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1.  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
2.  Model organisms inform the search for the genes and developmental pathology underlying malformations of the human hindbrain 
Seminars in pediatric neurology  2009;16(3):155-163.
Congenital malformations the human hindbrain, including the cerebellum, are poorly understood largely because their recognition is a relatively recent advance for imaging diagnostics. Cerebellar malformations are the most obvious and best characterized hindbrain malformations due to their relative ease to view by MRI and the recent identification of several causative genes1. Malformations of the pons and medulla have also been described both in isolation and in association with cerebellar malformations2. Although little is understood regarding the specific developmental pathologies underlying hindbrain malformations in humans, much is known regarding the mechanisms and genes driving hindbrain development in vertebrate model organisms. Thus, studies in vertebrate models provide a developmental framework in which to categorize human hindbrain malformations and serve to inform our thinking regarding disrupted developmental processes and candidate genes. Here we survey the basic principles of vertebrate hindbrain development and integrate our current knowledge of human hindbrain malformations into this framework.
PMCID: PMC2778478  PMID: 19778712
3.  Midbrain–hindbrain involvement in lissencephalies 
Neurology  2009;72(5):410-418.
To determine the involvement of the midbrain and hindbrain (MHB) in the groups of classic (cLIS), variant (vLIS), and cobblestone complex (CBSC) lissencephalies and to determine whether a correlation exists between the cerebral malformation and the MHB abnormalities.
MRI scans of 111 patients (aged 1 day to 32 years; mean 5 years 4 months) were retrospectively reviewed. After reviewing the brain involvement on MRI, the cases were reclassified according to known mutation (LIS1, DCX, ARX, VLDLR, RELN, MEB, WWS) or mutation phenotype (LIS1-P, DCX-P, RELN-P, ARX-P, VLDLR-P) determined on the basis of characteristic MRI features. Abnormalities in the MHB were then recorded. For each structure, a score was assigned, ranging from 0 (normal) to 3 (severely abnormal). The differences between defined groups and the correlation between the extent of brain agyria/pachygyria and MHB involvement were assessed using Kruskal–Wallis and χ2 McNemar tests.
There was a significant difference in MHB appearance among the three major groups of cLIS, vLIS, and CBSC. The overall score showed a severity gradient of MHB involvement: cLIS (0 or 1), vLIS (7), and CBSC (11 or 12). The extent of cerebral lissencephaly was significantly correlated with the severity of MHB abnormalities (p = 0.0029).
Our study focused on posterior fossa anomalies, which are an integral part of cobblestone complex lissencephalies but previously have not been well categorized for other lissencephalies. According to our results and the review of the literature, we propose a new classification of human lissencephalies.
= autosomal;
= agenesis of corpus callosum;
= autosomal dominant;
= anteroposterior;
= autosomal recessive;
= cerebellar;
= cobblestone complex;
= classic lissencephaly;
= congenital muscular dystrophy;
= cell-sparse zone;
= dorsal–ventral;
= Fukuyama congenital muscular dystrophy;
= inferior vermis hypoplasia;
= lateral ventricle;
= medulla;
= midbrain;
= Miller–Dieker syndrome;
= muscle–eye–brain;
= midbrain and hindbrain;
= magnetic resonance;
= not determined;
= pons;
= rostrocaudal;
= subcortical band heterotopia;
= subependymal linear heterotopia;
= vermis;
= variant lissencephaly;
= weighted image;
= Walker–Warburg syndrome;
= X-linked dominant;
= X-linked recessive.
PMCID: PMC2677533  PMID: 19020296
4.  Congenital hypoplasia of the cerebellum: developmental causes and behavioral consequences 
Over the last 60 years, the spotlight of research has periodically returned to the cerebellum as new techniques and insights have emerged. Because of its simple homogeneous structure, limited diversity of cell types and characteristic behavioral pathologies, the cerebellum is a natural home for studies of cell specification, patterning, and neuronal migration. However, recent evidence has extended the traditional range of perceived cerebellar function to include modulation of cognitive processes and implicated cerebellar hypoplasia and Purkinje neuron hypo-cellularity with autistic spectrum disorder. In the light of this emerging frontier, we review the key stages and genetic mechanisms behind cerebellum development. In particular, we discuss the role of the midbrain hindbrain isthmic organizer in the development of the cerebellar vermis and the specification and differentiation of Purkinje cells and granule neurons. These developmental processes are then considered in relation to recent insights into selected human developmental cerebellar defects: Joubert syndrome, Dandy–Walker malformation, and pontocerebellar hypoplasia. Finally, we review current research that opens up the possibility of using the mouse as a genetic model to study the role of the cerebellum in cognitive function.
PMCID: PMC3759752  PMID: 24027500
cerebellum; development; defects; hypoplasia; genetics; function; behavior; autism spectrum disorders
5.  Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth 
eLife  null;3:e03962.
Loss of Foxc1 is associated with Dandy-Walker malformation, the most common human cerebellar malformation characterized by cerebellar hypoplasia and an enlarged posterior fossa and fourth ventricle. Although expressed in the mouse posterior fossa mesenchyme, loss of Foxc1 non-autonomously induces a rapid and devastating decrease in embryonic cerebellar ventricular zone radial glial proliferation and concurrent increase in cerebellar neuronal differentiation. Subsequent migration of cerebellar neurons is disrupted, associated with disordered radial glial morphology. In vitro, SDF1α, a direct Foxc1 target also expressed in the head mesenchyme, acts as a cerebellar radial glial mitogen and a chemoattractant for nascent Purkinje cells. Its receptor, Cxcr4, is expressed in cerebellar radial glial cells and conditional Cxcr4 ablation with Nes-Cre mimics the Foxc1−/− cerebellar phenotype. SDF1α also rescues the Foxc1−/− phenotype. Our data emphasizes that the head mesenchyme exerts a considerable influence on early embryonic brain development and its disruption contributes to neurodevelopmental disorders in humans.
eLife digest
The part of the brain responsible for coordinating and fine-tuning movement, sensory processing and some cognitive functions—the cerebellum—is found tucked away at the back of the brain, where it sits in a hollow in the skull called the posterior fossa. In a relatively common neurological disorder called Dandy-Walker malformation, part of the cerebellum doesn't develop and the posterior fossa is abnormally large.
One contributing factor to Dandy-Walker malformation is the loss of a protein called Foxc1. This protein is a so-called transcription factor, meaning it activates other genes, and so it has various important roles in helping an embryo to develop. In mouse embryos, the gene that produces Foxc1 is not activated in the developing cerebellum itself, but rather in the adjacent mesenchyme, a primitive embryonic tissue that will develop into the membranes that cover the brain and the skull bones that define the posterior fossa. This led Haldipur et al. to propose that the mesenchyme and the cerebellum communicate with each other as they develop.
To investigate this idea, Haldipur et al. carefully analysed how the development of the mouse cerebellum goes awry when Foxc1 is absent. This revealed that Foxc1-deficient mice have lower numbers of a type of cell called radial glial cells in their cerebellum. These are ‘progenitor’ cells that develop into the various types of cell found in the cerebellum, and also act as a scaffold for other neurons to migrate across. Therefore, the loss of radial glial cells in Foxc1-deficient mice substantially disrupts how the cerebellum develops, and how the neurons in the cerebellum work.
One gene activated by the Foxc1 protein encodes another protein called SDF1-alpha. This protein is released from the tissue that will develop into the posterior fossa, and binds to a receptor protein that is present on radial glial cells in the cerebellum. When this binding occurs, the radial glial cells grow and divide, and so the embryo's cerebellum also grows. Haldipur et al. found that mouse embryos specifically missing this receptor develop many of the abnormalities seen in Foxc1-deficient mice and further, when SDF1-alpha was provided back into Foxc1-deficient cerebella, the defects were rescued. This suggests that the cerebellar defects caused by the loss of Foxc1 stem from disrupting the signalling pathways that are triggered by the interaction between SDF1-alpha and its receptor.
These studies highlight that the brain does not develop in isolation. It is strongly dependent on the signals it receives from the embryonic mesenchyme that surrounds it. Identifying these signals and understanding how they can be disrupted by both genetic and non-genetic causes, such as inflammation, may be key to understanding this important class of brain birth defects.
PMCID: PMC4281880  PMID: 25513817
neurodevelopmental disorder; radial glia; cerebellum; Cxcl12; foxc1; mouse
6.  Mouse IDGenes: a reference database for genetic interactions in the developing mouse brain 
The study of developmental processes in the mouse and other vertebrates includes the understanding of patterning along the anterior–posterior, dorsal–ventral and medial– lateral axis. Specifically, neural development is also of great clinical relevance because several human neuropsychiatric disorders such as schizophrenia, autism disorders or drug addiction and also brain malformations are thought to have neurodevelopmental origins, i.e. pathogenesis initiates during childhood and adolescence. Impacts during early neurodevelopment might also predispose to late-onset neurodegenerative disorders, such as Parkinson’s disease. The neural tube develops from its precursor tissue, the neural plate, in a patterning process that is determined by compartmentalization into morphogenetic units, the action of local signaling centers and a well-defined and locally restricted expression of genes and their interactions. While public databases provide gene expression data with spatio-temporal resolution, they usually neglect the genetic interactions that govern neural development. Here, we introduce Mouse IDGenes, a reference database for genetic interactions in the developing mouse brain. The database is highly curated and offers detailed information about gene expressions and the genetic interactions at the developing mid-/hindbrain boundary. To showcase the predictive power of interaction data, we infer new Wnt/β-catenin target genes by machine learning and validate one of them experimentally. The database is updated regularly. Moreover, it can easily be extended by the research community. Mouse IDGenes will contribute as an important resource to the research on mouse brain development, not exclusively by offering data retrieval, but also by allowing data input.
Database URL:
PMCID: PMC4139671  PMID: 25145340
7.  Developmental disorders of the midbrain and hindbrain 
Malformations of the midbrain (MB) and hindbrain (HB) have become topics of considerable interest in the neurology and neuroscience literature in recent years. The combined advances of imaging and molecular biology have improved analyses of structures in these areas of the central nervous system, while advances in genetics have made it clear that malformations of these structures are often associated with dysfunction or malformation of other organ systems. This review focuses upon the importance of communication between clinical researchers and basic scientists in the advancement of knowledge of this group of disorders. Disorders of anteroposterior (AP) patterning, cerebellar hypoplasias, disorders associated with defects of the pial limiting membrane (cobblestone cortex), disorders of the Reelin pathway, and disorders of the primary cilium/basal body organelle (molar tooth malformations) are the main focus of the review.
PMCID: PMC3294267  PMID: 22408608
midbrain; hindbrain; cerebellum; malformations
8.  Contribution of Rare Copy Number Variants to Isolated Human Malformations 
PLoS ONE  2012;7(10):e45530.
Congenital malformations are present in approximately 2–3% of liveborn babies and 20% of stillborn fetuses. The mechanisms underlying the majority of sporadic and isolated congenital malformations are poorly understood, although it is hypothesized that the accumulation of rare genetic, genomic and epigenetic variants converge to deregulate developmental networks.
Methodology/Principal Findings
We selected samples from 95 fetuses with congenital malformations not ascribed to a specific syndrome (68 with isolated malformations, 27 with multiple malformations). Karyotyping and Multiplex Ligation-dependent Probe Amplification (MLPA) discarded recurrent genomic and cytogenetic rearrangements. DNA extracted from the affected tissue (46%) or from lung or liver (54%) was analyzed by molecular karyotyping. Validations and inheritance were obtained by MLPA. We identified 22 rare copy number variants (CNV) [>100 kb, either absent (n = 7) or very uncommon (n = 15, <1/2,000) in the control population] in 20/95 fetuses with congenital malformations (21%), including 11 deletions and 11 duplications. One of the 9 tested rearrangements was de novo while the remaining were inherited from a healthy parent. The highest frequency was observed in fetuses with heart hypoplasia (8/17, 62.5%), with two events previously related with the phenotype. Double events hitting candidate genes were detected in two samples with brain malformations. Globally, the burden of deletions was significantly higher in fetuses with malformations compared to controls.
Our data reveal a significant contribution of rare deletion-type CNV, mostly inherited but also de novo, to human congenital malformations, especially heart hypoplasia, and reinforce the hypothesis of a multifactorial etiology in most cases.
PMCID: PMC3463597  PMID: 23056206
9.  Oculocerebrocutaneous syndrome: the brain malformation defines a core phenotype 
Journal of Medical Genetics  2005;42(12):913-921.
Background: Oculocerebrocutaneous syndrome (OCCS) is characterised by orbital cysts and anophthalmia or microphthalmia, focal aplastic or hypoplastic skin defects, skin appendages, and brain malformations. The eye and skin abnormalities are well described but the neuropathological features less so. To date, 28 patients with an unequivocal diagnosis of OCCS have been reported, with a preponderance of males.
Objective: To evaluate the brain imaging studies, clinical records, photographs, and pathological material of two new and nine previously reported cases of OCCS.
Results: There was a consistent pattern of malformations in eight of the 11 cases, consisting of frontal predominant polymicrogyria and periventricular nodular heterotopia, enlarged lateral ventricles or hydrocephalus, agenesis of the corpus callosum sometimes associated with interhemispheric cysts, and a novel mid-hindbrain malformation. The latter consisted of a giant and dysplastic tectum, absent cerebellar vermis, small cerebellar hemispheres in most cases, and a large posterior fossa fluid collection.
Conclusions: The mid-hindbrain malformation appears pathognomonic for OCCS. The eye and skin features of OCCS show considerable overlap with several other syndromes, such as encephalocraniocutaneous lipomatosis, oculo-auriculo-vertebral spectrum, and focal dermal hypoplasia, none of which has a comparable pattern of brain malformations. In particular the unique mid-hindbrain malformation also distinguishes OCCS from related syndromes with comparable forebrain anomalies. The pattern of malformation described thus helps in differentiating OCCS from other entities. The mid-hindbrain malformation points to a defect of the mid-hindbrain organiser as the underlying pathogenic mechanism.
PMCID: PMC1735958  PMID: 15879499
10.  A unifying hypothesis for hydrocephalus, Chiari malformation, syringomyelia, anencephaly and spina bifida 
This work is a modified version of the Casey Holter Memorial prize essay presented to the Society for Research into Hydrocephalus and Spina Bifida, June 29th 2007, Heidelberg, Germany. It describes the origin and consequences of the Chiari malformation, and proposes that hydrocephalus is caused by inadequate central nervous system (CNS) venous drainage. A new hypothesis regarding the pathogenesis, anencephaly and spina bifida is described.
Any volume increase in the central nervous system can increase venous pressure. This occurs because veins are compressible and a CNS volume increase may result in reduced venous blood flow. This has the potential to cause progressive increase in cerebrospinal fluid (CSF) volume. Venous insufficiency may be caused by any disease that reduces space for venous volume. The flow of CSF has a beneficial effect on venous drainage. In health it moderates central nervous system pressure by moving between the head and spine. Conversely, obstruction to CSF flow causes localised pressure increases, which have an adverse effect on venous drainage.
The Chiari malformation is associated with hindbrain herniation, which may be caused by low spinal pressure relative to cranial pressure. In these instances, there are hindbrain-related symptoms caused by cerebellar and brainstem compression. When spinal injury occurs as a result of a Chiari malformation, the primary pathology is posterior fossa hypoplasia, resulting in raised spinal pressure. The small posterior fossa prevents the flow of CSF from the spine to the head as blood enters the central nervous system during movement. Consequently, intermittent increases in spinal pressure caused by movement, result in injury to the spinal cord. It is proposed that posterior fossa hypoplasia, which has origins in fetal life, causes syringomyelia after birth and leads to damage to the spinal cord in spina bifida. It is proposed that hydrocephalus may occur as a result of posterior fossa hypoplasia, where raised pressure occurs as a result of obstruction to flow of CSF from the head to the spine, and cerebral injury with raised pressure occurs in anencephaly by this mechanism.
The current view of dysraphism is that low central nervous system pressure and exposure to amniotic fluid, damage the central nervous system. The hypothesis proposed in this essay supports the view that spina bifida is a manifestation of progressive hydrocephalus in the fetus. It is proposed that that mesodermal growth insufficiency influences both neural tube closure and central nervous system pressure, leading to dysraphism.
PMCID: PMC2365936  PMID: 18405364
11.  Dampened hippocampal oscillations and enhanced spindle activity in an asymptomatic model of developmental cortical malformations 
Developmental cortical malformations comprise a large spectrum of histopathological brain abnormalities and syndromes. Their genetic, developmental and clinical complexity suggests they should be better understood in terms of the complementary action of independently timed perturbations (i.e., the multiple-hit hypothesis). However, understanding the underlying biological processes remains puzzling. Here we induced developmental cortical malformations in offspring, after intraventricular injection of methylazoxymethanol (MAM) in utero in mice. We combined extensive histological and electrophysiological studies to characterize the model. We found that MAM injections at E14 and E15 induced a range of cortical and hippocampal malformations resembling histological alterations of specific genetic mutations and transplacental mitotoxic agent injections. However, in contrast to most of these models, intraventricularly MAM-injected mice remained asymptomatic and showed no clear epilepsy-related phenotype as tested in long-term chronic recordings and with pharmacological manipulations. Instead, they exhibited a non-specific reduction of hippocampal-related brain oscillations (mostly in CA1); including theta, gamma and HFOs; and enhanced thalamocortical spindle activity during non-REM sleep. These data suggest that developmental cortical malformations do not necessarily correlate with epileptiform activity. We propose that the intraventricular in utero MAM approach exhibiting a range of rhythmopathies is a suitable model for multiple-hit studies of associated neurological disorders.
PMCID: PMC3995045  PMID: 24782720
oscillations; multi-site recordings; hippocampal heterotopia; epilepsy
12.  Joubert Syndrome and related disorders 
Joubert syndrome (JS) and related disorders (JSRD) are a group of developmental delay/multiple congenital anomalies syndromes in which the obligatory hallmark is the molar tooth sign (MTS), a complex midbrain-hindbrain malformation visible on brain imaging, first recognized in JS. Estimates of the incidence of JSRD range between 1/80,000 and 1/100,000 live births, although these figures may represent an underestimate. The neurological features of JSRD include hypotonia, ataxia, developmental delay, intellectual disability, abnormal eye movements, and neonatal breathing dysregulation. These may be associated with multiorgan involvement, mainly retinal dystrophy, nephronophthisis, hepatic fibrosis and polydactyly, with both inter- and intra-familial variability. JSRD are classified in six phenotypic subgroups: Pure JS; JS with ocular defect; JS with renal defect; JS with oculorenal defects; JS with hepatic defect; JS with orofaciodigital defects. With the exception of rare X-linked recessive cases, JSRD follow autosomal recessive inheritance and are genetically heterogeneous. Ten causative genes have been identified to date, all encoding for proteins of the primary cilium or the centrosome, making JSRD part of an expanding group of diseases called "ciliopathies". Mutational analysis of causative genes is available in few laboratories worldwide on a diagnostic or research basis. Differential diagnosis must consider in particular the other ciliopathies (such as nephronophthisis and Senior-Loken syndrome), distinct cerebellar and brainstem congenital defects and disorders with cerebro-oculo-renal manifestations. Recurrence risk is 25% in most families, although X-linked inheritance should also be considered. The identification of the molecular defect in couples at risk allows early prenatal genetic testing, whereas fetal brain neuroimaging may remain uninformative until the end of the second trimester of pregnancy. Detection of the MTS should be followed by a diagnostic protocol to assess multiorgan involvement. Optimal management requires a multidisciplinary approach, with particular attention to respiratory and feeding problems in neonates and infants. Cognitive and behavioral assessments are also recommended to provide young patients with adequate neuropsychological support and rehabilitation. After the first months of life, global prognosis varies considerably among JSRD subgroups, depending on the extent and severity of organ involvement.
PMCID: PMC2913941  PMID: 20615230
13.  Cilia in the nervous system: linking cilia function and neurodevelopmental disorders 
Current opinion in neurology  2011;24(2):98-105.
Purpose of review
Ciliopathies are genetic disorders caused by defects of primary ciliary structure and/or function and are characterized by pleiotropic clinical features. The ciliopathies include several partially overlapping syndromes such as Joubert syndrome, Bardet–Biedl syndrome and Meckel–Gruber syndrome, all of which have pronounced neurodevelopmental features. Here we focus on potential roles of cilia in central nervous system function, to explore how impairments may cause brain malformation and neurodevelopmental disease.
Recent findings
Cilia have long been considered as ‘sensory cellular antennae’, responding as chemo-sensors, mechano-sensors and thermo-sensors, although their roles in development were not well understood until recently. The surprising finding that disparate syndromes are all due to defects of the primary cilia, along with the recent advances in genetics, has helped elucidate further roles of primary cilia beyond sensory functions. Several molecules that are associated with key signaling pathways have been discovered in primary cilia. These include sonic hedgehog, wingless, planar cell polarity and fibroblast growth factor, which are essential for many cellular processes. Additionally, mutations in ‘ciliome’ genes have largely shown developmental defects such as abnormal body axis and brain malformation, implying disrupted cilia-related signaling pathways. Accordingly, the emerging theme is that primary cilia may play roles as modulators of signal transduction to help shape cellular responses within the environmental context during both development and homeostasis.
The link between cilia and signal pathways has become a framework for understanding the pathogenesis of ciliopathies. Despite recent progress in ciliary biology, fundamental questions remain about how cilia regulate neuronal function in the central nervous system. Therefore, investigation of ciliary function in the nervous system may reveal cilia-modulating mechanisms in neurodevelopmental processes, as well as suggest new treatments for disease.
PMCID: PMC3984876  PMID: 21386674
brain; central nervous system; cilia; ciliopathy; Joubert syndrome; neuron; signaling pathways
14.  Species differences in the expression of AHI1, a protein implicated in the neurodevelopmental disorder Joubert syndrome, with preferential accumulation to stigmoid bodies 
Joubert syndrome (JBTS) is an autosomal recessive disorder characterized by cerebellum and brainstem malformations. Individuals with JBTS have abnormal breathing and eye movements, ataxia, hypotonia, and cognitive difficulty, and they display mirror movements. Mutations in the Abelson-helper integration site-1 gene (AHI1) cause JBTS in humans, suggesting that AHI1 is required for hindbrain development; however AHI1 may also be required for neuronal function. Support for this idea comes from studies demonstrating that the AHI1 locus is associated with schizophrenia. To gain further insight into the function of AHI1 in both the developing and mature CNS, we determined the spatial and temporal expression patterns of the gene products of AHI1 orthologs throughout development, in human, mouse, and zebrafish. Murine Ahi1 was distributed throughout the cytoplasm, dendrites, and axons of neurons, but was absent in glial cells. Ahi1 expression in the mouse brain was observed as early as embryonic day 10.5 and persisted into adulthood, with peak expression during the first post-natal week. Murine Ahi1 was observed in neurons of the hindbrain, midbrain, and ventral forebrain. Generally, the AHI1/Ahi1/ahi1 orthologs had a conserved distribution pattern in human, mouse, and zebrafish, but mouse Ahi1 was not present in the developing and mature cerebellum. Ahi1 was also observed consistently in the stigmoid body, a poorly characterized cytoplasmic organelle found in neurons. Overall, these results suggest roles for AHI1 in neurodevelopmental processes that underlie most of the neuroanatomical defects in JBTS, and perhaps in neuronal functions that contribute to schizophrenia.
PMCID: PMC2600576  PMID: 18785627
mouse; human; zebrafish; hindbrain
15.  Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis) 
Journal of medical genetics  2009;47(1):8-21.
To identify genetic causes of COACH syndrome
COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD).
In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced.
19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%).
Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.
PMCID: PMC3501959  PMID: 19574260
16.  A developmental and genetic classification for malformations of cortical development: update 2012 
Brain  2012;135(5):1348-1369.
Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics and imaging has resulted in an explosive increase in our knowledge of cerebral cortex development and in the number and types of malformations of cortical development that have been reported. These advances continue to modify our perception of these malformations. This review addresses recent changes in our perception of these disorders and proposes a modified classification based upon updates in our knowledge of cerebral cortical development.
PMCID: PMC3338922  PMID: 22427329
cerebral cortex; malformation of cortical development; microcephaly; cortical dysplasia; polymicrogyria
17.  Midbrain–hindbrain malformations in patients with malformations of cortical development and epilepsy: A series of 220 patients 
Epilepsy Research  2013;106(1-2):181-190.
•We assessed midbrain–hindbrain in a large series of cortical malformation patients.•Midbrain–hindbrain malformations are commonly linked to cortical malformations.•Midbrain–hindbrain malformations are associated with severe clinical phenotype.
Midbrain–hindbrain malformations (MHM) may coexist with malformations of cortical development (MCD). This study represents a first attempt to investigate the spectrum of MHM in a large series of patients with MCD and epilepsy. We aimed to explore specific associations between MCD and MHM and to compare two groups of patients: MCD with MHM (wMHM) and MCD without MHM (w/oMHM) with regard to clinical and imaging features.
Two hundred and twenty patients (116 women/104 men, median age 28 years, interquartile range 20–44 years at the time of assessment) with MCD and epilepsy were identified at the Departments of Neurology and Pediatrics, Innsbruck Medical University, Austria. All underwent high-resolution MRIs (1.5-T) between 01.01.2002 and 31.12.2011. Midbrain–hindbrain structures were visually assessed by three independent raters.
MHM were seen in 17% (38/220) of patients. The rate of patients wMHM and w/oMHM differed significantly (p = 0.004) in three categories of MCD (category I – to abnormal neuronal proliferation; category II – to abnormal neuronal migration; and category III – due to abnormal neuronal late migration/organization): MCD due to abnormal neuronal migration (31%) and organization (23%) were more commonly associated with MHM compared to those with MCD due to abnormal neuronal proliferation (9%). Extensive bilateral MCD were seen more often in patients wMHM compared to those w/oMHM (63% vs. 36%; p = 0.004). In wMHM group compared to w/oMHM group there were higher rates of callosal dysgenesis (26% vs. 4%; p < 0.001) and hippocampal abnormalities (52% vs. 27%; p < 0.001). Patients wMHM were younger (median 25 years vs. 30 years; p = 0.010) at the time of assessment and had seizure onset at an earlier age (median 5 years vs. 12 years; p = 0.043) compared to those w/oMHM. Patients wMHM had higher rates of learning disability (71% vs. 38%; p < 0.001), delayed developmental milestones (68% vs. 35%; p < 0.001) and neurological deficits (66% vs. 47%; p = 0.049) compared to those w/oMHM.
The groups (wMHM and w/oMHM) did not differ in their response to antiepileptic treatment, seizure outcome, seizure types, EEG abnormalities and rate of status epilepticus. Presence of MHM in patients with MCD and epilepsy is associated with severe morphological and clinical phenotypes.
PMCID: PMC3885798  PMID: 23810707
Epilepsy; Cortical dysplasia; MRI; Developmental disorders; Midbrain–hindbrain
18.  Novel Approaches to Studying the Genetic Basis of Cerebellar Development 
Cerebellum (London, England)  2010;9(3):272-283.
The list of genes that when mutated cause disruptions in cerebellar development is rapidly increasing. The study of both spontaneous and engineered mouse mutants has been essential to this progress, as it has revealed much of our current understanding of the developmental processes required to construct the mature cerebellum. Improvements in brain imaging, such as magnetic resonance imaging (MRI) and the emergence of better classification schemes for human cerebellar malformations, have recently led to the identification of a number of genes which cause human cerebellar disorders. In this review we argue that synergistic approaches combining classical molecular techniques, genomics, and mouse models of human malformations will be essential to fuel additional discoveries of cerebellar developmental genes and mechanisms.
PMCID: PMC2921561  PMID: 20387026
Cerebellum; Neurological and targeted mouse mutants; Congenital human cerebellar malformations; Genomics; Genetics; Ataxia
19.  Holoprosencephaly 
Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face. It is estimated to occur in 1/16,000 live births and 1/250 conceptuses. Three ranges of increasing severity are described: lobar, semi-lobar and alobar HPE. Another milder subtype of HPE called middle interhemispheric variant (MIHF) or syntelencephaly is also reported. In most of the cases, facial anomalies are observed in HPE, like cyclopia, proboscis, median or bilateral cleft lip/palate in severe forms, ocular hypotelorism or solitary median maxillary central incisor in minor forms. These latter midline defects can occur without the cerebral malformations and then are called microforms. Children with HPE have many medical problems: developmental delay and feeding difficulties, epilepsy, instability of temperature, heart rate and respiration. Endocrine disorders like diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia and growth hormone deficiency are frequent. To date, seven genes have been positively implicated in HPE: Sonic hedgehog (SHH), ZIC2, SIX3, TGIF, PTCH, GLI2 and TDGF1. A molecular diagnosis can be performed by gene sequencing and allele quantification for the four main genes SHH, ZIC2, SIX3 and TGIF. Major rearrangements of the subtelomeres can also be identified by multiplex ligation-dependent probe amplification (MLPA). Nevertheless, in about 70% of cases, the molecular basis of the disease remains unknown, suggesting the existence of several other candidate genes or environmental factors. Consequently, a "multiple-hit hypothesis" of genetic and/or environmental factors (like maternal diabetes) has been proposed to account for the extreme clinical variability. In a practical approach, prenatal diagnosis is based on ultrasound and magnetic resonance imaging (MRI) rather than on molecular diagnosis. Treatment is symptomatic and supportive, and requires a multidisciplinary management. Child outcome depends on the HPE severity and the medical and neurological complications associated. Severely affected children have a very poor prognosis. Mildly affected children may exhibit few symptoms and may live a normal life.
PMCID: PMC1802747  PMID: 17274816
20.  MicroRNA-17-92, a Direct Ap-2α Transcriptional Target, Modulates T-Box Factor Activity in Orofacial Clefting 
PLoS Genetics  2013;9(9):e1003785.
Among the most common human congenital anomalies, cleft lip and palate (CL/P) affects up to 1 in 700 live births. MicroRNA (miR)s are small, non-coding RNAs that repress gene expression post-transcriptionally. The miR-17-92 cluster encodes six miRs that have been implicated in human cancers and heart development. We discovered that miR-17-92 mutant embryos had severe craniofacial phenotypes, including incompletely penetrant CL/P and mandibular hypoplasia. Embryos that were compound mutant for miR-17-92 and the related miR-106b-25 cluster had completely penetrant CL/P. Expression of Tbx1 and Tbx3, the DiGeorge/velo-cardio-facial (DGS) and Ulnar-mammary syndrome (UMS) disease genes, was expanded in miR-17-92 mutant craniofacial structures. Both Tbx1 and Tbx3 had functional miR seed sequences that mediated gene repression. Analysis of miR-17-92 regulatory regions uncovered conserved and functional AP-2α recognition elements that directed miR-17-92 expression. Together, our data indicate that miR-17-92 modulates expression of critical T-box transcriptional regulators during midface development and is itself a target of Bmp-signaling and the craniofacial pioneer factor AP-2α. Our data are the first genetic evidence that an individual miR or miR cluster is functionally important in mammalian CL/P.
Author Summary
CL/P are very common birth defects in humans. The genetic mechanism underlying CL/P pathogenesis is poorly understood. MiRs, small non-coding RNAs that function to post-transcriptionally regulate gene expression, have been identified as pivotal modulators of various developmental events and diseases. To date, there is no individual miR or miR cluster that has been identified as functionally essential in mammalian CL/P. Here, we have discovered that deletion of miR-17-92 cluster in mice results in craniofacial malformations including CL/P. Importantly, MIR-17-92 is located on a critical human chromosome region associated with 13q deletion syndrome, a chromosomal disorder that presents with defects including CL/P, suggesting the advantages of our animal model to study human disease. Moreover, our work demonstrated that miR-17-92 cluster directly repressed T-box factors, which have critical functions during craniofacial development. We further showed that miR-17-92 was directly activated by Bmp-signaling and transcription factor AP-2α. Together, our work identified a novel miR-mediated transcriptional network underlying CL/P, providing new insights into craniofacial developmental biology.
PMCID: PMC3777996  PMID: 24068957
21.  Transcription factors define the neuroanatomical organization of the medullary reticular formation 
The medullary reticular formation contains large populations of inadequately described, excitatory interneurons that have been implicated in multiple homeostatic behaviors including breathing, viserosensory processing, vascular tone, and pain. Many hindbrain nuclei show a highly stereotyped pattern of localization across vertebrates suggesting a strong underlying genetic organization. Whether this is true for neurons within the reticular regions of hindbrain is unknown. Hindbrain neurons are derived from distinct developmental progenitor domains each of which expresses distinct patterns of transcription factors (TFs). These neuronal populations have distinct characteristics such as transmitter identity, migration, and connectivity suggesting developmentally expressed TFs might identify unique subpopulations of neurons within the reticular formation. A fate-mapping strategy using perinatal expression of reporter genes within Atoh1, Dbx1, Lmx1b, and Ptf1a transgenic mice coupled with immunohistochemistry (IHC) and in situ hybridization (ISH) were used to address the developmental organization of a large subset of reticular formation glutamatergic neurons. All hindbrain lineages have relatively large populations that extend the entire length of the hindbrain. Importantly, the location of neurons within each lineage was highly constrained. Lmx1b- and Dbx1- derived populations were both present in partially overlapping stripes within the reticular formation extending from dorsal to ventral brain. Within each lineage, distinct patterns of gene expression and organization were localized to specific hindbrain regions. Rostro-caudally sub-populations differ sequentially corresponding to proposed pseudo-rhombomereic boundaries. Dorsal-ventrally, sub-populations correspond to specific migratory positions. Together these data suggests the reticular formation is organized by a highly stereotyped developmental logic.
PMCID: PMC3653110  PMID: 23717265
brainstem; transcription factors; reticular formation; fate-mapping; development; rhombomeres; hindbrain
22.  Modifier genes and non-genetic factors reshape anatomical deficits in Zfp423-deficient mice 
Human Molecular Genetics  2011;20(19):3822-3830.
Development of neural circuitry depends on the integration of signaling pathways to coordinate specification, proliferation and differentiation of cell types in the right number, in the right place, at the right time. Zinc finger protein 423 (Zfp423), a 30-zinc finger transcription factor, forms alternate complexes with components of several developmental signaling pathways, suggesting it as a point of signal integration during brain development. We previously showed that mice lacking Zfp423 have reduced proliferation of cerebellar precursor cells, resulting in complete loss of vermis and variable hypoplasia of cerebellar hemispheres. Here, we show that Zfp423−/− hemisphere malformations are shaped by both genetic and non-genetic factors, producing distinct phenotype distributions in different inbred genetic backgrounds. In genetic mapping studies, we identify four additive modifier loci (Amzn1–4) and seven synthetically interacting loci (Smzn1.1–3.1) that together explain approximately one-third of the phenotypic variance. Strain-specific sequence polymorphism and expression data provide a reduced list of functional variant candidate genes at each modifier locus. Environmental covariates add only modest explanatory power, suggesting an additional stochastic component. These results provide a comprehensive analysis of sources of phenotype variation in a model of hindbrain malformation.
PMCID: PMC3168291  PMID: 21729880
23.  Spatial Analysis of Expression Patterns Predicts Genetic Interactions at the Mid-Hindbrain Boundary 
PLoS Computational Biology  2009;5(11):e1000569.
The isthmic organizer mediating differentiation of mid- and hindbrain during vertebrate development is characterized by a well-defined pattern of locally restricted gene expression domains around the mid-hindbrain boundary (MHB). This pattern is established and maintained by a regulatory network between several transcription and secreted factors that is not yet understood in full detail. In this contribution we show that a Boolean analysis of the characteristic spatial gene expression patterns at the murine MHB reveals key regulatory interactions in this network. Our analysis employs techniques from computational logic for the minimization of Boolean functions. This approach allows us to predict also the interplay of the various regulatory interactions. In particular, we predict a maintaining, rather than inducing, effect of Fgf8 on Wnt1 expression, an issue that remained unclear from published data. Using mouse anterior neural plate/tube explant cultures, we provide experimental evidence that Fgf8 in fact only maintains but does not induce ectopic Wnt1 expression in these explants. In combination with previously validated interactions, this finding allows for the construction of a regulatory network between key transcription and secreted factors at the MHB. Analyses of Boolean, differential equation and reaction-diffusion models of this network confirm that it is indeed able to explain the stable maintenance of the MHB as well as time-courses of expression patterns both under wild-type and various knock-out conditions. In conclusion, we demonstrate that similar to temporal also spatial expression patterns can be used to gain information about the structure of regulatory networks. We show, in particular, that the spatial gene expression patterns around the MHB help us to understand the maintenance of this boundary on a systems level.
Author Summary
Understanding brain formation during development is a tantalizing challenge. It is also essential for the fight against neurodegenerative diseases. In vertebrates, the central nervous system arises from a structure called the neural plate. This tissue is divided into four regions, which continue to develop into forebrain, midbrain, hindbrain and spinal cord. Interactions between locally expressed genes and signaling molecules are responsible for this patterning. Two key signaling molecules in this process are Fgf8 and Wnt1 proteins. They are secreted from a signaling center located at the boundary between prospective mid- and hindbrain (mid-hindbrain boundary, MHB) and mediate development of these two brain regions. Here, we logically analyze the spatial gene expression patterns at the MHB and predict interactions involved in the differentiation of mid- and hindbrain. In particular, our analysis indicates that Wnt1 depends on Fgf8 for stable maintenance. A time-course analysis of Wnt1 expression after implantation of Fgf8-coated beads in mouse neural plate/tube explants experimentally validates our prediction about the interactions between these two key patterning molecules. Subsequently, we demonstrate that available data allows construction of a mathematical model able to explain the maintenance of the signaling center at the MHB. We begin to understand this small aspect of brain formation on a systems level.
PMCID: PMC2774268  PMID: 19936059
24.  A high throughput messenger RNA differential display screen identifies discrete domains of gene expression and novel patterning processes along the developing neural tube 
During early development the vertebrate neural tube is broadly organized into the forebrain, midbrain, hindbrain and spinal cord regions. Each of these embryonic zones is patterned by a combination of genetic pathways and the influences of local signaling centres. However, it is clear that much remains to be learned about the complete set of molecular cues that are employed to establish the identity and intrinsic neuronal diversity of these territories. In order to address this, we performed a high-resolution messenger RNA differential display screen to identify molecules whose expression is regionally restricted along the anteroposterior (AP) neuraxis during early chick development, with particular focus on the midbrain and hindbrain vesicles.
This approach identified 44 different genes, with both known and unknown functions, whose transcription is differentially regulated along the AP axis. The identity and ontological classification of these genes is presented. The wide variety of functional classes of transcripts isolated in this screen reflects the diverse spectrum of known influences operating across these embryonic regions. Of these 44 genes, several have been selected for detailed in situ hybridization analysis to validate the screen and accurately define the expression domains. Many of the identified cDNAs showed no identity to the current databases of known or predicted genes or ESTs. Others represent genes whose embryonic expression has not been previously reported. Expression studies confirmed the predictions of the primary differential display data. Moreover, the nature of identified genes, not previously associated with regionalisation of the brain, identifies novel potential mechanisms in that process.
This study provides an insight into some of the varied and novel molecular networks that operate during the regionalization of embryonic neural tissue and expands our knowledge of molecular repertoire used during development.
PMCID: PMC1397802  PMID: 16504111
25.  NFIA Haploinsufficiency Is Associated with a CNS Malformation Syndrome and Urinary Tract Defects 
PLoS Genetics  2007;3(5):e80.
Complex central nervous system (CNS) malformations frequently coexist with other developmental abnormalities, but whether the associated defects share a common genetic basis is often unclear. We describe five individuals who share phenotypically related CNS malformations and in some cases urinary tract defects, and also haploinsufficiency for the NFIA transcription factor gene due to chromosomal translocation or deletion. Two individuals have balanced translocations that disrupt NFIA. A third individual and two half-siblings in an unrelated family have interstitial microdeletions that include NFIA. All five individuals exhibit similar CNS malformations consisting of a thin, hypoplastic, or absent corpus callosum, and hydrocephalus or ventriculomegaly. The majority of these individuals also exhibit Chiari type I malformation, tethered spinal cord, and urinary tract defects that include vesicoureteral reflux. Other genes are also broken or deleted in all five individuals, and may contribute to the phenotype. However, the only common genetic defect is NFIA haploinsufficiency. In addition, previous analyses of Nfia−/− knockout mice indicate that Nfia deficiency also results in hydrocephalus and agenesis of the corpus callosum. Further investigation of the mouse Nfia+/− and Nfia−/− phenotypes now reveals that, at reduced penetrance, Nfia is also required in a dosage-sensitive manner for ureteral and renal development. Nfia is expressed in the developing ureter and metanephric mesenchyme, and Nfia+/− and Nfia−/− mice exhibit abnormalities of the ureteropelvic and ureterovesical junctions, as well as bifid and megaureter. Collectively, the mouse Nfia mutant phenotype and the common features among these five human cases indicate that NFIA haploinsufficiency contributes to a novel human CNS malformation syndrome that can also include ureteral and renal defects.
Author Summary
Central nervous system (CNS) and urinary tract abnormalities are common human malformations, but their variability and genetic complexity make it difficult to identify the responsible genes. Analysis of human chromosomal abnormalities associated with such disorders offers one approach to this problem. In five individuals described herein, a novel human syndrome that involves both CNS and urinary tract defects is associated with chromosomal disruption or deletion of NFIA, encoding a member of the Nuclear Factor I (NFI) family of transcription factors. This syndrome includes brain abnormalities (abnormal corpus callosum, hydrocephalus, ventriculomegaly, and Chiari type I malformation), spinal abnormalities (tethered spinal cord), and urinary tract abnormalities (vesicoureteral reflux). Nfia disruption in mice was already known to cause hydrocephalus and abnormal corpus callosum, and is now shown to exhibit renal defects and disturbed ureteral development. Other genes besides NFIA are also disrupted or deleted and may contribute to the observed phenotype. However, loss of one copy of NFIA is the only genetic defect common to all five patients. The authors thus provide evidence that genetic loss of NFIA contributes to a distinct CNS malformation syndrome with urinary tract defects of variable penetrance.
PMCID: PMC1877820  PMID: 17530927

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