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William B Dobyns - One of the best experts on this subject based on the ideXlab platform.
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Overlapping cortical malformations and mutations in TUBB2B and TUBA1A.
Brain : a journal of neurology, 2013Co-Authors: Thomas D. Cushion, Andrew E. Fry, Neil Stoodley, Ute Hehr, Seo-kyung Chung, William B Dobyns, Jonathan G L Mullins, Roxana Gunny, Arthur S Aylsworth, Prab PrabhakarAbstract:Polymicrogyria and lissencephaly are causally heterogeneous disorders of cortical brain development, with distinct neuropathological and neuroimaging patterns. They can be associated with additional structural cerebral anomalies, and recurrent phenotypic patterns have led to identification of recognizable syndromes. The lissencephalies are usually single-gene disorders affecting neuronal migration during cerebral cortical development. Polymicrogyria has been associated with genetic and environmental causes and is considered a malformation secondary to abnormal post-migrational development. However, the aetiology in many individuals with these cortical malformations is still unknown. During the past few years, mutations in a number of neuron-specific α- and β-tubulin genes have been identified in both lissencephaly and Polymicrogyria, usually associated with additional cerebral anomalies including callosal hypoplasia or agenesis, abnormal basal ganglia and cerebellar hypoplasia. The tubulin proteins form heterodimers that incorporate into microtubules, cytoskeletal structures essential for cell motility and function. In this study, we sequenced the TUBB2B and TUBA1A coding regions in 47 patients with a diagnosis of Polymicrogyria and five with an atypical lissencephaly on neuroimaging. We identified four β-tubulin and two α-tubulin mutations in patients with a spectrum of cortical and extra-cortical anomalies. Dysmorphic basal ganglia with an abnormal internal capsule were the most consistent feature. One of the patients with a TUBB2B mutation had a lissencephalic phenotype, similar to that previously associated with a TUBA1A mutation. The remainder had a Polymicrogyria-like cortical dysplasia, but the grey matter malformation was not typical of that seen in 'classical' Polymicrogyria. We propose that the cortical malformations associated with these genes represent a recognizable tubulinopathy-associated spectrum that ranges from lissencephalic to polymicrogyric cortical dysplasias, suggesting shared pathogenic mechanisms in terms of microtubular function and interaction with microtubule-associated proteins.
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megalencephaly capillary malformation mcap and megalencephaly polydactyly Polymicrogyria hydrocephalus mpph syndromes two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis
American Journal of Medical Genetics Part A, 2012Co-Authors: Ghayda M. Mirzaa, Karen W Gripp, Robert L Conway, Tally Lermansagie, Dawn H Siegel, Linda S Devries, Nancy Kramer, Elizabeth Hopkins, John M Graham, William B DobynsAbstract:The macrocephaly-capillary malformation syndrome (M-CM), which we here propose to rename the megalencephaly-capillary malformation syndrome (MCAP; alternatively the megalencephaly-capillary malformation-Polymicrogyria syndrome), and the more recently described megalencephaly-Polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) are two megalencephaly (MEG) disorders that involve a unique constellation of physical and neuroimaging anomalies. We compare the features in 42 patients evaluated for physical and neuroimaging characteristics of MCAP and MPPH and propose a more global view of these syndromes based on classes of developmental abnormalities that include primary MEG and growth dysregulation, developmental vascular anomalies (primarily capillary malformations), distal limb anomalies (such as syndactyly and polydactyly), cortical brain malformations (most distinctively Polymicrogyria, PMG), and variable connective tissue dysplasia. Based on these classes of developmental abnormalities, we propose that MCAP diagnostic criteria include progressive MEG with either vascular anomalies or syndactyly. In parallel, we propose that MPPH diagnostic criteria include progressive MEG and PMG, absence of the vascular anomalies and syndactyly characteristic of MCAP, and absence of brain heterotopia. © 2012 Wiley Periodicals, Inc.
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Polymicrogyria includes fusion of the molecular layer and decreased neuronal populations but normal cortical laminar organization
Journal of Neuropathology and Experimental Neurology, 2011Co-Authors: Alexander R Judkins, William B Dobyns, Daniel Martinez, Pamela Ferreira, Jeffrey A GoldenAbstract:Malformations of cortical development are frequently identified in surgical resections for intractable epilepsy. Among the more frequently identified are cortical dysplasia, pachygyria, and Polymicrogyria. The pathogenesis of these common developmental anomalies remains uncertain. Polymicrogyria is particularly vexing because there are multiple described forms (2, 4, and 6 layers) that have been attributed to multiple etiologies (e.g. ischemic, genetic, infectious, and toxic). We reviewed the pathology in 19 cases and performed cortical laminar analysis in 10 of these cases. Our data indicate that a defining feature of Polymicrogyriais fusion of the molecular layer and that most often there is a well-defined gray matter-white matter junction. Unexpectedly, the cortical laminae were normally positioned, but there were reduced neuronal populations within these laminae, particularly in the subgranular layers. On the basis of these data, we propose that the categorization of Polymicrogyria according to the number of lamina is artificial and should be abandoned, and Polymicrogyria should be defined according to the presence or absence of coexisting neuropathological features. Furthermore, our data indicate that Polymicrogyria is not a cell migration disorder, rather it should be considered a postmigration malformation of cortical development.
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significant overlap and possible identity of macrocephaly capillary malformation and megalencephaly Polymicrogyria polydactyly hydrocephalus syndromes
American Journal of Medical Genetics Part A, 2009Co-Authors: Karen W Gripp, Tally Lermansagie, Elizabeth Hopkins, Chana Vinkler, Dorit Lev, G Malinger, William B DobynsAbstract:We report on three patients with macrocephaly and Polymicrogyria, and additional anomalies seen in megalencephaly Polymicrogyria-polydactyly hydrocephalus (MPPH) and macrocephaly capillary malformation (MCM) syndromes. Based on their characteristic brain malformations they were originally diagnosed with MPPH. In one patient the phenotype evolved during early infancy, and ultimately resulted in a diagnosis of MCM. A second was prenatally diagnosed with MPPH, but postnatally visualized capillary malformations led to a diagnosis of MCM. In a third, the original MPPH diagnosis was reconsidered after a critical review revealed additional subtle findings suggestive of MCM. Characteristic brain malformations are thought to distinguish between MPPH with perisylvian Polymicrogyria, and MCM with megalencephaly with Chiari 1 malformation. However, Polymicrogyria was reported in a significant number of patients with MCM. Conversely, upon review of imaging studies of patients with MPPH, we noted progressive crowding of the posterior fossa and acquired tonsillar herniation, a process deemed characteristic for MCM. Thus, neither Polymicrogyria nor acquired tonsillar herniation are distinguishing features, and occur in both disorders. In addition to brain abnormalities, shared findings include cognitive impairment, coarse facial features and postaxial polydactyly. Facial nevus flammeus and cutis marmorata are most noticeable in infancy, and ligamentous laxity and redundant soft tissue are somewhat subjective findings. While asymmetric overgrowth is considered typical for MCM, it is not universally present. These variable and subtle findings can be identified in patients with MPPH. We propose that MPPH and MCM may not represent distinct entities and that the term MPPH-CM syndrome be used to describe this spectrum. © 2009 Wiley-Liss, Inc.
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consistent chromosome abnormalities identify novel Polymicrogyria loci in 1p36 3 2p16 1 p23 1 4q21 21 q22 1 6q26 q27 and 21q2
American Journal of Medical Genetics Part A, 2008Co-Authors: William B Dobyns, Ghayda M. Mirzaa, Gary D Clark, Susan L Christian, Kristin Petras, Jessica A Roseberry, Cynthia J Curry, Donna M McdonaldmcginnAbstract:Polymicrogyria is a malformation of cortical development characterized by loss of the normal gyral pattern, which is replaced by many small and infolded gyri separated by shallow, partly fused sulci, and loss of middle cortical layers. The pathogenesis is unknown, yet emerging data supports the existence of several loci in the human genome. We report on the clinical and brain imaging features, and results of cytogenetic and molecular genetic studies in 29 patients with Polymicrogyria associated with structural chromosome rearrangements. Our data map new Polymicrogyria loci in chromosomes 1p36.3, 2p16.1-p23, 4q21.21-q22.1, 6q26-q27, and 21q21.3-q22.1, and possible loci in 1q44 and 18p as well. Most and possibly all of these loci demonstrate incomplete penetrance and variable expressivity. We anticipate that these data will serve as the basis for ongoing efforts to identify the causal genes located in these regions.
A. J. Barkovich - One of the best experts on this subject based on the ideXlab platform.
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MRI analysis of sulcation morphology in Polymicrogyria
Epilepsia, 2010Co-Authors: A. J. BarkovichAbstract:Polymicrogyria (PMG) is a malformation of cortical development in which the process of normal cortical development is interrupted during the late stages of neuronal migration and during the stages of cortical organization; the result is the abnormal development of the deeper layers of the cerebral cortex and the formation of multiple small gyri. Patients with Polymicrogyria may present with developmental delay, focal neurologic signs and symptoms, or epilepsy, depending upon the portion(s) of brain involved. Affected patients may be micro-, normo-, or macrocephalic (Dobyns et al., 2008). Polymicrogyria may be associated with congenital infection (Barkovich and Linden, 1994, Wright et al., 1997), in utero ischemia (Hallervorden, 1949), or chromosomal mutations (Kuzniecky, 1994, Bingham et al., 1998, Leventer et al., 2001, Piao et al., 2002, Villard et al., 2002, Roll et al., 2006, Dobyns et al., 2008). No difference in neurologic manifestations has been detected in patients who have Polymicrogyria of different causes (Guerrini et al., 1992, Barkovich and Linden, 1994, Barkovich and Kjos, 1992), but the severity of the clinical presentation depends upon the extent of cortical involvement; bilateral involvement and involvement of more than half of a single hemisphere are poor prognostic indicators, portending moderate to severe developmental delay and significant motor dysfunction (Barkovich and Kjos, 1992). Polymicrogyria has a range of histologic appearances, all having in common a derangement of the normal six-layered lamination of the cortex (Evrard et al., 1989), with an associated derangement of sulcation. Thus, it would seem likely that the gross morphologic appearance of Polymicrogyria might vary, as well, perhaps depending upon the underlying cause or the pattern of distribution of the anomalous sulcation within the brain. However, this topic has not heretofore been addressed in the literature. We report the imaging characteristics of a large number of patients with Polymicrogyria and attempt to determine specific sulcation patterns and their variability.
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Polymicrogyria without porencephaly schizencephaly mri analysis of the spectrum and the prevalence of macroscopic findings in the clinical population
Neuroradiology, 2002Co-Authors: N. Hayashi, Y. Tsutsumi, A. J. BarkovichAbstract:Although the diagnosis of Polymicrogyria currently depends largely on non-invasive imaging, no large imaging-based studies of Polymicrogyria have been reported. Previous anatomic studies of Polymicrogyria have been based on autopsy studies and most of the cases in those series were associated with porencephaly or schizencephaly. This retrospective MRI analysis of a group of patients with Polymicrogyria, without associated porencephaly or schizencephaly, was conducted to elucidate gross morphological findings of Polymicrogyria in a clinical population. Seventy-one patients with Polymicrogyria diagnosed by MRI were reviewed by two radiologists. The location of Polymicrogyria, the associated white matter anomalies and other associated central nervous system anomalies were assessed. The Polymicrogyria was unilateral in 30 (42%) patients, bilateral in 41 (58%) patients. The lobes involved in Polymicrogyria were frontal 69%, parietal 63%, temporal 38%, and occipital 7%. The cortex in the Sylvian fissures was involved in 80%. The striate cortex, cingulate gyrus, hippocampus and the gyrus rectus were often spared. Diminished volume of white matter was noted in 48%, perivascular space dilatation in 27% and large cortical veins in 51%. Polymicrogyria develops in specific topological regions, the majority being centered around the Sylvian fissures, and a minority in the inferior and medial aspects of the cerebral hemispheres or the occipital lobes. Diminished volume of the white matter and dilated perivascular spaces deeply embedded close to the dysplastic cortex and abnormal cortical venous enlargement superficial to the dysplastic cortex may be useful adjuncts in making the diagnosis.
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Syndromes of bilateral symmetrical Polymicrogyria.
AJNR. American journal of neuroradiology, 1999Co-Authors: A. J. Barkovich, Robert F. Hevner, Renzo GuerriniAbstract:BACKGROUND AND PURPOSE: A number of anatomicoclinical syndromes have been described in which bilateral symmetrical Polymicrogyria is the underlying morphologic abnormality. We retrospectively reviewed the clinical, epileptic, and morphologic manifestations of bilateral symmetrical Polymicrogyria in 21 patients to determine whether certain areas are at particular risk for these syndromes. METHODS: Clinical records and brain MR studies of 21 patients with bilateral symmetrical Polymicrogyria were reviewed to confirm the presence and determine the location of Polymicrogyria and to qualitatively correlate location with developmental, neurologic, and epileptic histories. The locations we found were compared with published reports of bilateral symmetrical Polymicrogyria to determine whether these locations were random or whether predilections exist for certain areas. RESULTS: Analysis revealed six patients with bilateral frontal Polymicrogyria, nine with bilateral perisylvian Polymicrogyria, one with bilateral parietal Polymicrogyria, one with bilateral parasagittal parieto-occipital Polymicrogyria, two with bilateral frontal Polymicrogyria and bilateral perisylvian Polymicrogyria, one with bilateral perisylvian and bilateral parasagittal parieto-occipital Polymicrogyria, and one with bilateral perisylvian, bilateral parieto-occipital, and bilateral parasagittal parieto-occipital Polymicrogyria. Symptom complexes were nonspecific, but seemed additive according to the regions of brain involved. CONCLUSION: Bilateral symmetrical Polymicrogyria has a propensity to develop in specific regions of the cerebral cortex. When the regions are extensive, the areas involved often appear to be simple topological additions of those regions. These locations and the identification of several familial cases raise the possibility that genetic mechanisms influence the development of these malformations in some patients.
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Correlation of prenatal events with the development of Polymicrogyria.
American Journal of Neuroradiology, 1995Co-Authors: A. J. Barkovich, Howard A. Rowley, Andrew W. BollenAbstract:We report two cases of Polymicrogyria in which maternal insults were well documented during the first half of the second trimester of pregnancy. The clinical histories, MR studies, and, in one patient, autopsy results were carefully reviewed, and the timing and nature of the injuries correlated with known developmental events at the time of the injury. Our results support the theory that Polymicrogyria results from injury to, or disruption of normal cellular interactions at, the external limiting membrane (the "glial-pial barrier").
Karine Poirier - One of the best experts on this subject based on the ideXlab platform.
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Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly
Acta Neuropathologica Communications, 2014Co-Authors: Catherine Fallet-bianco, Laurence Loeuillet, Ferechte Razavi, Patrícia Dias, Cherif Beldjord, Karine Poirier, Fabien Guimiot, Karine Lascelles, Annie Laquerriere, Nathalie CarionAbstract:Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as “Tubulinopathies”. To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2–3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was Polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized Polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but Polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either Polymicrogyria (4/6) or microlissencephaly (2/6).
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The Wide Spectrum of Tubulinopathies: What Are the Key Features for the Diagnosis?
Brain, 2014Co-Authors: Nadia Bahi-buisson, Karine Poirier, Nathalie Boddaert, Yoann Saillour, Stéphanie Valence, Franck J. Fourniol, Nicolas Lebrun, Marie Hully, Catherine Fallet Bianco, Caroline ElieAbstract:Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5%), 18 in TUBB2B (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). No mutations were identified in TUBA8. Systematic review of patients' neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and Polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized Polymicrogyria-like cortical dysplasia (n = 6); and (v) a 'simplified' gyral pattern with area of focal Polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75% of cases) and are present in 100% of central pachygyria and Polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40%), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype-genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant Polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal Polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern.
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Focal Polymicrogyria are associated with submicroscopic chromosomal rearrangements detected by CGH microarray analysis.
European journal of medical genetics, 2012Co-Authors: Chloé Quélin, Cherif Beldjord, Karine Poirier, Nathalie Boddaert, Yoann Saillour, Agathe Roubertie, Isabelle Desguerre, Frank Letourneur, Jamel Chelly, Nadia Bahi-buissonAbstract:Abstract Polymicrogyria is a relatively common cortical malformation characterized by multiple small gyri with abnormal cortical lamination. The pathophysiological bases are heterogeneous and include extrinsic factors and genetic causes. Recent data has emphasized the high prevalence of chromosomal rearrangements in bilateral and mainly perisylvian Polymicrogyria in the context of multiple congenital abnormalities. We present here two cases of rare submicroscopic abnormalities ascertained by array-comparative genome hybridization screening of 18 patients with Polymicrogyria. The first patient is an 11 year-old female with developmental delay, behavioural disturbance, postnatal microcephaly, focal seizures and temporo-occipital Polymicrogyria. She presented a 7.2 Mb terminal deletion in the 6q27 region. The second patient is a 3 year-old boy with psychomotor retardation, spastic diplegia and right temporal Polymicrogyria who presented a 3 Mb duplication in the 22q11.2 region. These two patients exhibited focal temporal or occipital Polymicrogyria without additional brain malformations or multiple congenital abnormalities. This data suggest that patients with Polymicrogyria, even focal and/or unilateral and isolated forms, should be screened for submicroscopic chromosomal rearrangements using array-CGH.
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GPR56-related bilateral frontoparietal Polymicrogyria: further evidence for an overlap with the cobblestone complex
Brain - A Journal of Neurology, 2010Co-Authors: Nadia Bahi-buisson, Catherine Fallet-bianco, Karine Poirier, Nathalie Boddaert, Karine Lascelles, Caroline Elie, Nicola Specchio, Enrico Bertini, Okay Caglayan, Jérôme RambaudAbstract:GPR56 mutations cause an autosomal recessive Polymicrogyria syndrome that has distinctive radiological features combining bilateral frontoparietal Polymicrogyria, white matter abnormalities and cerebellar hypoplasia. Recent investigations of a GPR56 knockout mouse model suggest that bilateral bifrontoparietal Polymicrogyria shares some features of the cobblestone brain malformation and demonstrate that loss of GPR56 leads to a dysregulation of the maintenance of the pial basement membrane integrity in the forebrain and the rostral cerebellum. In light of these findings and other data in the literature, this study aimed to refine the clinical features with the first description of a foetopathological case and to define the range of cobblestone-like features in GPR56 bilateral bifrontoparietal Polymicrogyria in a sample of 14 patients.
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GPR56-related bilateral frontoparietal Polymicrogyria: further evidence for an overlap with the cobblestone complex
Brain : a journal of neurology, 2010Co-Authors: Nadia Bahi-buisson, Catherine Fallet-bianco, Karine Poirier, Nathalie Boddaert, Karine Lascelles, Caroline Elie, Nicola Specchio, Enrico Bertini, Okay Caglayan, Jérôme RambaudAbstract:GPR56 mutations cause an autosomal recessive Polymicrogyria syndrome that has distinctive radiological features combining bilateral frontoparietal Polymicrogyria, white matter abnormalities and cerebellar hypoplasia. Recent investigations of a GPR56 knockout mouse model suggest that bilateral bifrontoparietal Polymicrogyria shares some features of the cobblestone brain malformation and demonstrate that loss of GPR56 leads to a dysregulation of the maintenance of the pial basement membrane integrity in the forebrain and the rostral cerebellum. In light of these findings and other data in the literature, this study aimed to refine the clinical features with the first description of a foetopathological case and to define the range of cobblestone-like features in GPR56 bilateral bifrontoparietal Polymicrogyria in a sample of 14 patients. We identified homozygous GPR56 mutations in 14 patients from eight consanguineous families with typical bilateral bifrontoparietal Polymicrogyria and in one foetal case, out of 30 patients with bifrontoparietal Polymicrogyria referred for molecular screening. The foetal case, which was terminated at 35 weeks of gestation in view of suspicion of Walker Warburg syndrome, showed a cobblestone-like lissencephaly with a succession of normal, polymicrogyric and 'cobblestone-like' cortex with ectopic neuronal overmigration, agenesis of the cerebellar vermis and hypoplastic cerebellar hemispheres with additional neuronal overmigration in the pons and the cerebellar cortex. The 14 patients with GPR56 mutations (median 8.25 years, range 1.5-33 years) were phenotypically homogeneous with a distinctive clinical course characterized by pseudomyopathic behaviour at onset that subsequently evolved into severe mental and motor retardation. Generalized seizures (12/14) occurred later with onset ranging from 2.5 to 10 years with consistent electroencephalogram findings of predominantly anterior bursts of low amplitude α-like activity. Neuroimaging demonstrated a common phenotype with bilateral frontoparietally predominant Polymicrogyria (13/13), cerebellar dysplasia with cysts mainly affecting the superior vermis (11/13) and patchy to diffuse myelination abnormalities (13/13). Additionally, the white matter abnormalities showed a peculiar evolution from severe hypomyelination at 4 months to patchy lesions later in childhood. Taken as a whole, these observations collectively demonstrate that GPR56 bilateral bifrontoparietal Polymicrogyria combines all the features of a cobblestone-like lissencephaly and also suggest that GRP56-related defects produce a phenotypic continuum ranging from bilateral bifrontoparietal Polymicrogyria to cobblestone-like lissencephaly.
Nadia Bahi-buisson - One of the best experts on this subject based on the ideXlab platform.
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Bilateral frontoparietal Polymicrogyria.
Indian journal of pediatrics, 2014Co-Authors: Puneet Jain, Cherif Beldjord, Nadia Bahi-buisson, Suvasini Sharma, Satinder AnejaAbstract:Two male siblings, aged 4.5 and 10 y respectively, of a nonconsanguinous family, presented with delayed milestones and epilepsy. The older sibling had frequent seizures since 7 y of age. Seizures were generalized-tonic-clonic and were poorly controlled on valproate, phenytoin and clobazam. His younger sibling had seizures (myoclonic and generalized tonicclonic) since 2.5 y of age with partial response to valproate, levetiracetam and clobazam. The inter-ictal EEG showed multifocal epileptiform discharges in the older sibling and infrequent bilateral frontal spike-wave-discharges in the younger sibling. The examination of both the siblings revealed a normal head circumference, bilateral esotropia, pseudobulbar palsy andmild spasticity. Magnetic-Resonance-Imaging of the brain is shown as Fig. 1. One female sibling died (probable aspiration) at 3 y of age. She had global-developmental-delay and spasticity but no seizures. She was not investigated. There are three other female siblings who are alive and healthy. All coding exons 2–14 and exon/intron junctions in the gene GPR56 were sequenced. Both the siblings showed homozygous nucleotide mutation c.739_745 del (CAGGACC) leading to a protein variation p. Q247Cfs74. Both the parents were heterozygous for the same mutation. Polymicrogyria is a malformation-of-cortical-development characterized by excessive gyration and abnormal cortical structure and lamination. The various regional Polymicrogyria syndromes reported include bilateral perisylvian Polymicrogyria, bilateral frontal Polymicrogyria, bilateral frontoparietal Polymicrogyria (BFPP), bilateral parasagittal parietooccipital Polymicrogyria and unilateral multilobar Polymicrogyria [1]. BFPP is a recently described entity caused by mutations in G protein-coupled receptor 56 gene (GPR56). It has been rarely reported from India [2]. GPR56 gene may be critical for the preplate neurons, which are the earliest born neurons in the cortex with roles in cortical development and patterning [3]. Most patients present in infancy with severe hypotonia, ‘pseudomyopathic’ presentation and strabismus with normal serum creatine kinase levels. They later exhibit mental and motor retardation with pyramidal signs, epilepsy, language impairment, cerebellar signs and eye movement abnormalities. The neuroimaging shows bilateral Polymicrogyria with P. Jain : S. Sharma : S. Aneja Division of Pediatric Neurology, Department of Pediatrics, Lady HardingeMedical College and Associated Kalawati Saran Children’s Hospital, New Delhi, India
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The Wide Spectrum of Tubulinopathies: What Are the Key Features for the Diagnosis?
Brain, 2014Co-Authors: Nadia Bahi-buisson, Karine Poirier, Nathalie Boddaert, Yoann Saillour, Stéphanie Valence, Franck J. Fourniol, Nicolas Lebrun, Marie Hully, Catherine Fallet Bianco, Caroline ElieAbstract:Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5%), 18 in TUBB2B (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). No mutations were identified in TUBA8. Systematic review of patients' neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and Polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized Polymicrogyria-like cortical dysplasia (n = 6); and (v) a 'simplified' gyral pattern with area of focal Polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75% of cases) and are present in 100% of central pachygyria and Polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40%), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype-genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant Polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal Polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern.
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Focal Polymicrogyria are associated with submicroscopic chromosomal rearrangements detected by CGH microarray analysis.
European journal of medical genetics, 2012Co-Authors: Chloé Quélin, Cherif Beldjord, Karine Poirier, Nathalie Boddaert, Yoann Saillour, Agathe Roubertie, Isabelle Desguerre, Frank Letourneur, Jamel Chelly, Nadia Bahi-buissonAbstract:Abstract Polymicrogyria is a relatively common cortical malformation characterized by multiple small gyri with abnormal cortical lamination. The pathophysiological bases are heterogeneous and include extrinsic factors and genetic causes. Recent data has emphasized the high prevalence of chromosomal rearrangements in bilateral and mainly perisylvian Polymicrogyria in the context of multiple congenital abnormalities. We present here two cases of rare submicroscopic abnormalities ascertained by array-comparative genome hybridization screening of 18 patients with Polymicrogyria. The first patient is an 11 year-old female with developmental delay, behavioural disturbance, postnatal microcephaly, focal seizures and temporo-occipital Polymicrogyria. She presented a 7.2 Mb terminal deletion in the 6q27 region. The second patient is a 3 year-old boy with psychomotor retardation, spastic diplegia and right temporal Polymicrogyria who presented a 3 Mb duplication in the 22q11.2 region. These two patients exhibited focal temporal or occipital Polymicrogyria without additional brain malformations or multiple congenital abnormalities. This data suggest that patients with Polymicrogyria, even focal and/or unilateral and isolated forms, should be screened for submicroscopic chromosomal rearrangements using array-CGH.
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GPR56-related bilateral frontoparietal Polymicrogyria: further evidence for an overlap with the cobblestone complex
Brain - A Journal of Neurology, 2010Co-Authors: Nadia Bahi-buisson, Catherine Fallet-bianco, Karine Poirier, Nathalie Boddaert, Karine Lascelles, Caroline Elie, Nicola Specchio, Enrico Bertini, Okay Caglayan, Jérôme RambaudAbstract:GPR56 mutations cause an autosomal recessive Polymicrogyria syndrome that has distinctive radiological features combining bilateral frontoparietal Polymicrogyria, white matter abnormalities and cerebellar hypoplasia. Recent investigations of a GPR56 knockout mouse model suggest that bilateral bifrontoparietal Polymicrogyria shares some features of the cobblestone brain malformation and demonstrate that loss of GPR56 leads to a dysregulation of the maintenance of the pial basement membrane integrity in the forebrain and the rostral cerebellum. In light of these findings and other data in the literature, this study aimed to refine the clinical features with the first description of a foetopathological case and to define the range of cobblestone-like features in GPR56 bilateral bifrontoparietal Polymicrogyria in a sample of 14 patients.
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GPR56-related bilateral frontoparietal Polymicrogyria: further evidence for an overlap with the cobblestone complex
Brain : a journal of neurology, 2010Co-Authors: Nadia Bahi-buisson, Catherine Fallet-bianco, Karine Poirier, Nathalie Boddaert, Karine Lascelles, Caroline Elie, Nicola Specchio, Enrico Bertini, Okay Caglayan, Jérôme RambaudAbstract:GPR56 mutations cause an autosomal recessive Polymicrogyria syndrome that has distinctive radiological features combining bilateral frontoparietal Polymicrogyria, white matter abnormalities and cerebellar hypoplasia. Recent investigations of a GPR56 knockout mouse model suggest that bilateral bifrontoparietal Polymicrogyria shares some features of the cobblestone brain malformation and demonstrate that loss of GPR56 leads to a dysregulation of the maintenance of the pial basement membrane integrity in the forebrain and the rostral cerebellum. In light of these findings and other data in the literature, this study aimed to refine the clinical features with the first description of a foetopathological case and to define the range of cobblestone-like features in GPR56 bilateral bifrontoparietal Polymicrogyria in a sample of 14 patients. We identified homozygous GPR56 mutations in 14 patients from eight consanguineous families with typical bilateral bifrontoparietal Polymicrogyria and in one foetal case, out of 30 patients with bifrontoparietal Polymicrogyria referred for molecular screening. The foetal case, which was terminated at 35 weeks of gestation in view of suspicion of Walker Warburg syndrome, showed a cobblestone-like lissencephaly with a succession of normal, polymicrogyric and 'cobblestone-like' cortex with ectopic neuronal overmigration, agenesis of the cerebellar vermis and hypoplastic cerebellar hemispheres with additional neuronal overmigration in the pons and the cerebellar cortex. The 14 patients with GPR56 mutations (median 8.25 years, range 1.5-33 years) were phenotypically homogeneous with a distinctive clinical course characterized by pseudomyopathic behaviour at onset that subsequently evolved into severe mental and motor retardation. Generalized seizures (12/14) occurred later with onset ranging from 2.5 to 10 years with consistent electroencephalogram findings of predominantly anterior bursts of low amplitude α-like activity. Neuroimaging demonstrated a common phenotype with bilateral frontoparietally predominant Polymicrogyria (13/13), cerebellar dysplasia with cysts mainly affecting the superior vermis (11/13) and patchy to diffuse myelination abnormalities (13/13). Additionally, the white matter abnormalities showed a peculiar evolution from severe hypomyelination at 4 months to patchy lesions later in childhood. Taken as a whole, these observations collectively demonstrate that GPR56 bilateral bifrontoparietal Polymicrogyria combines all the features of a cobblestone-like lissencephaly and also suggest that GRP56-related defects produce a phenotypic continuum ranging from bilateral bifrontoparietal Polymicrogyria to cobblestone-like lissencephaly.
Pascale Bomont - One of the best experts on this subject based on the ideXlab platform.
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Mutations in the β-tubulin gene TUBB2B result in asymmetrical Polymicrogyria
Nature Genetics, 2009Co-Authors: Xavier Hubert Jaglin, Catherine Fallet-bianco, Karine Poirier, Nadia Bahi-buisson, Yoann Saillour, Emmanuelle Buhler, Guoling Tian, Françoise Phan-dinh-tuy, Xiang Peng Kong, Pascale BomontAbstract:Jamel Chelly and colleagues report that de novo mutations in TUBB2B , encoding a β-tubulin, are associated with asymmetrical Polymicrogyria and other brain malformations. They also show that in utero knockdown of Tubb2b in rat results in defective neuronal migration. Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a β-tubulin gene, TUBB2B , in four individuals and a 27-gestational-week fetus with bilateral asymmetrical Polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly and pachygyria, but also Polymicrogyria malformations.
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Mutations in the beta-tubulin gene TUBB2B result in asymmetrical Polymicrogyria.
Nature Genetics, 2009Co-Authors: Xavier Hubert Jaglin, Catherine Fallet-bianco, Karine Poirier, Nadia Bahi-buisson, Yoann Saillour, Emmanuelle Buhler, Guoling Tian, Françoise Phan-dinh-tuy, Xiang Peng Kong, Pascale BomontAbstract:Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical Polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly and pachygyria, but also Polymicrogyria malformations.
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Mutations in the [beta]-tubulin gene TUBB2B result in asymmetrical Polymicrogyria
Nature genetics, 2009Co-Authors: Xavier Hubert Jaglin, Catherine Fallet-bianco, Karine Poirier, Nadia Bahi-buisson, Yoann Saillour, Emmanuelle Buhler, Guoling Tian, Françoise Phan-dinh-tuy, Xiang Peng Kong, Pascale BomontAbstract:Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a b-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical Polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly and pachygyria, but also Polymicrogyria malformations. The crucial role of the tubulin superfamily in diverse cellular processes 1 and the association of TUBA1A mutations with a broad