration of neuronal precursors to the cortical plate and the formation of furrows and convolutions in the post‑migration period of embryonic development. In recent years, a significant role of hereditary factors in the occurrence of LIS has been shown due to the improvement of methods of molecular genetic diagnostics. Today, 13 genetic variants have been identified in the LIS group, six of which are inherited autosomal recessively, five are autosomal dominant, and two are linked to the X chromosome. It is shown that 80 % of cases of hereditary LIS is caused by mutations in two genes: PAFAH1B1 , which is responsible for the occurrence of the LIS 1 type with an au‑ tosomal dominant type of inheritance, and in the DCX gene, localized on the X chromosome. The rest of the genetic variants account for from 1 % to 5 % of cases of defects accompanied by dysgenesis of the cerebral cortex. In recent years, the number of works devoted to the analysis of clinical and genetic characteristics of monogenic variants of LIS has increased. The results of such studies will allow us to improve our understanding not only of the pathogenetic mechanisms of this group of diseases, but also of the molecular basis for the formation of brain structures in the normal embryonic period. Objective: to describe the clinical and genetic characteristics of three Russian patients with autosomal dominant LIS type 3 (OMIM: 611603) caused by mutations in the TUBA1A gene. Materials and methods. All patients were under observation in the consultative and diagnostic department of Research Centre for Medical Genetics. The diagnosis was established on the basis of clinical data, genealogical anamnesis, results of brain MRI, EEG night video monitoring and exome sequencing by NGS. The validation of the identified nucleotide substitutions and analysis of the disease segregation were performed using the Sanger direct automatic sequencing method. Results. The clinical and genetic characteristics of three patients with newly identified and previously described mutation in the TUBA1A gene were analyzed. Possible effects of new missense mutations in the gene on the function of the protein product of the gene are discussed. Conclusions. The results of the analysis of the clinical and genetic characteristics of the patients we observed contribute to the study of the polymorphism of clinical manifestations resulting from mutations in the TUBA1A gene. The previously stated assumption about a wide range of malformations of the brain in patients with mutations in this gene was confirmed, which should be taken into account when making a diagnosis.

Tubulinopathies are a heterogeneous group of complex cortical malformations that are associated with mutations in tubulin genes. TUBB3 gene mutation is associated with a broader spectrum of central nervous system malformations and constitutes about 10% of all tubulinopathies. The diagnosis may not be immediately apparent on imaging, though the differential diagnosis may be narrowed based on imaging findings and allow for more directed genetic testing. We report a 22-year-old gravida-1 nulliparous female whose routine second trimester fetal ultrasound revealed ventriculomegaly and possible agenesis of the corpus callosum. Fetal magnetic resonance imaging showed severe lateral and third ventriculomegaly and a dysplastic, z-shaped brainstem without any evidence of ocular abnormalities. Genetic testing revealed a pathogenic mutation in TUBB3.

International audience; The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

Background The ALDH7A1 gene is known to be responsible for autosomal recessive pyridoxine-dependent epilepsy (OMIM 266100). The phenotypic spectrum of ALDH7A1 mutations is very heterogeneous ranging from refractory epilepsy and neurodevelopmental delay, to multisystem neonatal disorder. Aim The present study aims at describing the phenotype associated with a novel homozygous ALDH7A1 mutation and the spectrum of brain malformations associated with pyridoxine-dependent epilepsy. Methods We conducted a literature review on the Internet database Pubmed (up to November 2017) searching for ALDH7A1 mutations associated with brain malformations and brain MRI findings. Results We present the case of two siblings, children of related parents. The proband presented neonatal focal seizures not responding to conventional antiepileptic drugs. Electroencephalography showed a suppression burst pattern and several multifocal ictal patterns, responsive to pyridoxine. Brain MRI was normal. Molecular analysis by targeted next-generation sequencing panel for epileptic encephalopathy disclosed a homozygous missense mutation of ALDH7A1. The same mutation was then found in a stored sample of DNA from peripheral blood of an older sister dead 3 years earlier. This girl presented a complex brain malformation diagnosed with a foetal MRI and had neonatal refractory seizures with suppression burst pattern. She died at 6 months of age. Literature review The brain abnormalities most frequently reported in pyridoxine-dependent epilepsy include: agenesia/hypoplasia of the corpus callosum, not specific white matter abnormalities, large cisterna magna, ventriculomegaly, haemorrhages, cerebellum hypoplasia/dysplasia, and, more rarely, dysplasia of the brainstem and hydrocephalus. Discussion and conclusions ALDH7A1 mutations have been associated to different brain abnormalities, documented by MRI only in few cases. The study cases expand the clinical spectrum of ALDH7A1 associated conditions, suggesting to look for ALDH7A1 mutations not only in classical phenotypes but also in patients with brain malformations, mainly if there is a response to a pyridoxine trial.

Enlarged parietal foramina (PFM) are congenital calvarial defects characterized by bilateral parietal bone defects (>5 mm), occurring on each side of the sagittal suture along its posterior aspect. While often lacking underlying intracranial malformations, there has been increasing recognition of coexisting brain malformations in certain subtypes. We present a case of a 12-year-old girl presenting with new-onset grand mal seizure with developmental delay and a known family history of epilepsy. Brain MRI revealed large, bilateral parietal bone defects with underlying cortical malformation (polymicrogyria and ulegyria) and vascular abnormalities (persistent falcine sinus), related to PFM. This case report describes the genetic basis for recognized subtypes of PFM and the rare association of brain malformations associated with PFM due to mutations in the ALX4 homeobox gene.

Publisher Copyright: © 2020 by the authors. An inherited neurologic syndrome in a family of mixed-breed Oriental cats has been characterized as forebrain commissural malformation, concurrent with ventriculomegaly and interhemispheric cysts. However, the genetic basis for this autosomal recessive syndrome in cats is unknown. Forty-three cats were genotyped on the Illumina Infinium Feline 63K iSelect DNA Array and used for analyses. Genome-wide association studies, including a sib-transmission disequilibrium test and a case-control association analysis, and homozygosity mapping, identified a critical region on cat chromosome A3. Short-read whole genome sequencing was completed for a cat trio segregating with the syndrome. A homozygous 7 bp deletion in growth differentiation factor 7 (GDF7) (c.221_227delGCCGCGC [p.Arg74Profs]) was identified in affected cats, by comparison to the 99 Lives Cat variant dataset, validated using Sanger sequencing and genotyped by fragment analyses. This variant was not identified in 192 unaffected cats in the 99 Lives dataset. The variant segregated concordantly in an extended pedigree. In mice, GDF7 mRNA is expressed within the roof plate when commissural axons initiate ventrally-directed growth. This finding emphasized the importance of GDF7 in the neurodevelopmental process in the mammalian brain. A genetic test can be developed for use by cat breeders to eradicate this variant.

Neurocutaneous melanosis (NCM; MIM # 249400; ORPHA: 2481], first reported by the Bohemian pathologist Rokitansky in 1861, and now more precisely defined as neurocutaneous melanocytosis, is a rare, congenital syndrome characterised by the association of (1) congenital melanocytic nevi (CMN) of the skin with overlying hypertrichosis, presenting as (a) large (LCMN) or giant and/or multiple (MCMN) melanocytic lesions (or both; sometimes associated with smaller "satellite" nevi) or (b) as proliferative melanocytic nodules; and (2) melanocytosis (with infiltration) of the brain parenchyma and/or leptomeninges. CMN of the skin and leptomeningeal/nervous system infiltration are usually benign, more rarely may progress to melanoma or non-malignant melanosis of the brain. Approximately 12% of individuals with LCMN will develop NCM: wide extension and/or dorsal axial distribution of LCMN increases the risk of NCM. The CMN are recognised at birth and are distributed over the skin according to 6 or more patterns (6B patterns) in line with the archetypical patterns of distribution of mosaic skin disorders. Neurological manifestations can appear acutely in infancy, or more frequently later in childhood or adult life, and include signs/symptoms of intracranial hypertension, seizures/epilepsy, cranial nerve palsies, motor/sensory deficits, cognitive/behavioural abnormalities, sleep cycle anomalies, and eventually neurological deterioration. NMC patients may be symptomatic or asymptomatic, with or without evidence of the typical nervous system changes at MRI. Associated brain and spinal cord malformations include the Dandy-Walker malformation (DWM) complex, hemimegalencephaly, cortical dysplasia, arachnoid cysts, Chiari I and II malformations, syringomyelia, meningoceles, occult spinal dysraphism, and CNS lipoma/lipomatosis. There is no systemic involvement, or only rarely. Pathogenically, single postzygotic mutations in the NRAS (neuroblastoma RAS viral oncogene homologue; MIM # 164790; at 1p13.2) proto-oncogene explain the occurrence of single/multiple CMNs and melanocytic and non-melanocytic nervous system lesions in NCM: these disrupt the RAS/ERK/mTOR/PI3K/akt pathways. Diagnostic/surveillance work-ups require physical examination, ophthalmoscopy, brain/spinal cord magnetic resonance imaging (MRI) and angiography (MRA), positron emission tomography (PET), and video-EEG and IQ testing. Treatment strategies include laser therapy, chemical peeling, dermabrasion, and surgical removal/grafting for CMNs and shunt surgery and surgical removal/chemo/radiotherapy for CNS lesions. Biologically targeted therapies tailored (a) BRAF/MEK in NCM mice (MEK162) and GCMN (trametinib); (b) PI3K/mTOR (omipalisib/GSK2126458) in NMC cells; (c) RAS/MEK (vemurafenib and trametinib) in LCMNs cells; or created experimental NMC cells (YP-MEL).

Contains fulltext : 218305.pdf (Publisher’s version ) (Closed access) BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor beta signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function.

Objective Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed. Methods Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed. Results Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56 EEG at onset, and clinical outcome. On brain imaging, 100 98 and 96.36with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63 should also be considered a common feature in AIC, our study highlighted the presence (in 76.36 of basal ganglia dysmorphisms (never previously reported). Conclusion The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome. Classification of Evidence This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes. Objective Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed.Methods Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed.Results Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported).Conclusion The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome.Classification of Evidence This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.

Developmental absence (agenesis) of the corpus callosum (AgCC) is a congenital brain malformation resulting from disruption of corpus callosum formation, a structure that is crucial for the transfer and integration of information, including attention processes, across the brain. This study aimed to investigate previously proposed candidates for alternative inter-hemispheric pathways in AgCC by examining (1) white matter volume and microstructure of the anterior and posterior commissures in children with AgCC compared to typically developing controls (TDC), and (2) in children with AgCC, examine the associations of white matter volume and microstructure of the anterior and posterior commissures and any remaining corpus callosum with attention processes. Participants were 21 children with AgCC (13 complete, 8 partial) recruited from The Royal Children's Hospital, Melbourne, and 30 TDC aged 8–17 years. T1-and diffusion-weighted MR sequences were used to calculate volume and microstructural parameters. Neuropsychological testing assessed attention processes. We found the anterior commissure was significantly larger in volume in children with AgCC than TDC (p = .027), with reduced mean FA (p = .001) associated with increased mean RD (p < .001). In children with AgCC, we found microstructural properties of the anterior commissure associated with attentional processes, specifically, mean FA of the anterior commissure was associated with better divided attention (p = .03), and the association between alerting attention and mean AD and RD was found to be moderated by age (p = .027, p = .008) and the degree of corpus callosum agenesis (p = .025, p = .016). Furthermore, in partial AgCC, larger posterior commissure volume was associated with better orienting attention (p = .035). In conclusion, we provide evidence that the volume and microstructure of the anterior commissure are altered in children with AgCC, and this neuroplastic response might have an influence on attention processes.

Background The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A. Results In three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G > A, p.(Gly436Asp) variant was novel, the two variants c.518C > T, p.(Pro173Leu) and c.641G > A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (agyria-pachygyria) (70%), although reporting was incomplete in the different studies. We identified a total of 121 specific variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein model, 38.6% of all disease-causing variants including those in the C-terminal region are predicted to affect the binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication. Conclusions With 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting. Electronic supplementary material The online version of this article (10.1186/s13023-019-1020-x) contains supplementary material, which is available to authorized users.

Since the neuroradiological features of patients with 22q11.2 deletion syndrome are not well-understood, examinations using functional imaging were performed in this study. Brain magnetic resonance imaging (MRI) and 1H-magnetic resonance spectroscopy (MRS) were performed using a clinical 3-Tesla MR imager in 4 patients with 22q11.2 deletion syndrome (2 boys and 2 girls; aged 2-6 years.) and 20 age- and sex-matched healthy control subjects. Furthermore, interictal 123I-iomazenil (IMZ) single photon emission computed tomography (SPECT) was examined in 2 of the 4 patients. Among the 4 patients with 22q11.2 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 123I-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 22q11.2 deletion syndrome in this study, brain malformations and disturbances of the GABAergic nervous system would be underlying mechanisms of the neurodevelopmental abnormalities in this syndrome.

Valproic acid (VPA) is a teratogenic drug used in pregnant women for the treatment of epilepsy and mood disorders. Fetal valproate syndrome (FVS) is characterized by a number of abnormalities associated with VPA exposure in utero including neural tube defects, congenital heart defects, limb defects, genitourinary defects, brain, eye and respiratory anomalies, and abdominal wall defects. Complex cardiac defect and trigonocephaly have rarely been reported and multicystic dysplastic kidney has never been detected in FVS. We here report a female infant who was born to a mother with a history of low-dose VPA monotherapy (250 mg/day) during pregnancy and who had presented with a combination of unilateral multicystic dysplastic kidney, multicomplex cardiac defect including severe coarctation of aorta, Ebstein anomaly, secundum atrial septal defect, mesocardia along with trigonocephaly due to metopic craniosynostosis, typical facial appearance and limb defects. To our knowledge, this is the first case presented with multicystic dysplastic kidney, complex cardiac defect, trigonocephaly and other limb and facial defects because of exposure to very low-dose VPA monotherapy (250 mg/day) in utero. We conclude that VPA must be used very cautiously in pregnant women even as monotherapy and in low doses to prevent major congenital defects.

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.

Background. Specific clinical conditions could compromise cochlear implantation outcomes and drastically reduce the chance of an acceptable development of perceptual and linguistic capabilities. These conditions should certainly include the presence of inner ear malformations or brain abnormalities. The aims of this work were to study the diagnostic value of high resolution computed tomography (HRCT) and magnetic resonance imaging (MRI) in children with sensorineural hearing loss who were candidates for cochlear implants and to analyse the anatomic abnormalities of the ear and brain in patients who underwent cochlear implantation. We also analysed the effects of ear malformations and brain anomalies on the CI outcomes, speculating on their potential role in the management of language developmental disorders.Methods. The present study is a retrospective observational review of cochlear implant outcomes among hearing-impaired children who presented ear and/or brain anomalies at neuroimaging investigations with MRI and HRCT. Furthermore, genetic results from molecular genetic investigations (GJB2/GJB6and, additionally, in selected cases,SLC26A4or mitochondrial-DNA mutations) on this study group were herein described. Longitudinal and cross-sectional analysis was conducted using statistical tests.Results. Between January 1, 1996 and April 1, 2012, at the ENT-Audiology Department of the University Hospital of Ferrara, 620 cochlear implantations were performed. There were 426 implanted children at the time of the present study (who were Conclusions. Good outcomes with cochlear implants are possible in patients who present with inner ear or brain abnormalities, even if central nervous system anomalies represent a negative prognostic factor that is made worse by the concomitant presence of cochlear malformations. Common cavity and stenosis of the internal auditory canal (less than 2 mm) are negative prognostic factors even if brain lesions are absent.

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.

Target of rapamycin (TOR) was first identified in yeast as a target molecule of rapamycin, an anti-fugal and immunosuppressant macrolide compound. In mammals, its orthologue is called mTOR (mammalian TOR). mTOR is a serine/threonine kinase that converges different extracellular stimuli, such as nutrients and growth factors, and diverges into several biochemical reactions, including translation, autophagy, transcription, and lipid synthesis among others. These biochemical reactions govern cell growth and cause cells to attain an anabolic state. Thus, the disruption of mTOR signaling is implicated in a wide array of diseases such as cancer, diabetes, and obesity. In the central nervous system (CNS), the mTOR signaling cascade is activated by nutrients, neurotrophic factors, and neurotransmitters that enhances protein (and possibly lipid) synthesis and suppresses autophagy. These processes contribute to normal neuronal growth by promoting their differentiation, neurite elongation and branching, and synaptic formation during development. Therefore, disruption of mTOR signaling may cause neuronal degeneration and abnormal neural development. While reduced mTOR signaling is associated with neurodegeneration, excess activation of mTOR signaling causes abnormal development of neurons and glia, leading to brain malformation. In this review, we first introduce the current state of molecular knowledge of mTOR complexes and signaling in general. We then describe mTOR activation in neurons, which leads to translational enhancement, and finally discuss the link between mTOR and normal/abnormal neuronal growth during development.

The authors report a wide and updated revision of hydranencephaly, including a literature review, and present the case of a patient affected by this condition, still alive at 36 months. Hydranencephaly is an isolated and with a severe prognosis abnormality, affecting the cerebral mantle. In this condition, the cerebral hemispheres are completely or almost completely absent and are replaced by a membranous sac filled with cerebrospinal fluid. Midbrain is usually not involved. Hydranencephaly is a relatively rare cerebral disorder. Differential diagnosis is mainly relevant when considering severe hydrocephalus, poroencephalic cyst and alobar holoprosencephaly. Ethical questions related to the correct criteria for the surgical treatment are also discussed.

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.

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-Calve-Perthes disease (LCPD) [LCPD-like presentation]. Array-CGH analysis and mutation analysis of the RASA1 gene were normal in both patients.

Cataloged from PDF version of article. The biological basis for regional and inter-species differences in cerebral cortical morphology is poorly understood. We focused on consanguineous Turkish families with a single affected member with complex bilateral occipital cortical gyration abnormalities. By using whole-exome sequencing, we initially identified a homozygous 2-bp deletion in LAMC3, the laminin 33 gene, leading to an immediate premature termination codon. In two other affected individuals with nearly identical phenotypes, we identified a homozygous nonsense mutation and a compound heterozygous mutation. In human but not mouse fetal brain, LAMC3 is enriched in postmitotic cortical plate neurons, localizing primarily to the somatodendritic compartment. LAMC3 expression peaks between late gestation and late infancy, paralleling the expression of molecules that are important in dendritogenesis and synapse formation. The discovery of the molecular basis of this unusual occipital malformation furthers our understanding of the complex biology underlying the formation of cortical gyrations. © 2011 Nature America, Inc. All rights reserved.

In this study, we aimed to (1) propose landmarks for the hippocampus in a rat brain using an experimental study and (2) investigate hippocampus shape changes in a rat brain with epilepsy using the statistical shape analysis method. We have used the statistical shape analysis method to illustrate hippocampal shape deformation due to epilepsy. Statistical shape analysis is of increasing interest to the neuroimaging community because of its potential for locating morphological changes. Nineteen rat brains (ten healthy and nine epileptic) with hematoxylin and eosin images of the hippocampus were used. The results strongly indicated that the normalized hippocampal shape of the epileptic group was different from the nonepileptic group; deformation was seen most significantly in the medial regions of the cornu ammonis (CA1 and CA3) of the hippocampus. In conclusion, our landmark-based methodology detected regional differences in the hippocampus in epilepsy. This study may serve as an initial reference for future studies on shape alteration of the hippocampus associated with certain medical conditions.

Ciftcioglu, Engin/0000-0003-4402-3004; Kopuz, Cem/0000-0003-1710-9208 WOS: 000448068300010 PubMed: 26417484 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.

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.

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.

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:21:42Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:44:25Z : No. of bitstreams: 1 2-s2.0-32244442191.pdf: 215165 bytes, checksum: 39be905176b23a840b6c19f8403d8db6 (MD5) Made available in DSpace on 2014-05-27T11:21:42Z (GMT). No. of bitstreams: 0 Previous issue date: 2005-12-01 Apert syndrome is characterized by craniosynostosis, symmetric syndactyly and other systemic malformations, with mental retardation usually present. The objective of this study was to correlate brain malformations and timing for surgery with neuropsychological evaluation. We also tried to determine other relevant aspects involved in cognitive development of these patients such as social classification of families and parents' education. Eighteen patients with Apert syndrome were studied, whose ages were between 14 and 322 months. Brain abnormalities were observed in 55.6% of them. The intelligence quotient or developmental quotient values observed were between 45 and 108. Mental development was related to the quality of family environment and parents' education. Mental development was not correlated to brain malformation or age at time of operation. In conclusion, quality of family environment was the most significant factor directly involved in mental development of patients with Apert syndrome. Department of Craniofacial Surgery Hospital de Reabilitação de Anomalias Craniofaciais University of Sao Paulo (USP), Bauru, SP Department of Neuroradiology Hospital Alemão Oswaldo Cruz, São Paulo SP Department of Neurosurgery Hospital Das Clínicas University of Sao Paulo (USP), São Paulo SP Department of Neurology and Psychiatry Hospital Das Clínicas University of the State of São Paulo (UNESP), Botucatu SP Department of Surgery Hospital Das Clínicas University of the State of Sao Paulo (UNESP), Botucatu SP Department of Fonoaudiology Faculty of Odontology University of Sao Paulo (USP), Bauru SP , Rua Moyses Leme da Silva 1-30, 17017-335 Bauru SP Department of Neurology and Psychiatry Hospital Das Clínicas University of the State of São Paulo (UNESP), Botucatu SP Department of Surgery Hospital Das Clínicas University of the State of Sao Paulo (UNESP), Botucatu SP

Cancer diagnosed during pregnancy constitutes a difficult clinical condition with a devastating impact on the patient's somatic and psychosocial health and possibly on foetal integrity. This circumstance also raises several moral, religious, social and familial dilemmas. In this review we critically present available evidence regarding the incidence, epidemiology and genetics of cancer in pregnant women, its presentation, diagnosis and staging as well as therapeutic management. Issues such as maternal/foetal prognosis, need for termination of pregnancy, risk of foetal health injury and necessity of psychosocial support are reviewed. Recent accumulating evidence suggests that, with appropriate management, poena magna should not be used to define neither cancer nor pregnancy. © 2005 Elsevier Ltd. All rights reserved. 42 2 126 140

Baraitser-Winter syndrome is a rare autosomal recessive disorder characterized by developmental delay, dysmorphic features, and multiple malformations also involving the brain. We report a further case and provide updated information about an unrelated girl reported in the original paper by Baraitser and Winter. Both of them presented with pachygyria and the latter case was recently found to have subcortical band heterotopia on high resolution brain MRI imaging. These two patients and a review of the previously reported cases indicate that a specific pattern of brain anomalies falling in the agyria-pachygyria-band spectrum is associated with this dysmorphic syndrome, which may be considered another example of syndromic neuronal migration defect.

O termo disgenesia do corpo caloso refere-se a uma má-formação deste com origem na embriogênese do telencéfalo. O relato analisa os achados de tomografia computadorizada e ressonância magnética em 11 pacientes com disgenesia calosa e em um caso de corpo caloso normal com lipoma associado. Esta pode ser distinguida em três grupos: agenesia total (três casos), agenesia parcial (seis casos) e hipoplasia (dois casos). Anomalias associadas foram observadas em nove casos, incluindo má-formação de Chiari tipo II (um caso), esquizencefalia (um caso), cisto inter-hemisférico (dois casos), heterotopia nodular (um caso), cisto de Dandy-Walker (um caso) e lipoma do corpo caloso (quatro casos). Este artigo demonstra um espectro destes distúrbios, auxiliando na sua interpretação diagnóstica. Callosal dysgenesis is a malformation of the corpus callosum with origins in the embryogenesis of the telencephalon. We reviewed the computed tomography and magnetic resonance imaging findings of 11 patients with callosal dysgenesis and one patient with normal corpus callosum associated with a lipoma. The patients were divided into three distinct groups: total agenesis (three patients), partial agenesis (six patients) and hypoplasia (two patients). Associated abnormalities were observed in nine patients, including Chiari II malformation (one patient), schizencephaly (one patient), interhemispheric cyst (two patients), Dandy-Walker cyst (one patient), nodular heterotopy (one patient) and lipoma of the corpus callosum (four patients). This paper presents a review that may contribute to the diagnosis of these disorders.

Posture, quantity of spontaneous movement patterns, quality of general movements (GMs), and behavioural state organisation were studied in nine infants affected by documented brain malformations. A single 1 h video recording of five infants and two or more serial video recordings of another four infants were performed after birth. The graphic representation of single movement patterns (actogram) and of behavioural states of one video recording was performed in eight out of nine infants. The quality of GMs was assessed according to Prechtl's method in all video recordings. All nine infants showed a less variable posture than normal newborn infants and an unusual resting posture was detected in seven infants. Poor behavioural state organisation without sleep cycles was common to the nine infants and excessive wakefulness was observed in six infants. As for the quantity of single movement patterns, six infants lacked one or two movement patterns normally present in healthy newborn infants. An abnormal quality of GMs was noted in all nine infants and distinct motor abnormalities were observed in single infants. A monotonous and sometimes stereotyped sequence of different body parts involved in the movement (i.e. poor repertoire GMs) was common to all infants. In the four infants of whom two or more video recordings were available, initial poor repertoire GMs were followed by a further deterioration in movement quality. No relationship was found between the quantity of defective brain tissue, lack of a specific part of the brain, type and severity of GM and posture abnormalities.

Holoprosencephaly (HPE) is a brain malformation caused by a primary defect in induction and patterning of the rostral neurotube (basal forebrain) during the first 4 weeks of embryogenesis. T his defect results in incomplete separation of the cerebral hemispheres.Based on the degree of hemispheric nonseparation, HPE traditionally has been classified into three types: alobar, semilobar, and lobar.! In 1963, DeMyer et al. mentioned that defects in brain development may frequently coexist with abnormalities on the midfacial region. T he median facio-cerebral anomalies appear in various associated gradations and combinations.When combined in patterns, these facies always predict a severe, highly characteristic brain anomaly.2

Background Asparagine synthetase deficiency (OMIM# 615574) is a very rare newly described neurometabolic disorder characterized by congenital microcephaly and severe global developmental delay, associated with intractable seizures or hyperekplexia. Brain MRI typically shows cerebral atrophy with simplified gyral pattern and delayed myelination. Only 12 cases have been described to date. The disease is caused by homozygous or compound heterozygous mutations in the ASNS gene on chromosome 7q21. Case presentation Family 1 is a multiplex consanguineous family with five affected members, while Family 2 is simplex. One affected from each family was available for detailed phenotyping. Both patients (Patients 1 and 2) presented at birth with microcephaly and severe hyperekplexia, and were found to have gross brain malformation characterized by simplified gyral pattern, and hypoplastic cerebellum and pons. EEG showed no epileptiform discharge in Patient 2 but multifocal discharges in patient 1. Patient 2 is currently four years old with severe neurodevelopmental delay, quadriplegia and cortical blindness. Whole exome sequencing (WES) revealed a novel homozygous mutation in ASNS (NM_001178076.1) in each patient (c.970C > T:p.(Arg324*) and c.944A > G:p.(Tyr315Cys)). Conclusion Our results expand the mutational spectrum of the recently described asparagine synthetase deficiency and show a remarkable clinical homogeneity among affected individuals, which should facilitate its recognition and molecular confirmation for pertinent and timely genetic counseling. Electronic supplementary material The online version of this article (doi:10.1186/s12883-016-0633-0) contains supplementary material, which is available to authorized users.

Neuronal positioning is a fundamental process during brain development. Abnormalities in this process cause several types of brain malformations and are linked to neurodevelopmental disorders such as autism, intellectual disability, epilepsy, and schizophrenia. Little is known about the pathogenesis of developmental brain malformations associated with abnormal neuron positioning, which has hindered research into potential treatments. However, recent advances in neurogenetics provide clues to the pathogenesis of aberrant neuronal positioning by identifying causative genes. This may help us form a foundation upon which therapeutic tools can be developed. In this review, we first provide a brief overview of neural development and migration, as they relate to defects in neuronal positioning. We then discuss recent progress in identifying genes and brain malformations associated with aberrant neuronal positioning during human brain development.