Hypoplasia Of Corpus Callosum Research Articles

EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia.

The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.

Is there an encephalographic trait to septo-optic dysplasia? (de Morsier syndrome)

Objectives. Septo-optic dysplasia (SOD), also known as de Morsier syndrome is a rare congenital syndrome involving variable midline brain structures, characterized by visual impairment, pituitary deficiencies and specific brain abnormalities (especially midbrain malformations). The clinical phenotype is highly variable, from mild to extremely severe. The purpose of this paper is to present the electroencephalographic abnormalities in two clinical cases and correlate with the ones that have been described in the literature in order to find a specific trait of this syndrome. Methods and results. A 12-year-old girl was hospitalized in the pediatric neurology clinic for focal seizures, developmental delay and cerebral palsy. Clinical examination showed visual disturbances (nystagmus and oculomotor nerve palsy), unilateral pyramidal syndrome – left hemiparesis. Electroencephalography (EEG) revealed bilateral photosensitive epileptic form discharges, but asymmetrical, right more than left, with abnormal, slower background. MRI showed optic nerve hypoplasia and hypoplasia of the corpus callosum. The second case was also a girl, a 7-year-old who had only 2 focal right motor seizures with secondary generalization and developmental delay. Clinical examination showed visual impairment and bilateral nystagmus. The standard EEG evaluation didn’t reveal any abnormalities, with normal background. Cerebral MRI showed midline brain defects – agenesis of the septum pellucidum, agenesis of corpus callosum and optic nerve hypoplasia. Endocrine evaluation for pituitary function showed in the first case – increased thyroid-stimulating hormone and in the second case – decreased IGF1. Antiepileptic treatment was started in both cases, but seizures were refractory to treatment and persistent EEG abnormalities still present in the first case, with good evolution of epilepsy in the second case. Conclusions. The epileptiform abnormalities associated to SOD are present only if there is an associated cortical malformation.

Fetal Onset Ventriculomegaly and Subependymal Cysts in a Pyridoxine Dependent Epilepsy Patient

Pyridoxine dependent epilepsy (PDE) is caused by mutations in the ALDH7A1 gene encoding α-aminoadipic semialdehyde dehydrogenase. The classic clinical presentation is neonatal seizures responsive only to pyridoxine therapy. White matter abnormalities, corpus callosum agenesis or hypoplasia, megacisterna magna, cortical dysplasia, neuronal heterotopias, intracerebral hemorrhage, and hydrocephalus in neuroimaging have been reported in patients with PDE. We report a new patient with asymmetric progressive ventriculomegaly noted on fetal sonography at 22 weeks' gestation. Postnatal brain sonography on day 1 and MRI on day 5 confirmed bilateral asymmetric ventriculomegaly caused by bilateral subependymal cysts. Intractable seizures at age 7 days initially responded to phenobarbital. Markedly elevated urinary α-aminoadipic acid semialdehyde levels and compound heterozygous mutations in the ALDH7A1 gene (c.446C>A/c.919C>T) confirmed the diagnosis of PDE caused by ALDH7A1 genetic defect. Despite the presence of structural brain malformations and subependymal cysts, PDE should always be included in the differential diagnosis of neonatal seizures that are refractory to treatment with antiepileptic drugs.

Septo-optic dysplasia plus: a case report

BackgroundSepto-optic dysplasia, also referred to as de Morsier syndrome, is a congenital condition characterized by classic triad features: midline brain abnormalities, optic nerve hypoplasia and pituitary endocrine dysfunction. Sometimes, other various malformations appear within syndrome.Case presentationAn 11 and 1/2-year-old Caucasian Southeast European female patient with earlier established diagnoses of growth hormone deficiency, diabetes insipidus, seizures, mental retardation, optic nerve atrophy and right ptosis, was directed to us for consultative examination.The girl of short stature and low weight for her age had bilateral optic nerve hypoplasia, poor vision, nystagmus and right eye oculomotor palsy. Electroencephalogram revealed epileptic changes. Magnetic resonance imaging showed an empty sella syndrome, partial hypoplasia of corpus callosum, cavum of pellucid septum and diffuse polymicrogyria of the left temporal lobe. We found all elements of septo-optic dysplasia plus syndrome with right oculomotor nerve involvement.ConclusionBy earlier findings and evaluation, we established a diagnosis of septo-optic dysplasia plus. The case confirms the existence of various malformations within the syndrome and the need for the cooperation of several specialists in the diagnosis and treatment of children with the syndrome.

Multiple congenital anomalies‐intellectual disability (MCA‐ID) and neuroblastoma in a patient harboring a de novo 14q23.1q23.3 deletion

Neuroblastoma is the most frequent extra cranial solid tumor in infants and children. Genetic predisposition to neuroblastoma has been suspected previously due to familial cases of sporadic NB and predisposition to NB in several syndromes. Here, we report on a de novo 14q23.1-q23.3 microdeletion in a male presenting with a neuroblastoma diagnosed at 9 months, and spherocytosis, congenital heart defect, cryptorchidism, hypoplasia of corpus callosum, epilepsy, and developmental delay. Myc-associated-factor X (MAX) haploinsufficiency could be regarded as the predisposing factor to NB. Indeed 14q deletion is a recurrent somatic rearrangement in NB and MAX somatic and germline loss of function mutation have recently been described in pheochromocytoma and paraganglioma. However, MAX was expressed in the tumor of the patient we report on and, accordingly, loss of heterozygosity, mutation, or promoter methylation were excluded. In addition, we discuss the potential involvement in the clinical spectrum presented by the patient of five of the deleted genes, namely DAAM1, PLEKHG3, SPTB, AKAP5, and ARID4A.

LIN7A Depletion Disrupts Cerebral Cortex Development, Contributing to Intellectual Disability in 12q21-Deletion Syndrome

Interstitial deletion of 12q21 has been reported in four cases, which share several common clinical features, including intellectual disability (ID), low-set ears, and minor cardiac abnormalities. Comparative genomic hybridization (CGH) analysis using the Agilent Human Genome CGH 180K array was performed with the genomic DNA from a two-year-old Japanese boy with these symptoms, as well as hypoplasia of the corpus callosum. Consequently, a 14 Mb deletion at 12q21.2-q21.33 (nt. 77 203 574–91 264 613 bp), which includes 72 genes, was detected. Of these, we focused on LIN7A, which encodes a scaffold protein that is important for synaptic function, as a possible responsible gene for ID, and we analyzed its role in cerebral cortex development. Western blotting analyses revealed that Lin-7A is expressed on embryonic day (E) 13.5, and gradually increases in the mouse brain during the embryonic stage. Biochemical fractionation resulted in the enrichment of Lin-7A in the presynaptic fraction. Suppression of Lin-7A expression by RNAi, using in utero electroporation on E14.5, delayed neuronal migration on postnatal day (P) 2, and Lin-7A-deficient neurons remained in the lower zone of the cortical plate and the intermediate zone. In addition, when Lin-7A was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed; development of these neurons was disrupted such that one half did not extend into the contralateral hemisphere after leaving the corpus callosum. Taken together, LIN7A is a candidate gene responsible for 12q21-deletion syndrome, and abnormal neuronal migration and interhemispheric axon development may contribute to ID and corpus callosum hypoplasia, respectively.

Comparison of ultrasound and magnetic resonance imaging in the prenatal diagnosis of Apert syndrome: report of a case

The birth prevalence of Apert syndrome is estimated at 1:64,500 and accounts for about 4.5 % of all craniosynostosis with a male/female ratio equal to 1:1. It is associated to allelic mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. Majority cases are sporadic. Prenatal ultrasound diagnosis is based on the detection of abnormal cranial shape, midfacial hypoplasia and bilateral syndactyly of hands and feet, hypertelorism, and exorbitism. Other abnormalities includes central nervous system anomalies, congenital heart diseases, cleft palate, and urogenital diseases. A 37-year-old Caucasian woman, gravida 2, para 1, was referred to our center of Prenatal Diagnosis for routine ultrasound at 21 weeks of gestation. We detected irregular head shape, dolicocephaly, prominent forehead, bilateral mild ventriculomegaly, suspicion of partial agenesis of the corpus callosum, hypertelorism, and midfacial hypoplasia, with a depressed nasal bridge and syndactyly, prompting a suspicion for Apert syndrome. Magnetic resonance excluded agenesis of corpus callosum and confirmed bilateral mild ventriculomegaly. A follow-up ultrasound, performed at 23 weeks, confirmed the anomalies showed in the previous scan. An amniocentesis was performed. The results showed a normal male karyotype, while the molecular genetic test confirmed a mutation in FGFR2 gene. Fetus macroscopic analysis showed compatible features. Our case underlines the complementary role of ultrasound and magnetic resonance imaging in the early prenatal diagnosis of Apert syndrome.

Pericallosal Lipomas: A Series of 10 Cases with Clinical and Radiological Features.

A pericallosal lipoma is a fat-containing lesion occurring in the interhemispheric fissure closely related to the corpus callosum, which is often abnormal. This is the most common location for an intracranial lipoma. In this study, we aim to report on the clinical and radiographic aspects of ten patients diagnosed with pericallosal lipomas. A retrospective analysis of patients who presented to the neurology and neurosurgery outpatient clinics of Kayseri Training and Research Hospital between 2010 and 2014 revealed that 10 patients had the diagnosis of pericallosal lipoma. The clinical and magnetic resonance imaging data were obtained by reviewing their files. Ten patients with an average age of 35.8 years (11-80 years) were included in the study. The mean follow-up was 17 months (8-31 months). No neurological deficits related to the lesions were found during neurological examination in any of the patients. Four patients had tubulonodular lipomas while the other 6 presented with curvilinear lipomas. Four patients (40%) displayed a coexistent corpus callosum hypoplasia. In contrast to previous reports, 3 of these patients had a curvilinear lipoma while the remaining one had tubulonodular lipoma. Also, one of the patients displayed plaque lesions attributable to multiple sclerosis. During the follow-up period, no growth in the lipomas was recorded in any of the patients. No surgical intervention was performed as none of the patients displayed symptoms caused by the lipoma. In this study, we found a stronger association of corpus callosum hypoplasia with posteriorly situated curvilinear lipomas. Our results are in disagreement with previous studies, which suggested corpus callosum anomalies were more often associated with anteriorly situated tubulonodular lipomas. Pericallosal lipomas are benign, self-limiting or slow-growing lesions that generally remain asymptomatic. These lesions occur in the midline and surround critical neurovascular structures. Therefore, surgical intervention should be avoided in asymptomatic cases.

Septo-optic dysplasia with pachygyria

Optic nerve hypoplasia can be associated with other central nervous system malformations. When associated with the absence of the septum pellucidum or thinning of corpus callosum and pituitary hypoplasia, it is termed septo-optic dysplasia. Pachygyria is a rare congenital disorder characterized by a defect in migration of cerebral neurons resulting in failure of cortical gyri to develop.We report a case of a young learning-disabled male presenting with decreased vision, nystagmus, esotropia,, and seizures since childhood. Fundoscopy revealed bilateral optic nerve hypoplasia. Growth hormone levels were reduced. Magnetic resonance imaging revealed thinned optic nerves, optic chiasma and pituitary infundibulum, absent septum pellucidum, box-shaped ventricles and right frontal cortical thickening with few and broad gyri.This case report highlights a rare case of septo-optic dysplasia with pachygyria. It also emphasizes that every patient with optic nerve hypoplasia should have an endocrinal and neurological evaluation and neuro-radiographic imaging for associated abnormalities.

An 11-month-old boy with refractory epilepsy: Answer

The patient’s MRI (Fig. 1 of Images in Neuroscience: Question) shows right hemispheric lissencephaly of the temporo-parietooccipital region with frontal sparing (long arrows). There is associated right subcortical band heterotopia (arrowheads in A and B) and focal left sided subependymal nodular heterotopias (short arrows in A and B). Lissencephaly and the related malformation, subcortical band heterotopia, are classical neuronal migration defects [1]. Lissencephaly denotes a smooth brain with areas of absent and abnormally wide gyri (agyria and pachygyria, respectively), whereas subcortical band heterotopia indicates a double cortex condition [2]. The most common clinical presentation is epilepsy followed by global developmental delay, early infantile hypotonia, feeding difficulty and ophisthotonus [3]. Brain MRI displays a spectrum which varies from agyria (grade 1 and 2) to pachygyria (grade 3 and 4) to normal convolutions separated by narrow sulci overlying a heterotopia. In most patients a gradient exists between anterior and posterior regions. They may have associated corpus callosum and cerebellar hypoplasia. Recognition of these patterns enables focused molecular diagnosis, prognostication and estimation of genetic risk. To our knowledge, six associated genes have been described: LIS 1 (posterior predominance), DCX (anterior predominance), RELN and VLDLR (anterior predominant lissencephaly

Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation

BackgroundAutosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disease with severe microcephaly at birth due to a pronounced reduction in brain volume and intellectual disability. Biallelic mutations in the WD repeat-containing protein 62 gene WDR62 are the genetic cause of MCPH2. However, the exact underlying pathomechanism of MCPH2 remains to be clarified.Methods/resultsWe characterized the clinical, radiological, and cellular features that add to the human MCPH2 phenotype. Exome sequencing followed by Sanger sequencing in a German family with two affected daughters with primary microcephaly revealed in the index patient the compound heterozygous mutations c.1313G>A (p.R438H) / c.2864-2867delACAG (p.D955Afs*112) of WDR62, the second of which is novel. Radiological examination displayed small frontal lobes, corpus callosum hypoplasia, simplified hippocampal gyration, and cerebellar hypoplasia. We investigated the cellular phenotype in patient-derived lymphoblastoid cells and compared it with that of healthy female controls. WDR62 expression in the patient’s immortalized lymphocytes was deranged, and mitotic spindle defects as well as abnormal centrosomal protein localization were apparent.ConclusionWe propose that a disruption of centrosome integrity and/or spindle organization may play an important role in the development of microcephaly in MCPH2.

TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia

Cerebrofaciothoracic dysplasia (CFT) (OMIM #213980) is a multiple congenital anomaly and intellectual disability syndrome involving the cranium, face, and thorax. The characteristic features are cranial involvement with macrocrania at birth, brachycephaly, various CT/MRI findings including hypoplasia of corpus callosum, enlargement of septum pellicidum, and diffuse hypodensity of the grey matter, flat face, hypertelorism, cleft lip and cleft palate, low-set, posteriorly rotated ears, short neck, and multiple costal and vertebral anomalies. The underlying genetic defect remains unknown. Using combination of homozygosity mapping and whole-exome sequencing, we identified a homozygous nonsense founder mutation, p.Arg87Ter (c.259 C>T), in the human transmembrane and coiled-coil domains protein 1 (TMCO1) in four out of five families of Turkish origin. The entire critical region on chromosome 1q24 containing TMCO1 was excluded in the fifth family with characteristic findings of CFT providing evidence for genetic heterogeneity of CFT spectrum. Another founder TMCO1 mutation has recently been reported to cause a unique genetic condition, TMCO1-defect syndrome (OMIM #614132). TMCO1-defect syndrome shares many features with CFT. This study supports the fact that "TMCO1-defect syndrome," initially thought to represent a distinct disorder, indeed belongs to the genetically heterogeneous CFT dysplasia spectrum.

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms. Progeroid symptoms, dysmorphic features, hypotonia and psychomotor retardation are highly overlapping in the early phase of these disorders. This makes the genetic diagnosis often challenging. In search for discriminatory symptoms, we prospectively evaluated clinical, neurologic, metabolic and genetic features in our patient cohort referred for suspected ARCL. From a cohort of 26 children, we confirmed mutations in genes associated with ARCL in 16 children (14 probands), including 12 novel mutations. Abnormal glycosylation and gyration abnormalities were mostly, but not always associated with ATP6V0A2 mutations. Epilepsy was most common in ATP6V0A2 defects. Corpus callosum dysgenesis was associated with PYCR1 and ALDH18A1 mutations. Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects. Metabolic markers of mitochondrial dysfunction were found in one patient with PYCR1 mutations. So far unreported white matter abnormalities were found associated with GORAB and RIN2 mutations. We describe a large cohort of CL patients with neurologic involvement. Migration defects and corpus callosum hypoplasia were not always diagnostic for a specific genetic defect in CL. All patients with ATP6V0A2 defects had abnormal glycosylation. To conclude, central nervous system and metabolic abnormalities were discriminatory in this genetically heterogeneous group, although not always diagnostic for a certain genetic defect in CL.

Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome

AIMRecently, we reported a previously unrecognized symptom constellation comprising epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) associated with recessive mutations in the KCNJ10 gene. Here, we provide a detailed characterization of the clinical features of the syndrome to aid patient management with respect to diagnosis, prognostic counselling, and identification of best treatment modalities.METHODWe conducted a retrospective review of the detailed neurological and neuroradiological features of nine children (four females, five males; age range at last examination 6–20y) with genetically proven EAST syndrome.RESULTSAll children presented with tonic–clonic seizures in infancy. Later, non-progressive, cerebellar ataxia and hearing loss were noted. Whilst seizures mostly responded well to treatment, ataxia proved to be the most debilitating feature, with three patients non-ambulant. All available magnetic resonance imaging (MRI) revealed subtle symmetrical signal changes in the cerebellar dentate nuclei. Moreover, four patients had a small corpus callosum and brainstem hypoplasia, and three had a small spinal cord. Regional quantitative volumetric analysis of the images confirmed the corpus callosum and brainstem hypoplasia and showed further patterns of variation from the norm.INTERPRETATIONThe neurological features of EAST syndrome appear to be non-progressive, which is important for prognostic counselling. The spectrum of EAST syndrome includes consistent abnormalities on brain MRI, which may aid diagnosis. Further longitudinal documentation is required to determine the true natural history of the disorder.

West syndrome, microcephaly, grey matter heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2 mutation

West syndrome (WS) is an epileptic encephalopathy of childhood, defined by the presence of clustered spasms usually occurring before the age of 1 year, hypsarrhythmia on EEG that is notoriously...

ACTA2 mutation with childhood cardiovascular, autonomic and brain anomalies and severe outcome

Thoracic aortic aneurysm and dissection (TAAD) are associated with connective tissue disorders like Marfan syndrome and Loeys-Dietz syndrome, caused by mutations in the fibrillin-1, the TGFβ-receptor 1- and -2 genes, the SMAD3 and TGFβ2 genes, but have also been ascribed to ACTA2 gene mutations in adults, spread throughout the gene. We report on a novel de novo c.535C>T in exon 6 leading to p.R179C aminoacid substitution in ACTA2 in a toddler girl with primary pulmonary hypertension, persistent ductus arteriosus, extensive cerebral white matter lesions, fixed dilated pupils, intestinal malrotation, and hypotonic bladder. Recently, de novo ACTA2 R179H substitutions have been associated with a similar phenotype and additional cerebral developmental defects including underdeveloped corpus callosum and vermis hypoplasia in a single patient. The patient here shows previously undescribed abnormal lobulation of the frontal lobes and position of the gyrus cinguli and rostral dysplasis of the corpus callosum; she died at the age of 3 years during surgery due to vascular fragility and rupture of the ductus arteriosus. Altogether these observations support a role of ACTA2 in brain development, especially related to the arginine at position 179. Although all previously reported patients with R179H substitution successfully underwent the same surgery at younger ages, the severe outcome of our patient warns against the devastating effects of the R179C substitution on vasculature.

Bilateral Cavitations of Ganglionic Eminence: A Fetal MR Imaging Sign of Halted Brain Development

Ganglionic eminence is the main transitory proliferative structure of the ventral telencephalon in human fetal brain and it contributes for at least 35% to the population of cortical interneurons; however data on the human GE anomalies are scarce. We report 5 fetal MR imaging observations with bilateral symmetric cavitations in their GE regions resembling an inverted open C shape and separating the GE itself form the deeper parenchyma. Imaging, neuropathology, and follow-up features suggested a malformative origin. All cases had in common characteristics of lissencephaly with agenesis or severe hypoplasia of corpus callosum of probable different genetic basis. From our preliminary observation, it seems that GE cavitations are part of conditions which are also accompanied by severe cerebral structure derangement.

Mowat–Wilson syndrome in a fetus with antenatal diagnosis of short corpus callosum: Advocacy for standard autopsy

Mowat–Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene rarely diagnosed prenatally and with little fetal description reported. It is mainly characterized by moderate-to-severe intellectual disability, epilepsy, facial dysmorphism and various malformations including Hirschsprung disease and corpus callosum anomalies. Here we report a fetal case of MWS well described, suspected at standard autopsy. The association of a corpus callosum hypoplasia with a histological Hirschsprung disease and a typical facial gestalt allowed the guiding of genetic testing. Classical fetopathological examination still keeps indications in cases of syndromic association in the era of virtual autopsy.

Prenatal diagnosis of agenesis of the corpus callosum and cerebellar vermian hypoplasia associated with a microdeletion on chromosome 1p32a

Abstract We present the prenatal detection of a 1p32.1p31.3 microdeletion (3.46 Mb) by array comparative genomic hybridization (CGH) associated with fetal agenesis of the corpus callosum (ACC) and cerebellar vermian hypoplasia. Analysis of cultured amniocytes showed a normal karyotype. Our observations strengthen the association between this locus and central nervous system development. In addition, the fetus reported herein underscores the importance of array CGH analysis when ACC is detected prenatally, especially when there are additional central nervous system anomalies, to search for submicroscopic imbalances which can facilitate further management and parental counselling. Moreover, the presence of urinary tract anomalies should alert the clinician to the possibility of a 1p interstitial deletion, although the absence of such does not exclude it. Further reports will help to provide more information on the long-term outcomes of individuals with such microdeletion as there are only limited data.

Whole-Exome Sequencing Identifies Mutated C12orf57 in Recessive Corpus Callosum Hypoplasia

The corpus callosum is the principal cerebral commissure connecting the right and left hemispheres. The development of the corpus callosum is under tight genetic control, as demonstrated by abnormalities in its development in more than 1,000 genetic syndromes. We recruited more than 25 families in which members affected with corpus callosum hypoplasia (CCH) lacked syndromic features and had consanguineous parents, suggesting recessive causes. Exome sequence analysis identified C12orf57 mutations at the initiator methionine codon in four different families. C12orf57 is ubiquitously expressed and encodes a poorly annotated 126 amino acid protein of unknown function. This protein is without significant paralogs but has been tightly conserved across evolution. Our data suggest that this conserved gene is required for development of the human corpus callosum.