Brain Anomalies Research Articles

Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (GTS) is a childhood-onset neurodevelopmental disorder that is characterized by several motor and phonic tics. Tics usually develop before 10 years of age, exhibit a waxing and waning course and typically improve with increasing age. A prevalence of approximately 1% is estimated in children and adolescents. The condition can result in considerable social stigma and poor quality of life, especially when tics are severe (for example, with coprolalia (swearing tics) and self-injurious behaviours) or when GTS is accompanied by attention-deficit/hyperactivity disorder, obsessive-compulsive disorder or another neuropsychiatric disorder. The aetiology is complex and multifactorial. GTS is considered to be polygenic, involving multiple common risk variants combined with rare, inherited or de novo mutations. These as well as non-genetic factors (such as perinatal events and immunological factors) are likely to contribute to the heterogeneity of the clinical phenotype, the structural and functional brain anomalies and the neural circuitry involvement. Management usually includes psychoeducation and reassurance, behavioural methods, pharmacotherapy and, rarely, functional neurosurgery. Future research that integrates clinical and neurobiological data, including neuroimaging and genetics, is expected to reveal the pathogenesis of GTS at the neural circuit level, which may lead to targeted interventions.

Zika Virus Infects Early- and Midgestation Human Maternal Decidual Tissues, Inducing Distinct Innate Tissue Responses in the Maternal-Fetal Interface.

In view of the rapid spread of the current ZIKV epidemic and the severe manifestations of congenital ZIKV infection, it is crucial to learn the fundamental mechanisms of viral transmission from the mother to the fetus. Our studies of ZIKV infection in the authentic tissues of the human maternal-fetal interface unveil a route of transmission whereby virus originating from the mother could reach the fetal compartment via efficient replication within the maternal decidual aspect of the placenta, coinhabited by maternal and fetal cells. The identified distinct placental tissue innate immune responses and damage pathways could provide a mechanistic basis for some of the placental developmental abnormalities associated with ZIKV infection. The findings in the unique model of the human decidua should pave the way to future studies examining the interaction of ZIKV with decidual immune cells and to evaluation of therapeutic interventions aimed at the earliest stages of transmission.

Resting-State Brain Anomalies in Type 2 Diabetes: A Meta-Analysis.

Resting-state functional magnetic resonance imaging (fMRI) studies have revealed abnormal neural activity in patients with type 2 diabetes mellitus (T2DM). Nonetheless, these findings are heterogeneous and have not been quantitatively reviewed. Thus, we aimed to conduct a meta-analysis that identified consistent results of existing resting-state fMRI studies to determine concordant resting-state neural brain activity alterations in T2DM patients. A systematic search was conducted for resting-state fMRI studies comparing T2DM patients with healthy controls. Coordinates were extracted from clusters with significant differences. The meta-analysis was performed using the activation likelihood estimation method, and nine studies were included. This meta-analysis identified robustly reduced resting-state brain activity in the whole brain of T2DM patients, including the bilateral lingual gyrus, left postcentral gyrus, right inferior temporal gyrus, right cerebellar culmen, right insula and right posterior cingulate cortex (PCC). The present study demonstrates a characteristic pattern of resting-state brain anomalies that will contribute to the understanding of neuropathophysiological mechanisms underlying T2DM.

Neuroimaging findings of congenital Zika virus infection: a pictorial essay.

Zika virus (ZIKV) is a mosquito-borne arbovirus from the Flaviviridae family. It had caused several epidemics since its discovery in 1947, but there was no significant attention to this virus until the recent outbreak in Brazil in 2015. The main concern is the causal relationship between prenatal ZIKV infection and congenital microcephaly, which has been confirmed recently. Moreover, ZIKV may cause other central nervous system abnormalities such as brain parenchymal atrophy with secondary ventriculomegaly, intracranial calcification, malformations of cortical development (such as polymicrogyria, and lissencephaly-pachygyria), agenesis/hypoplasia of the corpus callosum, cerebellar and brainstem hypoplasia, sensorineural hearing-loss, and ocular abnormalities as well as arthrogryposis in the infected fetuses. Postnatal (acquired) ZIKV infection usually has an asymptomatic or mildly symptomatic course, while prenatal (congenital) ZIKV infection has a more severe course and may cause severe brain anomalies that are described as congenital Zika syndrome. In this pictorial essay, we aim to illustrate the prenatal and postnatal neuroimaging findings that may be seen in fetuses and neonates with congenital Zika syndrome, and will discuss possible radiological differential diagnoses. A detailed knowledge of these findings is paramount for an early correct diagnosis, prognosis determination, and counseling of the affected children and families.

To Hone Identification of Fetal Brain Anomalies In Utero, Turn to MRI

For almost all fetal anomalies, ultrasound is preferred for diagnostic imaging; however, in the fetal brain, magnetic resonance imaging (MRI) offers advantages for thoroughly assessing structure. Investigators in the U.K. studied the incremental clinical value of in-utero fetal brain magnetic resonance imaging (iuMRI) in 565 pregnant women within 2 weeks of ultrasound detection of …

Rhombencephalosynapsis and Chiari II Malformation with Spinal Deformities

Rhombencephalosynapsis is a rare congenital intracranial malformation. Partial rhombencephalosynapsis is a variation of this anomaly with few reported cases. We report a unique case of a patient with partial rhombencephalosynapsis associated with Chiari II, and various spinal malformations, which is very rare, and only few such cases have been reported in literature. These findings suggest that rhombencephalosynapsis can be associated with spinal malformations and, furthermore, that cases with the common features of rhombencephalosynapsis and Chiari II malformation can exist. Such an association likely represents a new anomaly of the hind brain with spine.

Pre- and Post- Natal Us and Mri Findings of Fetal Brain Lesions: A Pictorial Review

The purpose of this exhibition is to demonstrate and compare pre- and post-natal US and MRI findings of various anomalies involving fetal brain. The contents of this exhibition will be variable neural tube defects, midline anomalies including agenesis of corpus callosum and Dandy-Walker continuum, lissencephaly, intracranial hemorrhage, dural arterior venous fistula, dural sinus thrombosis, variable intracranial cystic lesions and brain tumors. Various anomalies may occur in the fetal brain. US is not only the first line but also a confirmative study in many cases of fetal brain anomalies. MRI is increasingly being used to evaluate the fetal brain, and is a valuable complement to prenatal US. Almost fetal brain anomalies show specific imaging features and can be diagnosed on the prenatal US and MRI. The exact prenatal diagnosis and thorough postnatal work-up of fetal brain anomalies are important for the prenatal and postnatal managements.

Application of array comparative genomic hybridization in Korean children under 6 years old with global developmental delay.

PurposeRecent advancements in molecular techniques have greatly contributed to the discovery of genetic causes of unexplained developmental delay. Here, we describe the results of array comparative genomic hybridization (CGH) and the clinical features of 27 patients with global developmental delay.MethodsWe included 27 children who fulfilled the following criteria: Korean children under 6 years with global developmental delay; children who had at least one or more physical or neurological problem other than global developmental delay; and patients in whom both array CGH and G-banded karyotyping tests were performed.ResultsFifteen male and 12 female patients with a mean age of 29.3±17.6 months were included. The most common physical and neurological abnormalities were facial dysmorphism (n=16), epilepsy (n=7), and hypotonia (n=7). Pathogenic copy number variation results were observed in 4 patients (14.8%): 18.73 Mb dup(2)(p24.2p25.3) and 1.62 Mb del(20p13) (patient 1); 22.31 Mb dup(2) (p22.3p25.1) and 4.01 Mb dup(2)(p21p22.1) (patient 2); 12.08 Mb del(4)(q22.1q24) (patient 3); and 1.19 Mb del(1)(q21.1) (patient 4). One patient (3.7%) displayed a variant of uncertain significance. Four patients (14.8%) displayed discordance between G-banded karyotyping and array CGH results. Among patients with normal array CGH results, 4 (16%) revealed brain anomalies such as schizencephaly and hydranencephaly. One patient was diagnosed with Rett syndrome and one with Möbius syndrome.ConclusionAs chromosomal microarray can elucidate the cause of previously unexplained developmental delay, it should be considered as a first-tier cytogenetic diagnostic test for children with unexplained developmental delay.

Use of MRI in the diagnosis of fetal brain abnormalities in utero (MERIDIAN): a multicentre, prospective cohort study

In-utero MRI (iuMRI) has shown promise as an adjunct to ultrasound but the comparative diagnostic performance has been poorly defined. We aimed to assess whether the diagnostic accuracy and confidence of the prenatal diagnosis of fetal brain abnormalities is improved with iuMRI and assess the clinical impact and patient acceptability of iuMRI. We did a multicentre, prospective, cohort study in the UK, at 16 fetal medicine centres, of pregnant women aged 16 years or older whose fetus had a brain abnormality detected by ultrasound at a gestational age of 18 weeks or more, had no contraindications to iuMRI, and consented to enter the study. Women carrying a fetus suspected of having a brain anomaly on ultrasound had iuMRI done within 14 days of ultrasound. The findings were reviewed by two independent panels and used to estimate diagnostic accuracy and confidence by comparison with outcome diagnoses. Changes in diagnosis, prognosis, and clinical management brought about by iuMRI and patient acceptability were assessed. Participants were recruited between July 29, 2011, and Aug 31, 2014. The cohort was subdivided by gestation into the 18 weeks to less than 24 weeks fetus cohort (n=369) and into the 24 weeks or older fetus cohort (n=201). Diagnostic accuracy was improved by 23% (95% CI 18-27) in the 18 weeks to less than 24 weeks group and 29% (23-36) in the 24 weeks and older group (p<0·0001 for both groups). The overall diagnostic accuracy was 68% for ultrasound and 93% for iuMRI (difference 25%, 95% CI 21-29). Dominant diagnoses were reported with high confidence on ultrasound in 465 (82%) of 570 cases compared with 544 (95%) of 570 cases on iuMRI. IuMRI provided additional diagnostic information in 387 (49%) of 783 cases, changed prognostic information in at least 157 (20%), and led to changes in clinical management in more than one in three cases. IuMRI also had high patient acceptability with at least 95% of women saying they would have an iuMRI study if a future pregnancy were complicated by a fetal brain abnormality. iuMRI improves diagnostic accuracy and confidence for fetal brain anomalies and leads to management changes in a high proportion of cases. This finding, along with the high patient acceptability, leads us to propose that any fetus with a suspected brain abnormality on ultrasound should have iuMRI to better inform counselling and management decisions. National Institute for Health Research Health Technology Assessment programme.

Digenic mutations of human OCRL paralogs in Dent's disease type 2 associated with Chiari I malformation.

OCRL1 and its paralog INPP5B encode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations in OCRL1 cause the X-linked Dent disease type 2 (DD2; OMIM# 300555), characterized by low-molecular weight proteinuria, hypercalciuria, and the variable presence of cataracts, glaucoma and intellectual disability without structural brain anomalies. Disease-causing mutations in INPP5B have not been described in humans. Here, we report the case of an 11-year-old boy with short stature and an above-average IQ; severe proteinuria, hypercalciuria and osteopenia resulting in a vertebral compression fracture; and Chiari I malformation with cervico-thoracic syringohydromyelia requiring suboccipital decompression. Sequencing revealed a novel, de novo DD2-causing 462 bp deletion disrupting exon 3 of OCRL1 and a maternally inherited, extremely rare (ExAC allele frequency 8.4×10−6) damaging missense mutation in INPP5B (p.A51V). This mutation substitutes an evolutionarily conserved amino acid in the protein’s critical PH domain. In silico analyses of mutation impact predicted by SIFT, PolyPhen2, MetaSVM and CADD algorithms were all highly deleterious. Together, our findings report a novel association of DD2 with Chiari I malformation and syringohydromyelia, and document the effects of digenic mutation of human OCRL paralogs. These findings lend genetic support to the hypothesis that impaired ciliogenesis may contribute to the development of Chiari I malformation, and implicates OCRL-dependent PIP3 metabolism in this mechanism.

Three-dimensional ultrasound in evaluation of fetal brain anomalies

Background and objective: Prenatal diagnosis of central nervous system anomalies by two-dimensional sonography is challenging because of difficulties in obtaining complete visualization of the fetal brain during routine examinations. Three-dimensional sonography has been introduced as a tool for studying the fetal central nervous system because of its ability to facilitate examinations of the fetal brain. This study aimed to visualize an intracranial structure of the fetal central nervous system anomaly using transabdominal three-dimensional sonography. Methods: A prospective cross–sectional (observational) study in which three-dimensional ultrasound examination was performed in 82 patients between 12 and 38 weeks of gestation suspected to have fetal brain malformation detected by conventional two-dimensional ultrasound. Each anomaly was reviewed again to determine whether three-dimensional ultrasound data were advantageous compared to two-dimensional ultrasound. Results: Three-dimensional images provided additional information in 43 (52.4%) of cases including extracerebral anomalies. The three-dimensional ultrasound was advantageous in evaluating the encephaloceles (10 of 43 cases) in that the exact location of the extracranial mass and the amount of extracranial tissue in the encephalocele was better defined with the simultaneous display of three orthogonal planes images that could not be obtained with two-dimensional ultrasound were seen with three-dimensional ultrasound. Conclusion: Three-dimensional ultrasound is an excellent adjunctive tool to two-dimensional ultrasound in the evaluation of fetal anomalies

Brain basis of childhood speech and language disorders: are we closer to clinically meaningful MRI markers?

Developmental speech and language disorders are common, seen in one in 20 preschool children, in the absence of frank neurological deficits or intellectual impairment. They are a key reason parents seek help from paediatricians. Complex neurogenetic and environmental contributions underpin the disorders, yet few specific causes are known. With the advent of quantitative brain imaging, a growing number of studies have investigated neural contributions. Here, we discuss current MRI approaches and recent findings (January 2014-June 2016) in the field. Five relevant studies were identified (n = 3 - speech disorder and n = 2 - language disorder). Significant variability in MRI approaches and heterogeneity of participant phenotypes was seen. Children with speech disorder had structural and functional anomalies in the left supramarginal gyrus and functional anomalies in the posterior cerebellum bilaterally - regions critical for sensory-motor integration or feedback. Children with language disorder showed increased mean and radial diffusivity of the left arcuate fasciculus, although a widespread cortical and subcortical network of regions was implicated. Limited evidence exists for specific regional brain anomalies in this population. MRI prognostic markers of speech and language ability are not currently available at an individual level. Further work is required to disentangle neurobiological contributions to speech and language disorders for affected children.

Zika virus infection and biological treatment for reproductive medicine.

The recent Zika virus (ZIKV) epidemic is particularly challenging in the field of reproductive medicine as various biological tissues and byproducts, such as intravenous immunoglobulin G or cells are utilized during reproductive cycles, and an infected mother has an increased risk of having babies with fetal microcephaly and other congenital brain anomalies. In this review, current guidelines for prevention of sexual transmission of ZIKV, ZIKV testing, and tissue and blood product usages are summarized for physicians caring for those planning pregnancy or going through infertility treatment.

Incidence of Zika Virus Disease by Age and Sex - Puerto Rico, November 1, 2015-October 20, 2016.

Zika virus is a flavivirus transmitted primarily by Aedes species mosquitoes; symptoms of infection include rash, arthralgia, fever, and conjunctivitis.*,† Zika virus infection during pregnancy can cause microcephaly and other serious brain anomalies (1), and in rare cases, Zika virus infection has been associated with Guillain-Barré syndrome (2) and severe thrombocytopenia (3). This report describes the incidence of reported symptomatic Zika virus disease in the U.S. territory of Puerto Rico by age and sex. During November 1, 2015-October 20, 2016, 62,500 suspected Zika virus disease cases were reported to the Puerto Rico Department of Health (PRDH); 29,345 (47%) were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) testing, or were presumptively diagnosed based on serological testing. The highest incidence among confirmed or presumptive cases occurred among persons aged 20-29 years (1,150 cases per 100,000 residents). Among 28,219 (96.2%) nonpregnant patients with confirmed or presumptive Zika virus disease, incidence was higher among women (936 per 100,000 population) than men (576 per 100,000) for all age groups ≥20 years, and the majority (61%) of reported Zika virus disease cases occurred in females. Among suspected Zika virus disease cases in nonpregnant adults aged ≥40 years, the percentage that tested positive among females (52%) was higher than that among males (47%) (p<0.01). Reasons for the higher incidence of Zika virus disease among women aged ≥20 years are not known; serosurveys of persons living near confirmed Zika virus disease cases might help to elucidate these findings. Residents of and travelers to Puerto Rico should remove or cover standing water, practice mosquito abatement, employ mosquito bite avoidance behaviors, take precautions to reduce the risk for sexual transmission, and seek medical care for any acute illness with rash or fever.

Ciliopathies: Genetics in Pediatric Medicine

Ciliary disorders, which are also referred to as ciliopathies, are a group of hereditary disorders that result from dysfunctional cilia. The latter are cellular organelles that stick up from the apical plasma membrane. Cilia have important roles in signal transduction and facilitate communications between cells and their surroundings. Ciliary disruption can result in a wide variety of clinically and genetically heterogeneous disorders with overlapping phenotypes. Because cilia occur widespread in our bodies many organs and sensory systems can be affected when they are dysfunctional. Ciliary disorders may be isolated or syndromic, and common features are cystic liver and/or kidney disease, blindness, neural tube defects, brain anomalies and intellectual disability, skeletal abnormalities ranging from polydactyly to abnormally short ribs and limbs, ectodermal defects, obesity, situs inversus, infertility, and recurrent respiratory tract infections. In this review, we summarize the features, frequency, morbidity, and mortality of each of the different ciliopathies that occur in pediatrics. The importance of genetics and the occurrence of genotype-phenotype correlations are indicated, and advances in gene identification are discussed. The use of next-generation sequencing by which a gene panel or all genes can be screened in a single experiment is highlighted as this technology significantly lowered costs and time of the mutation detection process in the past. We discuss the challenges of this new technology and briefly touch upon the use of whole-exome sequencing as a diagnostic test for ciliary disorders. Finally, a perspective on the future of genetics in the context of ciliary disorders is provided.

The Desire for Amputation or Paralyzation: Evidence for Structural Brain Anomalies in Body Integrity Identity Disorder (BIID).

BackgroundBody Integrity Identity Disorder (BIID) is a condition in which individuals perceive a mismatch between their internal body scheme and physical body shape, resulting in an absolute desire to be either amputated or paralyzed. The condition is hypothesized to be of congenital nature, but evidence for a neuro-anatomical basis is sparse.MethodsWe collected T1-weighted structural magnetic resonance imaging scans on a 3T scanner in eight individuals with BIID and 24 matched healthy controls, and analyzed the data using voxel-based morphometry.ResultsThe results showed reduced grey matter volume in the left dorsal and ventral premotor cortices and larger grey matter volume in the cerebellum (lobule VIIa) in individuals with BIID compared to controls.ConclusionThe premotor cortex and cerebellum are thought to be crucial for the experience of body-ownership and the integration of multisensory information. Our results suggest that BIID is associated with structural brain anomalies and might result from a dysfunction in the integration of multisensory information, leading to the feeling of disunity between the mental and physical body shape.

Fetal Brain Anomalies Associated with Ventriculomegaly or Asymmetry: An MRI-Based Study.

Fetal lateral ventriculomegaly is a relatively common finding with much debate over its clinical significance. The purpose of this study was to examine the association between ventriculomegaly and asymmetry and concomitant CNS findings as seen in fetal brain MR imaging. Fetal brain MR imaging performed for various indications, including ventriculomegaly, with or without additional ultrasound findings, was assessed for possible inclusion. Two hundred seventy-eight cases found to have at least 1 lateral ventricle with a width of ≥10 mm were included in the study. Ventriculomegaly was considered mild if the measurement was 10-11.9 mm; moderate if, 12-14.9 mm; and severe if, ≥15 mm. Asymmetry was defined as a difference of ≥2 mm between the 2 lateral ventricles. Fetal brain MR imaging findings were classified according to severity by predefined categories. The risk of CNS findings appears to be strongly related to the width of the ventricle (OR, 1.38; 95% CI, 1.08-1.76; P = .009). The prevalence of associated CNS abnormalities was significantly higher (P = .005) in symmetric ventriculomegaly compared with asymmetric ventriculomegaly (38.8% versus 24.2%, respectively, for all CNS abnormalities and 20% versus 7.1%, respectively, for major CNS abnormalities). In this study, we demonstrate that the rate of minor and major findings increased with each millimeter increase in ventricle width and that the presence of symmetric ventricles in mild and moderate ventriculomegaly was a prognostic indicator for CNS abnormalities.

Neuroimaging findings in Mowat\u2013Wilson syndrome: a study of 54 patients

Purpose:Mowat–Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined.Methods:Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype–phenotype correlations.Results:Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis.Conclusion:This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016

Optimal Segmentation Framework for Detection of Brain Anomalies

Optimal Segmentation Framework for Detection of Brain Anomalies

Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly

Cobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia. COB occurs in a wide range of genetic disorders known as dystroglycanopathies, which are congenital muscular dystrophies associated with brain and eye anomalies and range from Walker-Warburg syndrome to Fukuyama congenital muscular dystrophy. Each of these conditions has been associated with alpha-dystroglycan defects or with mutations in genes encoding basement membrane components, which are known to interact with alpha-dystroglycan. Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan. Most affected individuals showed brainstem and cerebellum hypoplasia, as well as ventriculomegaly. However, the minority of the affected individuals had eye defects or elevated muscle creatine phosphokinase, separating the TMTC3 COB phenotype from typical congenital muscular dystrophies. Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement.