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Ultrasonographic and MRI findings in the different type I lissencephaly subtypes: a Ultrasonographic pattern of MDS showing complete agyria with hypoplastic frontal lobes and dysmorphic corpus callosum and septum pellucidum (arrowhead). b, c MRI data in a DCX-mutated fetus displaying lissencephaly with moderate ventricular dilatation but no apparent infratentorial anomalies. d MRI performed at postnatal day 2 in a male newborn with XLAG syndrome, exhibiting pachygyria, more severe in the anterior regions and corpus callosum agenesis but with no infratentorial lesions.
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Type I lissencephaly or agyria-pachygyria is a rare developmental disorder which results from a defect of neuronal migration. It is characterized by the absence of gyri and a thickening of the cerebral cortex and can be associated with other brain and visceral anomalies. Since the discovery of the first genetic cause (deletion of chromosome 17p13.3...
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Citations
... Lissencephaly or "smooth brain" forms a major group of brain malformations that occur because of defective neuronal migration in early pregnancy because of genetic mutations [3]. Apart from genetics, other environmental factors such as hypoxia, infection, radiation, and so on, have a role in the pathogenesis of the disease. ...
Malformations of cortical development (MCD) are a group of disorders affecting the normal development of the human cortex and are significant causes of delay in psychomotor development and epilepsy in children. Lissencephaly (smooth brain) forms a major group of brain malformations. Microtubules help in the migration of neuronal cells. Defect in tubulin gene alpha-tubulin (TUBA), beta-tubulin (TUBB), and gamma-tubulin (TUBG) leads to defective neuronal migration. This group of disorders is termed as "tubulinopathies." The important genes implicated in causing lissencephaly are LIS1, XLIS, and TUBA1A gene. Recently, a mutation in the TUBG1 gene is associated with it. Here, we report a one-and-a-half-year-old girl with global developmental delay, microcephaly, infantile-onset epilepsy, epileptic spasms, dysmorphism, and motor signs. There was no significant birth history. Neuroimaging (MRI) showed a broad thick gyri and a decreased number of sulci suggestive of lissencephaly/pachygyria spectrum. There was dilatation of the ventricles, and no grey matter heterotopia was noted. Sleep EEG showed multifocal epileptiform discharges. The child was treated with multiple anti-seizure medicines (ASMs). A genetic test, whole exome sequencing, was done to determine the etiology of MCD. A heterozygous missense variation in exon 6 of the TUBG1 gene was identified and reported as a “variant of unknown significance.” Still, because the genotype matched with the clinical phenotype of the patient, it was considered clinically significant. Therefore, a complete diagnosis of TUBG1 mutation-associated cortical malformation (lissencephaly/pachygyria) with microcephaly and early-onset epilepsy was established. TUBG1 mutation is de novo in most cases, but parental testing is recommended. The parents of such patients need to be counseled about the need for prenatal testing and the risk of the disease to siblings. The overall prognosis in such cases is poor because of refractory seizures, physical limitations, and intellectual disability.
... There is also associated reduction in patient functional capabilities, learning process, concentration, and social interaction [ 13 ,14 ]. Patients with lissencephaly have poor progno-sis with short life span due to multiple environmental and developmental factors [15] . Our patient was achieving milestones normally when suddenly there was a decline noted in her speech and with the passage of time learning disabilities were observed. ...
Band heterotopia of brain Seizures a b s t r a c t Double cortex syndrome is an uncommon familial syndrome with X-linked dominant inheritance and most commonly presents with developmental delay and seizures. We present a case of a 14-year-old girl who came to neurology department of the hospital with severe generalized tonic-clonic fits and loss of consciousness. The mother of child gave history of uneventful antenatal period and labor. There was history of immediate cry and normal APGAR score. She was achieving milestones normally until at the age of 3 years when she suffered decline in her speech and vision. She had problems with learning with lack of concentration during her schooling. Physical examination was also unremarkable. Her lab values including complete blood count, serum calcium, and arterial blood gas tests, all were within normal limits. Electroencephalogram showed significant changes suggestive of epilepsy. Magnetic resonance imaging of brain showed continuous band of gray matter that was located deep and paralleling the cortex in both cerebral hemispheres suggestive of band heterotopia or double cortex syndrome. She was discharged and prescribed antiepileptics; and was advised regular outpatient follow-up.
... This question needs futher investigation in the future. Centrosomal proteins have been linked to many diseases of brain development (Friocourt et al., 2011). The three most common phenotypes are (i) neural migration disorders; (ii) generalized disorders of growth where the brain and body are both affected, e.g., mutations in PCNT result in microcephalic osteodysplastic primordial dwarfism type II (Griffith et al., 2008;Rauch et al., 2008); (iii) primary microcephalies where the brain alone is affected and significantly reduced in size, which has been discussed in great detail in recent years. ...
... As AJs and cell-cell adhesions ensure the fidelity of neural network development, failures in their assembly and disassembly could underlie the defective neurogenesis and synaptogenesis detected in Arx disease mice (25). Moreover, cytoskeleton, migration and neuronal plasticity-which are among the topranked terms identified in our proteomic datasets-have been functionally linked to the anatomic defects and neuronal migration alterations previously described in ARX patients (29,(67)(68)(69)(70)(71). ...
... Nevertheless, these functions were also linked to the aberrant corticogenesis and defective neuronal maturation detected in Arx mutant brains (17,69,72,73). Related to these evidences, the decreased amount of α-tubulin observed by us in Arx KO/Y and Arx (GCG)7/Y brain could explain the defective connectivity and axonogenesis detected-even if at different level of severity-in Arx mutant mice and ARX patients (17,69,72). ...
... Nevertheless, these functions were also linked to the aberrant corticogenesis and defective neuronal maturation detected in Arx mutant brains (17,69,72,73). Related to these evidences, the decreased amount of α-tubulin observed by us in Arx KO/Y and Arx (GCG)7/Y brain could explain the defective connectivity and axonogenesis detected-even if at different level of severity-in Arx mutant mice and ARX patients (17,69,72). ...
X-linked lissencephaly with abnormal genitalia (XLAG) and developmental epileptic encephalopathy-1 (DEE1) are caused by mutations in the Aristaless-related homeobox (ARX) gene, which encodes a transcription factor responsible of brain development. It has been unknown whether the phenotypically diverse XLAG and DEE1 phenotypes may converge on shared pathways. To address this question, a label-free quantitative proteomic approach was applied to neonatal brain of Arx knockout (ArxKO/Y) and knock-in polyalanine (Arx(GCG)7/Y) mice that are respectively models for XLAG and DEE1. Gene ontology and protein–protein interaction analysis revealed that cytoskeleton, protein synthesis and splicing control are deregulated in an allelic-dependent manner. Decreased α-tubulin content was observed both in Arx mice and Arx/alr-1(KO) C. elegans animals and a disorganized neurite network in murine primary neurons was consistent with an allelic-dependent secondary tubulinopathy. As distinct features of Arx(GCG)7/Y mice, we detected eIF4A2 overexpression and translational suppression in cortex and primary neurons. Allelic-dependent differences were also established in alternative splicing (AS) regulated by PUF60 and SAM68. Abnormal AS repertoires in Neurexin-1, a gene encoding multiple pre-synaptic organizers implicated in synaptic remodelling, were detected in Arx/alr-1(KO) animals and in Arx(GCG)7/Y epileptogenic brain areas and depolarized cortical neurons. Consistent with a conserved role of ARX in modulating AS, we propose that the allelic-dependent secondary synaptopathy results from aberrant Neurexin-1 repertoire. Overall, our data reveal alterations mirroring the overlapping and variant effects caused by null and polyalanine expanded mutations in ARX. The identification of these effects can aid in the design of pathway-guided therapy for ARX-endophenotypes and NDDs with overlapping comorbidities.
... Protein modeling of the identified sites of mutations and cell functional studies suggested that some mutations result in defective interactions in the tubulin heterodimer assembly pathway, while others may alter the three-dimensional conformation of the TUBA1A protein and/or compromise its interaction with microtubule-associated proteins (MAPs) or Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s12035-020-02193-w. microtubule motors such as kinesin [10]. However, because TUBA1A mutations are not clustered in any specific region of the gene, the identification of mechanisms responsible for brain malformations remains challenging. ...
Tubulin α-1 A (TUBA1A) mutations cause a wide spectrum of brain abnormalities. Although many mutations have been identified and functionally verified, there are clearly many more, and the relationship between TUBA1A mutations and brain malformations remains unclear. The aim of this study was to identify a TUBA1A mutation in a fetus with severe brain abnormalities, verify it functionally, and determine the mechanism of the mutation-related pathogenesis. A de novo missense mutation of the TUBA1A gene, c.167C>G p.T56R/P.THR56Arg, was identified by exon sequencing. Computer simulations showed that the mutation results in a disruption of lateral interactions between the microtubules. Transfection of 293T cells with TUBA1A p.T56R showed that the mutated protein is only partially incorporated into the microtubule network, resulting in a decrease in the rate of microtubule re-integration in comparison with the wild-type protein. The mechanism of pathological changes induced by the mutant gene was determined by knockdown and overexpression. It was found that knockdown of TUBA1A reduced the generation of neural progenitor cells, while overexpression of wild-type or mutant TUBA1A promoted neurogenesis. Our identification and functional verification of the novel TUBA1A mutation extends the TUBA1A gene-phenotype database. Loss-of-function of TUBA1A was shown to play an important role in early neurogenesis of TUBA1A mutation-related brain malformations.
... Histologically, classic lissencephaly is characterised by a smooth brain surface with a thick cortex consisting of a reduced number of disorganised cortical neuronal layers. Variations of the microscopic presentation have been described depending on the underlying genetic aetiology [7,8]. ...
... Molecular-histological correlations are often lacking, an exception being the histological spectrum for genes commonly linked to lissencephaly, cobblestone malformations and for a number of tubulin genes [8,12,18]. ...
Aims
Malformations of cortical development (MCD) include a heterogeneous spectrum of clinical, imaging, molecular and histopathological entities. While the understanding of genetic causes of MCD has improved with the availability of next‐generation sequencing modalities, genotype‐histopathological correlations remain limited. This is the first systematic review of molecular and neuropathological findings in patients with MCD to provide a comprehensive overview of the literature.
Methods
A systematic review was performed between November 2019 and February 2020. A MEDLINE search was conducted for 132 genes previously linked to MCD in order to identify studies reporting macroscopic and/or microscopic findings in patients with a confirmed genetic cause.
Results
81 studies were included in this review reporting neuropathological features associated with pathogenic variants in 46 genes (46/132 genes, 34.8%). Four groups emerged, consisting of (1) 13 genes with well‐defined histological‐genotype correlations, (2) 27 genes for which neuropathological reports were limited, (3) 5 genes with conflicting neuropathological features, and (4) 87 genes for which no histological data were available. Lissencephaly and polymicrogyria were reported most frequently. Associated brain malformations were variably present, with abnormalities of the corpus callosum as most common associated feature.
Conclusions
Neuropathological data in patients with MCD with a defined genetic cause is available only for a small number of genes. As each genetic cause might lead to unique histopathological features of MCD, standardized thorough neuropathological assessment and reporting should be encouraged. Histologic features can help improve the understanding of the pathogenesis of MCD and generate hypotheses with impact on further research directions.
... The pathology is characterized by an arrest of neuronal migration reducing the cortex in four pseudo layers (instead of six in healthy conditions). With an outer marginal layer of neurons, a superficial layer of pyramidal neurons, a variable cell sparse layer and a deep cellular layer composed by medium and small-sized neurons (Friocourt et al., 2011;Leventer, 2007). ...
Neocortex development is highly regulated and mutations in genes involved in this process may lead to genetic diseases. Microlissencephaly is a congenital and poorly understood brain malformation characterized by the presence of both microcephaly (small brain) and lissencephaly (smooth brain). Our collaborators recently identified compound heterozygous mutations causing this pathology in the human WD repeat domain 81 (WDR81) gene. WDR81 is a poorly characterized protein involved in endosomal maturation through Pi3K regulation. The goal of my PhD project is to characterize the function of WDR81 in the developing brain, and identify how mutations in this gene may lead to pathological brain development.Using CRISPR/Cas9, I have generated a WDR81 knock-out mouse, which shows strong neuronal migration defects and microcephaly, mimicking the human phenotype. I demonstrated that the reduced brain size was not due to increased apoptosis or altered cell fate, but to reduced neural stem cell proliferation. I also observe this phenotype in patient-derived fibroblasts, altogether suggesting altered processing of proliferative signals. Fluorescent EGF uptake assay reveals a strong intracellular accumulation of EGF in early phases endosomes that fails to be processed and cleared giving as well defects in the activation of the receptor itself. My results indicate that mutant cells indeed poorly respond to EGF stimulation.I then investigated the exciting possibility that reduced brain growth (microcephaly) and increased brain growth (megalencephaly) may represent two sides of the same coin. Because my data point to opposite effects on similar pathways, I overexpressed megalencephaly-causing mutated factors in WDR81 KO brains, and tested whether they were able to rescue the microcephaly-causing proliferation defects. My result show that indeed a megalencephaly-causing mutation can overcome the effect of a microcephaly-causing mutation on the proliferation of radial glial progenitors. These two pathologies can therefore arise from a highly related cause: an imbalance in cell cycle regulation leading either to reduced brain growth or to brain overgrowth.
... Lissencephaly type I refers to a series of neuronal migration disorders, which includes a disorganized cortex either without gyri (agyria), with abnormal and simplified gyri (pachygyria), or featuring abnormally positioned ectopic neurons within the white matter resulting in a 'double cortex' or subcortical band heterotopia phenotype (Romero et al., 2017, see following subsection). It can be caused by mutations in genes coding for microtubule associated proteins such as LIS1, DCX, TUBA1A, TUBB2A and TUBG1 (Bahi-Buisson et al., 2008, Cushion et al., 2013, Des Portes et al., 1998, Des Portes et al., 1998, Fallet-Bianco, et al., 2008, Friocourt et al., 2011, Morris-Rosendalh et al., 2008, 2013, Reiner et al., 1993. Mutations in proteins contributing to the actin cytoskeleton compartment can also lead to lissencephaly type I-like phenotypes. ...
Cerebral cortical development is a finely regulated process, depending on diverse progenitor cells. Abnormal behavior of the latter can give rise to cortical malformations. Mutations in Eml1/EML1 were identified in the HeCo mouse, as well as in three families presenting severe subcortical heterotopia (SH). SH is characterized by the presence of mislocalized neurons in the white matter. At early stages of corticogenesis, abnormally positioned apical radial glia progenitors (aRG) were found cycling outside the proliferative ventricular zone (VZ) in the HeCo cortical wall. I focused my research on characterizing aRG in the VZ to assess why some cells leave this region and thus to further understand SH mechanisms. Combining confocal and electron microscopy (EM), I uncovered abnormalities of centrosomes and primary cilia in Eml1-mutant aRGs: primary cilia are shorter, and often remain basally oriented within vesicles. Searching for Eml1-interacting partners using mass spectrometry (MS), combined with exome sequencing of SH patient DNAs, allowed us to identify a ciliary Eml1-interacting partner, RPGRIP1L, showing mutations in a SH patient. Gene ontology analyses of MS data pointed to Golgi apparatus and protein transport as enriched categories. Indeed, Golgi abnormalities were identified in HeCo aRGs. Altogether, these data indicate that the Golgi-to-primary cilium axis is perturbed in Eml1mutant conditions, pointing to new intracellular pathways involved in severe neurodevelopmental disorders.
... The authors also seek to highlight the ability for an individual with a severely abnormal neurological physiology to be successful in society depending on genetic mosaicism lending residual function and parental involvement in individual success. 1 Genetic variants resulting in lissencephaly are varied in both their specific karyotype location and their phenotypic presentations. 2 The dominant mechanisms by which cortical lamination is disrupted can be due to a failure of neuronal migration, a failure of neuronal path finding, or an imbalance in DNA replication in utero. 3 The 2 main classifications of lissencephaly are therefore defined as either type 1, which is a failure to differentiate the cortex into all of the appropriate 6 layers (instead resulting in 4 layers), or type 2, which is a complete failure to layer the cortex at all. ...
... Mutations in the gene cause the neuronal migration disorders subcortical band heterotopia in females and classic lissencephaly in males. 2 Although lissencephaly can be diagnosed in utero, patients who presented before the popularization of in utero testing and genetic diagnosis will often go undiagnosed until presenting to clinic with behavioral or developmental abnormalities. Although the clinical manifestations of lissencephaly normally present in individuals during early development, the diagnosis of a DCX mutation specifically causing the lissencephaly can be delayed for years or even decades. ...
Doublecortin (DCX) mutations cause abnormal development of the DCX protein that normally aids in neuronal migration during fetal development. These mutations lead to lissencephaly, or the appearance of a “smooth brain,” which is varying levels of pachygyria or agyria in severe cases. Many genetic variants of the mutation have been identified, and an even greater range of phenotypic presentations have been described in the literature. The X-linked lissencephaly (DCX) mutation leads to an X-linked gender-dependent condition that causes subcortical heterotopia in females and lissencephaly in males. The authors report the case of a 13-year-old male who presented to our clinic for new-onset seizure disorder. He had a past medical history of developmental delay and features of autism spectrum disorder which was diagnosed at age 5 years at an outside clinic. Magnetic resonance imaging (MRI) brain at age 5 years showed pachygyria of the frontal and temporal lobes. After extensive genetic testing over the course of over a decade, the patient was found to have a de novo mutation in the DCX gene diagnosed via whole-exome sequencing. Specifically, he was found to have a mosaic mutation of the DCX gene as a c.30-31 deletion. His previous MRI findings were consistent with a diagnosis of X-linked sporadic lissencephaly sequence and included mainly a diffuse bilateral pachygyria (isolated lissencephaly sequence X chromosome). Thickening of the cortex and pachygyria or agyria are classic findings of lissencephaly, but do not help specify any mutation in the gene, of which there are over 70 possibilities. Our patient is unique in that most individuals with DCX mutation have infantile seizures, severe intellectual disability, orthopedic complications, and postnatal microcephaly, which our patient does not have.
... All affected patients showed severe LIS with complete agyria, severe cerebellar hypoplasia and corpus callosal dysgenesis (72). On histopathological examination, a combination of twolayer lamination (similar to that observed in TUBA1Aassociated LIS) and three-layer lamination (reminiscent of ARX-related LIS) was seen (80). ...
Malformations of cortical development (MCD) are a heterogenous group of disorders with diverse genotypic and phenotypic variations. Lissencephaly is a subtype of MCD caused by defect in neuronal migration, which occurs between 12 and 24 weeks of gestation. The continuous advancement in the field of molecular genetics in the last decade has led to identification of at least 19 lissencephaly-related genes, most of which are related to microtubule structural proteins (tubulin) or microtubule-associated proteins (MAPs). The aim of this review article is to bring together current knowledge of gene mutations associated with lissencephaly and to provide a comprehensive genotype-phenotype correlation. Illustrative cases will be presented to facilitate the understanding of the described genotype-phenotype correlation.
