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1.  Evolutionarily Dynamic Alternative Splicing of GPR56 Regulates Regional Cerebral Cortical Patterning 
Science (New York, N.Y.)  2014;343(6172):764-768.
The human neocortex has numerous specialized functional areas whose formation is poorly understood. Here, we describe a 15–base pair deletion mutation in a regulatory element of GPR56 that selectively disrupts human cortex surrounding the Sylvian fissure bilaterally including “Broca’s area,” the primary language area, by disrupting regional GPR56 expression and blocking RFX transcription factor binding. GPR56 encodes a heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor required for normal cortical development and is expressed in cortical progenitor cells. GPR56 expression levels regulate progenitor proliferation. GPR56 splice forms are highly variable between mice and humans, and the regulatory element of gyrencephalic mammals directs restricted lateral cortical expression. Our data reveal a mechanism by which control of GPR56 expression pattern by multiple alternative promoters can influence stem cell proliferation, gyral patterning, and, potentially, neocortex evolution.
PMCID: PMC4480613  PMID: 24531968
2.  Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes 
Brain  2014;137(6):1579-1613.
Individuals with corpus callosum malformations are phenotypically diverse, and often present with broad neurodevelopmental disorders. Edwards et al. review the clinical features of these patients and provide a comprehensive classification of syndromes associated with callosal agenesis, based on a neural developmental framework that will guide future advances in the field.
The corpus callosum is the largest fibre tract in the brain, connecting the two cerebral hemispheres, and thereby facilitating the integration of motor and sensory information from the two sides of the body as well as influencing higher cognition associated with executive function, social interaction and language. Agenesis of the corpus callosum is a common brain malformation that can occur either in isolation or in association with congenital syndromes. Understanding the causes of this condition will help improve our knowledge of the critical brain developmental mechanisms required for wiring the brain and provide potential avenues for therapies for callosal agenesis or related neurodevelopmental disorders. Improved genetic studies combined with mouse models and neuroimaging have rapidly expanded the diverse collection of copy number variations and single gene mutations associated with callosal agenesis. At the same time, advances in our understanding of the developmental mechanisms involved in corpus callosum formation have provided insights into the possible causes of these disorders. This review provides the first comprehensive classification of the clinical and genetic features of syndromes associated with callosal agenesis, and provides a genetic and developmental framework for the interpretation of future research that will guide the next advances in the field.
PMCID: PMC4032094  PMID: 24477430
corpus callosum; axon guidance; neuronal specification; neurogenesis; midline patterning
3.  The Developmental Brain Disorders Database (DBDB): A Curated Neurogenetics Knowledge Base With Clinical and Research Applications 
The number of single genes associated with neurodevelopmental disorders has increased dramatically over the past decade. The identification of causative genes for these disorders is important to clinical outcome as it allows for accurate assessment of prognosis, genetic counseling, delineation of natural history, inclusion in clinical trials, and in some cases determines therapy. Clinicians face the challenge of correctly identifying neurodevelopmental phenotypes, recognizing syndromes, and prioritizing the best candidate genes for testing. However, there is no central repository of definitions for many phenotypes, leading to errors of diagnosis. Additionally, there is no system of levels of evidence linking genes to phenotypes, making it difficult for clinicians to know which genes are most strongly associated with a given condition. We have developed the Developmental Brain Disorders Database (DBDB:, a publicly available, online-curated repository of genes, phenotypes, and syndromes associated with neurodevelopmental disorders. DBDB contains the first referenced ontology of developmental brain phenotypes, and uses a novel system of levels of evidence for gene-phenotype associations. It is intended to assist clinicians in arriving at the correct diagnosis, select the most appropriate genetic test for that phenotype, and improve the care of patients with developmental brain disorders. For researchers interested in the discovery of novel genes for developmental brain disorders, DBDB provides a well-curated source of important genes against which research sequencing results can be compared. Finally, DBDB allows novel observations about the landscape of the neurogenetics knowledge base.
PMCID: PMC4279915  PMID: 24700709
developmental brain disorders; database; bioinformatics; levels of evidence
4.  Somatic Mutations in Cerebral Cortical Malformations 
The New England journal of medicine  2014;371(8):733-743.
Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated.
Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing.
Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria.
Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.)
PMCID: PMC4274952  PMID: 25140959
5.  Maternal or neonatal infection: association with neonatal encephalopathy outcomes 
Pediatric research  2014;76(1):93-99.
Perinatal infection may potentiate brain injury among children born preterm. The objective of this study was to examine whether maternal and/or neonatal infection are associated with adverse outcomes among term neonates with encephalopathy.
Cohort study of 258 term newborns with encephalopathy whose clinical records were examined for signs of maternal infection (chorioamnionitis) and infant infection (sepsis). Multivariate regression was used to assess associations between infection, pattern and severity of injury on neonatal MRI, as well as neurodevelopment at 30 months (neuromotor exam, or Bayley Scales of Infant Development II MDI <70 or Bayley III cognitive score <85).
Chorioamnionitis was associated with lower risk of moderate-severe brain injury (adjusted OR 0.3; 95% CI 0.1–0.7, P=0.004), and adverse cognitive outcome in children when compared to no chorioamnionitis. Children with signs of neonatal sepsis were more likely to exhibit watershed predominant injury than those without (P=0.007).
Among neonates with encephalopathy, chorioamnionitis was associated with a lower risk of brain injury and adverse outcomes, whereas signs of neonatal sepsis carried an elevated risk. The etiology of encephalopathy and timing of infection and its associated inflammatory response may influence whether infection potentiates or mitigates injury in term newborns.
PMCID: PMC4062582  PMID: 24713817
6.  SLC25A22 is a Novel Gene for Migrating Partial Seizures in Infancy 
Annals of neurology  2013;74(6):873-882.
To identify a genetic cause for migrating partial seizures in infancy (MPSI).
We characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism (SNP) 500K data to identify regions with evidence for linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22.
In a consanguineous pedigree with two individuals with MPSI, we identified two regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only one variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembraine domain of the protein, disrupts mitochondrial glutamate transport.
We have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome sequencing can be used for disease gene discovery. Finally, as SLC25A22 had been implicated in the distinct syndrome neonatal epilepsy with suppression bursts on EEG, we have expanded the phenotypic spectrum associated with SLC25A22.
PMCID: PMC4031329  PMID: 24596948
7.  Midbrain-Hindbrain Malformations: Advances in Clinical Diagnosis, Imaging, and Genetics 
The Lancet. Neurology  2013;12(4):381-393.
Historically, the midbrain and hindbrain (MBHB) have been considered “support staff” for the cerebrum, which has typically been acknowledged as the most important part of the brain. Radiologists and pathologists did not regularly examine these structures, also known as the brainstem and cerebellum, because they are small and difficult to remove without damage. With recent improvements in neuroimaging, neuropathology and neurogenetics, many developmental disorders of the MBHB have emerged as significant causes of neurodevelopmental dysfunction. This review provides an overview of MBHB disorders important to clinicians and developmental biologists. A basic understanding of MBHB embryology is essential to understanding the malformations that occur in MBHB structures; therefore, a brief embryology review is provided, as is a review of MBHB anatomy as assessed by MRI, and an approach to MRI analysis of the individual structures. Clinical features common to many MBHB disorders are presented, followed by a more in depth summary of the clinical presentations, MRI features and genetic causes of many common, and some less common, malformations. Research advances that may change how we treat these patients in the future are briefly discussed. The information provided in this review will improve the clinical acumen of the practicing neurologist in regard to malformations of the MBHB, while at the same time adding to their understanding of brainstem and cerebellar development, genetics, and function.
PMCID: PMC4158743  PMID: 23518331
8.  Brain without Anatomy: Construction and Comparison of Fully Network-Driven Structural MRI Connectomes 
PLoS ONE  2014;9(5):e96196.
MRI connectomics methods treat the brain as a network and provide new information about its organization, efficiency, and mechanisms of disruption. The most commonly used method of defining network nodes is to register the brain to a standardized anatomical atlas based on the Brodmann areas. This approach is limited by inter-subject variability and can be especially problematic in the context of brain maturation or neuroplasticity (cerebral reorganization after brain damage). In this study, we combined different image processing and network theory methods and created a novel approach that enables atlas-free construction and connection-wise comparison of diffusion MRI-based brain networks. We illustrated the proposed approach in three age groups: neonates, 6-month-old infants, and adults. First, we explored a data-driven method of determining the optimal number of equal-area nodes based on the assumption that all cortical areas of the brain are connected and, thus, no part of the brain is structurally isolated. Second, to enable a connection-wise comparison, alignment to a “reference brain” was performed in the network domain within each group using a matrix alignment algorithm with simulated annealing. The correlation coefficients after pair-wise network alignment ranged from 0.6102 to 0.6673. To test the method’s reproducibility, one subject from the 6-month-old group and one from the adult group were scanned twice, resulting in correlation coefficients of 0.7443 and 0.7037, respectively. While being less than 1 due to parcellation and noise, statistically, these values were significantly higher than inter-subject values. Rotation of the parcellation largely explained the variability. Through the abstraction from anatomy, the developed framework allows for a fully network-driven analysis of structural MRI connectomes and can be applied to subjects at any stage of development and with substantial differences in cortical anatomy.
PMCID: PMC4006896  PMID: 24789312
9.  Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans 
Neurology  2013;81(16):1378-1386.
To identify the genetic cause of a syndrome causing cerebellar ataxia and eye movement abnormalities.
We identified 2 families with cerebellar ataxia, eye movement abnormalities, and global developmental delay. We performed genetic analyses including single nucleotide polymorphism genotyping, linkage analysis, array comparative genomic hybridization, quantitative PCR, and Sanger sequencing. We obtained eye movement recordings of mutant mice deficient for the ortholog of the identified candidate gene, and performed immunohistochemistry using human and mouse brain specimens.
All affected individuals had ataxia, eye movement abnormalities, most notably tonic upgaze, and delayed speech and cognitive development. Homozygosity mapping identified the disease locus on chromosome 4q. Within this region, a homozygous deletion of GRID2 exon 4 in the index family and compound heterozygous deletions involving GRID2 exon 2 in the second family were identified. Grid2-deficient mice showed larger spontaneous and random eye movements compared to wild-type mice. In developing mouse and human cerebella, GRID2 localized to the Purkinje cell dendritic spines. Brain MRI in 2 affected children showed progressive cerebellar atrophy, which was more severe than that of Grid2-deficient mice.
Biallelic deletions of GRID2 lead to a syndrome of cerebellar ataxia and tonic upgaze in humans. The phenotypic resemblance and similarity in protein expression pattern between humans and mice suggest a conserved role for GRID2 in the synapse organization between parallel fibers and Purkinje cells. However, the progressive and severe cerebellar atrophy seen in the affected individuals could indicate an evolutionarily unique role for GRID2 in the human cerebellum.
PMCID: PMC3806907  PMID: 24078737
10.  Complication begets clarification in classification 
Brain  2013;136(2):368-373.
PMCID: PMC3572928  PMID: 23413256
11.  Schizencephaly: Association With Young Maternal Age, Alcohol Use, and Lack of Prenatal Care 
Journal of child neurology  2012;28(2):10.1177/0883073812467850.
Schizencephaly is a rare malformation of cortical development characterized by congenital clefts extending from the pial surface to the lateral ventricle that are lined by heterotopic gray matter. The clinical presentation is variable and can include motor or cognitive impairment and epilepsy. The causes of schizencephaly are heterogeneous and can include teratogens, prenatal infection, or maternal trauma. Reported genetic causes include chromosomal aneuploidy, EMX2 mutations, and possible autosomal recessive familial cases based on recurrence in siblings. In an effort to identify risk factors for schizencephaly, we conducted a survey of 48 parents or primary caretakers of patients with schizencephaly born between 1983 and 2004. We discovered that young maternal age, lack of prenatal care, and alcohol use were all significantly associated with risk of schizencephaly. Our results suggest that there are important nongenetic, intrauterine events that predispose to schizencephaly.
PMCID: PMC3876412  PMID: 23266945
schizencephaly; magnetic resonance imaging (MRI); cortical dysplasia; genetics; prenatal care
12.  Brain injury and development in newborns with critical congenital heart disease 
Neurology  2013;81(3):241-248.
To determine the relationship between radiologically identifiable brain injuries and delayed brain development as reflected by brain metabolic and microstructural integrity.
Term newborns with congenital heart disease (CHD) (120 preoperatively and 104 postoperatively) were studied with MRI to determine brain injury severity (BIS), microstructure reflected by fractional anisotropy (FA) and average diffusivity (Dav), and metabolism reflected by N-acetylaspartate (NAA)/choline (Cho) and lactate/Cho. Brain development is characterized by increasing NAA/Cho and white matter FA, and by decreasing Dav and lactate/Cho.
Newly acquired brain injury was common (41% preoperative, 30% postoperative). Lower white matter FA (p = 0.005) and lower NAA/Cho (p = 0.01) were associated with increasing preoperative BIS. Higher neonatal illness severity scores (p = 0.03), lower preoperative oxygen saturation (p = 0.002), hypotension (p < 0.001), and septostomy (p = 0.002) were also predictive of higher preoperative BIS. Preoperative FA, Dav, and NAA/Cho did not predict new postoperative BIS. Increasing preoperative BIS predicted higher postoperative Dav (p = 0.002) and lactate/Cho (p = 0.008). Within the postoperative scan, new brain injuries were associated with lower white matter FA (p = 0.04). Postoperative BIS (new lesions) was associated with lower postoperative systolic (p = 0.03) and mean (p = 0.05) blood pressures.
Brain injuries in newborns with CHD are strongly related to abnormalities of brain microstructural and metabolic brain development, especially preoperatively. Both newly acquired preoperative and postoperative brain injuries are related to potentially modifiable clinical risk factors.
PMCID: PMC3770166  PMID: 23771484
13.  Neural Stem Cell Engraftment and Myelination in the Human Brain 
Science translational medicine  2012;4(155):155ra137.
Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy caused by mutation of the proteolipid protein 1 gene. Defective oligodendrocytes in PMD fail to myelinate axons, causing global neurological dysfunction. Human central nervous system stem cells (HuCNS-SCs) can develop into oligodendrocytes and confer structurally normal myelin when transplanted into a hypomyelinating mouse model. A 1-year open-label phase 1 study was undertaken to evaluate safety and to detect evidence of myelin formation after HuCNS-SC transplantation. Allogeneic HuCNS-SCs were surgically implanted into the frontal lobe white matter in four male subjects with an early-onset severe form of PMD. Immunosuppression was administered for 9 months. Serial neurological evaluations, developmental assessments, and cranial magnetic resonance imaging (MRI) and MR spectroscopy, including high-angular resolution diffusion tensor imaging (DTI), were performed at baseline and after transplantation. The neurosurgical procedure, immunosuppression regimen, and HuCNS-SC transplantation were well tolerated. Modest gains in neurological function were observed in three of the four subjects. No clinical or radiological adverse effects were directly attributed to the donor cells. Reduced T1 and T2 relaxation times were observed in the regions of transplantation 9 months after the procedure in the three subjects. Normalized DTI showed increasing fractional anisotropy and reduced radial diffusivity, consistent with myelination, in the region of transplantation compared to control white matter regions remote to the transplant sites. These phase 1 findings indicate a favorable safety profile for HuCNS-SCs in subjects with PMD. The MRI results suggest durable cell engraftment and donor-derived myelin in the transplanted host white matter.
PMCID: PMC3893824  PMID: 23052294
14.  Pediatric brain injury: Can DTI scalars predict functional outcome? 
Pediatric radiology  2013;43(1):55-59.
Diffusion imaging has made significant inroads into the clinical diagnosis of a variety of diseases by inferring changes in microstructure, namely cell membranes, myelin sheath and other structures that inhibit water diffusion. This review discusses recent progress in the use of diffusion parameters in predicting functional outcome. Studies in the literature using only scalar parameters from diffusion measurements, such as apparent diffusion coefficient (ADC) and fractional anisotropy (FA), are summarized. Other more complex mathematical models and post-processing uses are also discussed briefly.
PMCID: PMC3755904  PMID: 23288477
15.  Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion 
The 22q13.3 deletion causes a neurodevelopmental syndrome, also known as Phelan-McDermid syndrome (MIM #606232), characterized by developmental delay and severe delay or absence of expressive speech. Two patients with hemizygous chromosome 22q13.3 telomeric deletion were referred to us when brain-imaging studies revealed cerebellar vermis hypoplasia (CBVH). To determine whether developmental abnormalities of the cerebellum are a consistent feature of the 22q13.3 deletion syndrome, we examined brain-imaging studies for 10 unrelated subjects with 22q13 terminal deletion. In 7 cases where the availability of DNA and array technology allowed, we mapped deletion boundaries using comparative intensity analysis with single nucleotide polymorphism (SNP) microarrays. Approximate deletion boundaries for 3 additional cases were derived from clinical or published molecular data. We also examined brain-imaging studies for a patient with an intragenic SHANK3 mutation. We report the first brain-imaging data showing that some patients with 22q13 deletions have severe posterior CBVH, and one individual with a SHANK3 mutation has a normal cerebellum. This genotype-phenotype study suggests that the 22q13 deletion phenotype includes abnormal posterior fossa structures that are unlikely to be attributed to SHANK3 disruption. Other genes in the region, including PLXNB2 and MAPK8IP2, display brain expression patterns and mouse mutant phenotypes critical for proper cerebellar development. Future studies of these genes may elucidate their relationship to 22q13.3 deletion phenotypes.
PMCID: PMC3733662  PMID: 23225497
cerebellum; chromosome; deletion; SHANK3
16.  A Machine Learning Approach to Automated Structural Network Analysis: Application to Neonatal Encephalopathy 
PLoS ONE  2013;8(11):e78824.
Neonatal encephalopathy represents a heterogeneous group of conditions associated with life-long developmental disabilities and neurological deficits. Clinical measures and current anatomic brain imaging remain inadequate predictors of outcome in children with neonatal encephalopathy. Some studies have suggested that brain development and, therefore, brain connectivity may be altered in the subgroup of patients who subsequently go on to develop clinically significant neurological abnormalities. Large-scale structural brain connectivity networks constructed using diffusion tractography have been posited to reflect organizational differences in white matter architecture at the mesoscale, and thus offer a unique tool for characterizing brain development in patients with neonatal encephalopathy. In this manuscript we use diffusion tractography to construct structural networks for a cohort of patients with neonatal encephalopathy. We systematically map these networks to a high-dimensional space and then apply standard machine learning algorithms to predict neurological outcome in the cohort. Using nested cross-validation we demonstrate high prediction accuracy that is both statistically significant and robust over a broad range of thresholds. Our algorithm offers a novel tool to evaluate neonates at risk for developing neurological deficit. The described approach can be applied to any brain pathology that affects structural connectivity.
PMCID: PMC3840059  PMID: 24282501
17.  Congenital Microcephaly with Simplified Gyral Pattern: Associated Findings and their Significance 
AJNR. American journal of neuroradiology  2011;32(6):10.3174/ajnr.A2440.
Background and Purpose
Primary microcephalies are incompletely understood malformations that are often associated with developmental brain anomalies, yet it is not understood if the associated anomalies result from the microcephaly itself or from associated developmental/genetic mishaps. This study reviewed and analyzed a large number of MRI scans of children with microcephaly to determine the frequency of associated morphological findings and to assess whether these findings were associated with the severity of the microcephaly.
Materials and Methods
MRIs of 119 patients with clinically diagnosed microcephaly were retrospectively reviewed, focusing on the degree of microcephaly, simplification of gyri, white matter volume, abnormalities of corpus callosum, size and structure of posterior fossa contents, and myelination. Associations among the findings were evaluated using the Spearman correlation coefficient and the Fisher exact test.
Among 7 patients with mild, 42 with moderate, and 70 with extreme microcephaly, a significant correlation was identified between a greater degree of microcephaly and both a greater degree of simplified gyration and decreased white matter volume. The severity of callosal anomaly showed a lower, but still significant, correlation with the severity of microcephaly. Degree of hypoplasia of posterior fossa structures, delay in myelination, and abnormality of basal ganglia did not correlate with the degree of microcephaly.
A strong correlation was found between the degree of microcephaly, the volume of white matter, and the presence of a simplified gyral pattern. These associations should be considered when attempting to use neuroimaging for segregation and classification of patients with microcephaly.
PMCID: PMC3838394  PMID: 21454410
18.  MRI Analysis of Sulcation Morphology in Polymicrogyria 
Epilepsia  2010;51(0 1):10.1111/j.1528-1167.2009.02436.x.
PMCID: PMC3821984  PMID: 20331706
Polymicrogyria; cerebral cortex; magnetic resonance imaging; brain malformation
19.  Mapping directionality specific volume changes using tensor based morphometry: An application to the study of gyrogenesis and lateralization of the human fetal brain 
NeuroImage  2012;63(2):947-958.
Tensor based morphometry (TBM) is a powerful approach to analyze local structural changes in brain anatomy. However, conventional scalar TBM methods do not completely capture all direction specific volume changes required to model complex changes such as those during brain growth. In this paper, we describe novel TBM descriptors for studying direction-specific changes in a subject population which can be used in conjunction with scalar TBM to analyze local patterns in directionality of volume change during brain development. We also extend the methodology to provide a new approach to mapping directional asymmetry in deformation tensors associated with the emergence of structural asymmetry in the developing brain. We illustrate the use of these methods by studying developmental patterns in the human fetal brain, in vivo. Results show that fetal brain development exhibits a distinct spatial pattern of anisotropic growth. The most significant changes in the directionality of growth occurs in the cortical plate at major sulci. Our analysis also detected directional growth asymmetry in the peri-sylvian region and the medial frontal lobe of the fetal brain.
PMCID: PMC3732053  PMID: 22503938
Structural MRI; Fetal imaging; tensor based morphometry; directional growth modeling; brain development
AJNR. American journal of neuroradiology  2010;31(9):10.3174/ajnr.A2133.
Background and purpose
Changes of the major forebrain commissures in lissencephaly have not been systematically studied. This study investigated the developmental differences of the commissures in patients with varying types of lissencephaly to determine whether specific commissural features may help in distinguishing among lissencephaly phenotypes.
Materials and methods
MRI of 124 patients were retrospectively reviewed. Patients were classified as classic(cLIS), variant(vLIS) and Cobblestone lissencephaly(CBSC) according to cortical phenotype; few patients had genetic diagnoses. Abnormalities of the corpus callosum, anterior (AC), and hippocampal commissures (HC) were recorded, and the overall shape was regarded as hypogenetic, hypoplastic, dysmorphic, angled splenium and convex corpus compared with ge matched controls. Correlations between commissural characteristics and cortical patterns were analyzed using Monte Carlo simulation of chi-square, ‘extention to mxn table’, and Fisher’s exact tests as appropriate (p<0.05).
Patients were classified as cLIS (57.4%), vLIS (38.4%) or CBSC (4.2%). The most common callosal developmental anomaly was hypogenesis with absent rostrum, small inferior genu and small splenium. An angled (90°) splenium was found to be significantly associated with cLIS; and excessively convex corpus callosum with VLDLR mutations. ACC with enlarged anterior commissure was found in all ARX mutations.
Specific patterns of the commissure anomalies were associated with certain types of lissencephaly. Callosal anomalies were more common than those of AC or HC. Developmental differences of commissures may be useful as an imaging criterion in differentiating the groups of lissencephalies and may give insight into the processes causing these malformations.
PMCID: PMC3809006  PMID: 20522570
21.  Both Rare and De Novo Copy Number Variants Are Prevalent in Agenesis of the Corpus Callosum but Not in Cerebellar Hypoplasia or Polymicrogyria 
PLoS Genetics  2013;9(10):e1003823.
Agenesis of the corpus callosum (ACC), cerebellar hypoplasia (CBLH), and polymicrogyria (PMG) are severe congenital brain malformations with largely undiscovered causes. We conducted a large-scale chromosomal copy number variation (CNV) discovery effort in 255 ACC, 220 CBLH, and 147 PMG patients, and 2,349 controls. Compared to controls, significantly more ACC, but unexpectedly not CBLH or PMG patients, had rare genic CNVs over one megabase (p = 1.48×10−3; odds ratio [OR] = 3.19; 95% confidence interval [CI] = 1.89–5.39). Rare genic CNVs were those that impacted at least one gene in less than 1% of the combined population of patients and controls. Compared to controls, significantly more ACC but not CBLH or PMG patients had rare CNVs impacting over 20 genes (p = 0.01; OR = 2.95; 95% CI = 1.69–5.18). Independent qPCR confirmation showed that 9.4% of ACC patients had de novo CNVs. These, in comparison to inherited CNVs, preferentially overlapped de novo CNVs previously observed in patients with autism spectrum disorders (p = 3.06×10−4; OR = 7.55; 95% CI = 2.40–23.72). Interestingly, numerous reports have shown a reduced corpus callosum area in autistic patients, and diminished social and executive function in many ACC patients. We also confirmed and refined previously known CNVs, including significantly narrowing the 8p23.1-p11.1 duplication present in 2% of our current ACC cohort. We found six novel CNVs, each in a single patient, that are likely deleterious: deletions of 1p31.3-p31.1, 1q31.2-q31.3, 5q23.1, and 15q11.2-q13.1; and duplications of 2q11.2-q13 and 11p14.3-p14.2. One ACC patient with microcephaly had a paternally inherited deletion of 16p13.11 that included NDE1. Exome sequencing identified a recessive maternally inherited nonsense mutation in the non-deleted allele of NDE1, revealing the complexity of ACC genetics. This is the first systematic study of CNVs in congenital brain malformations, and shows a much higher prevalence of large gene-rich CNVs in ACC than in CBLH and PMG.
Author Summary
Here, we systematically test the genetic etiology of three common developmental brain malformations: agenesis of the corpus callosum (ACC), cerebellar hypoplasia (CBLH), and polymicrogyria (PMG) by copy number variation (CNV) analysis in a large cohort of brain malformation patients and controls. We found significantly more ACC but not CBLH or PMG patients with rare genic CNVs over one megabase and with rare CNVs impacting over 20 genes when compared with controls. De novo CNVs were found in 9.4% of ACC patients, and interestingly many such CNVs overlapped with de novo CNVs observed in autism. Notably, numerous studies have demonstrated a reduction in the corpus callosum area in autistic brains. Our analysis also refined previously known large CNVs that cause these malformations, and identified six novel CNVs that are likely deleterious. One ACC patient had inherited a deletion from the father which, through exome sequencing, was found to uncover a recessive nonsense mutation in NDE1 on the non-deleted allele inherited from the mother. Our study is the first to systematically evaluate the burden of rare genic CNVs in congenital brain malformations and shows that large gene-rich CNVs are more common in ACC than in CBLH and PMG.
PMCID: PMC3789824  PMID: 24098143
22.  Peritrigonal and temporo-occipital heterotopia with corpus callosum and cerebellar dysgenesis 
Neurology  2012;79(12):1244-1251.
To describe a homogeneous subtype of periventricular nodular heterotopia (PNH) as part of a newly defined malformation complex.
Observational study including review of brain MRI and clinical findings of a cohort of 50 patients with PNH in the temporo-occipital horns and trigones, mutation analysis of the FLNA gene, and anatomopathologic study of a fetal brain.
There were 28 females and 22 males. All were sporadic with the exception of an affected mother and son. Epilepsy occurred in 62%, cerebellar signs in 56%, cognitive impairment in 56%, and autism in 12%. Seventy percent were referred within the 3rd year of life. Imaging revealed a normal cerebral cortex in 76% and abnormal cortical folding in 24%. In all patients the hippocampi were under-rotated and in 10% they merged with the heterotopia. Cerebellar dysgenesis was observed in 84% and a hypoplastic corpus callosum in 60%. There was no gender bias or uneven gender distribution of clinical and anatomic severity. No mutations of FLNA occurred in 33 individuals examined. Heterotopia in the fetal brain revealed cytoarchitectonic characteristics similar to those associated with FLNA mutations; cortical pathology was not typical of polymicrogyria. Cerebellar involvement was more severe and the hippocampi appeared simple and under-rotated.
This series delineates a malformation complex in which PNH in the trigones and occipito-temporal horns is associated with hippocampal, corpus callosum, and cerebellar dysgenesis. This subtype of PNH is distinct from classic PNH caused by FLNA mutations.
PMCID: PMC3440449  PMID: 22914838
23.  3D Morphometric Analysis of Human Fetal Cerebellar Development 
Cerebellum (London, England)  2012;11(3):761-770.
To date, growth of the human fetal cerebellum has been estimated primarily from linear measurements from ultrasound and 2D magnetic resonance imaging (MRI). In this study, we use 3D analytical methods to develop normative growth trajectories for the cerebellum in utero. We measured cerebellar volume, linear dimensions, and local surface curvature from 3D reconstructed MRI of the human fetal brain (N = 46). We found that cerebellar volume increased approximately 7-fold from 20 to 31 gestational weeks. The better fit of the exponential curve (R2 = 0.96) compared to the linear curve (R2 = 0.92) indicated acceleration in growth. Within-subject cerebellar and cerebral volumes were highly correlated (R2 = 0.94), though the cerebellar percentage of total brain volume increased from approximately 2.4% to 3.7% (R2 = 0.63). Right and left hemispheric volumes did not significantly differ. Transcerebellar diameter, vermal height, and vermal anterior to posterior diameter increased significantly at constant rates. From the local curvature analysis, we found that expansion along the inferior and superior aspects of the hemispheres resulted in decreased convexity, which is likely due to the physical constraints of the dura surrounding the cerebellum and the adjacent brainstem. The paired decrease in convexity along the inferior vermis and increased convexity of the medial hemisphere represents development of the paravermian fissure, which becomes more visible during this period. In this 3D morphometric analysis of the human fetal cerebellum, we have shown that cerebellar growth is accelerating at a greater pace than the cerebrum and described how cerebellar growth impacts the shape of the structure.
PMCID: PMC3389138  PMID: 22198870
Cerebellum; Fetal MRI; Brain development; Posterior fossa; Vermis
24.  Neuropathology of brain and spinal malformations in a case of monosomy 1p36 
Monosomy 1p36 is the most common subtelomeric chromosomal deletion linked to mental retardation and seizures. Neuroimaging studies suggest that monosomy 1p36 is associated with brain malformations including polymicrogyria and nodular heterotopia, but the histopathology of these lesions is unknown. Here we present postmortem neuropathological findings from a 10 year-old girl with monosomy 1p36, who died of respiratory complications. The findings included micrencephaly, periventricular nodular heterotopia in occipitotemporal lobes, cortical dysgenesis resembling polymicrogyria in dorsolateral frontal lobes, hippocampal malrotation, callosal hypoplasia, superiorly rotated cerebellum with small vermis, and lumbosacral hydromyelia. The abnormal cortex exhibited “festooned” (undulating) supragranular layers, but no significant fusion of the molecular layer. Deletion mapping demonstrated single copy loss of a contiguous 1p36 terminal region encompassing many important neurodevelopmental genes, among them four HES genes implicated in regulating neural stem cell differentiation, and TP73, a monoallelically expressed gene. Our results suggest that brain and spinal malformations in monosomy 1p36 may be more extensive than previously recognized, and may depend on the parental origin of deleted genes. More broadly, our results suggest that specific genetic disorders may cause distinct forms of cortical dysgenesis.
PMCID: PMC3893467  PMID: 24252393
Periventricular nodular heterotopia; Hippocampal malrotation; Cortical dysgenesis; Malformations of cortical development; Hydromyelia; Mental retardation; Epilepsy
25.  Diencephalic–mesencephalic junction dysplasia: a novel recessive brain malformation 
Brain  2012;135(8):2416-2427.
We describe six cases from three unrelated consanguineous Egyptian families with a novel characteristic brain malformation at the level of the diencephalic–mesencephalic junction. Brain magnetic resonance imaging demonstrated a dysplasia of the diencephalic–mesencephalic junction with a characteristic ‘butterfly’-like contour of the midbrain on axial sections. Additional imaging features included variable degrees of supratentorial ventricular dilatation and hypoplasia to complete agenesis of the corpus callosum. Diffusion tensor imaging showed diffuse hypomyelination and lack of an identifiable corticospinal tract. All patients displayed severe cognitive impairment, post-natal progressive microcephaly, axial hypotonia, spastic quadriparesis and seizures. Autistic features were noted in older cases. Talipes equinovarus, non-obstructive cardiomyopathy and persistent hyperplastic primary vitreous were additional findings in two families. One of the patients required shunting for hydrocephalus; however, this yielded no change in ventricular size suggestive of dysplasia rather than obstruction. We propose the term ‘diencephalic–mesencephalic junction dysplasia’ to characterize this autosomal recessive malformation.
PMCID: PMC3407423  PMID: 22822038
diencephalon; mesencephalon; mental retardation; brainstem malformation; brain wiring

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