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1.
Eur J Med Genet ; 61(12): 759-764, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30268909

RESUMO

The advent of next generation sequencing has improved gene discovery in neurodevelopmental disorders. A greater understanding of the genetic basis of these disorders has expanded the spectrum of pathogenic genes, thus enhancing diagnosis and therapeutic management. Genetic overlap between distinct neurodevelopmental disorders has also been revealed, which can make determining a strict genotype-phenotype correlation more difficult. Intellectual disability and cortical malformations are two neurodevelopmental disorders particularly confronted by this difficulty. Indeed, for a given pathogenic gene, intellectual disability can be associated, or not, with cortical malformations. Here, we report for the first time, two individuals with the same de novo mutation in TBR1, leading to a frameshift starting at codon Thr532, and resulting in a premature stop codon 143 amino acids downstream (c.1588_1594dup, p.(Thr532Argfs*144)). These individuals presented with a developmental encephalopathy characterized by frontal pachygyria and severe intellectual disability. Remarkably, 11 TBR1 gene mutations were previously reported in intellectual disability and autism spectrum disorders. Our study supports the observation that TBR1-related disorders range from intellectual disability to frontal pachygyria. We also highlight the need for first-line, good quality neuroimaging for patients with intellectual disability.

2.
Eur J Med Genet ; 61(12): 765-772, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30315939

RESUMO

Mutations in COL4A1 have been reported in schizencephaly and porencephaly combined with microbleeds or calcifications, often associated with ocular and renal abnormalities, myopathy, elevated creatine kinase levels and haemolytic anaemia. In this study, we aimed to clarify the phenotypic spectrum of COL4A1/A2 mutations in the context of cortical malformations that include schizencephaly, polymicrogyria and/or heterotopia. METHODS: We screened for COL4A1/A2 mutations in 9 patients with schizencephaly and/or polymicrogyria suspected to be caused by vascular disruption and leading to a cerebral haemorrhagic ischaemic event. These included 6 cases with asymmetrical or unilateral schizencephaly and/or polymicrogyria and 3 cases with bilateral schizencephaly. RESULTS: One de novo missense COL4A1 mutation (c.3715 G > A, p.(Gly1239Arg)) and two COL4A2 mutations were found, respectively in one familial case (c.4129G > A, p.(Gly1377Arg)) and one sporadic patient (c.1776+1G > A). In three other cases, COL4A1 variants of unknown significance were identified. None of our patients demonstrated neuromuscular or hematological anomalies. Brain malformations included a combination of schizencephaly, mainly asymmetrical, with porencephaly or ventriculomegaly (3/3 mutated patients). We did not observe microbleeds or microcalcifications in any of our cases, hence we do not believe that they represent a distinctive feature of COL4A1/A2 mutations. CONCLUSIONS: Our study further emphasizes the need to search for both COL4A1 and COL4A2 mutations in children presenting with uni- or bilateral polymicrogyria with schizencephaly, even in the absence of intracranial microbleeds, calcification or associated systemic features.

3.
Eur J Med Genet ; 61(12): 755-758, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30121372

RESUMO

Autosomal recessive missense Rotatin (RTTN) mutations are responsible for syndromic forms of malformation of cortical development, ranging from isolated polymicrogyria to microcephaly associated with primordial dwarfism and other major malformations. We identified, by trio based whole exome sequencing, a homozygous missense mutation in the RTTN gene (c.2953A > G; p.(Arg985Gly)) in one Moroccan patient from a consanguineous family. The patient showed early onset primary microcephaly, detected in the fetal period, postnatal growth restriction, encephalopathy with hyperkinetic movement disorders and self-injurious behavior with sleep disturbance. Brain MRI showed an extensive dysgyria associated with nodular heterotopia, large interhemispheric arachnoid cyst and corpus callosum hypoplasia.

4.
Eur J Med Genet ; 61(12): 729-732, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29758293

RESUMO

Postnatal microcephaly comprises a heterogeneous group of neurodevelopmental disorders of varying severity, characterized by normal head size at birth, followed by a postnatal deceleration in head circumference of greater than 3 standard deviations (SD) below the mean. Many postnatal microcephaly syndromes are caused by mutations in genes known to be important for the regulation of gene expression in the developing forebrain. We studied a consanguineous Pakistani family with postnatal microcephaly, orofacial dyskinesia, spastic quadriplegia and, on MRI, cortical atrophy with myelination delay, suggestive of a FOXG1-like presentation. Using trio-based exome sequencing, we identified a homozygous missense mutation in the Transducin-like enhancer of split-1 (TLE1) gene, encoding for a non DNA-binding transcriptional corepressor, highly expressed in the postnatal brain. The regulation of the post-mitotic neural survival activity of TLE1 depends critically on an interaction with FOXG1, a gene shown to be involved in a postnatal microcephaly syndrome. Functional analysis on affected dermal fibroblasts showed a significant decrease in mitotic and proliferative index, indicating a lengthening of the cell cycle and a delay in mitosis, supporting that this gene could be a new candidate for postnatal microcephaly.

5.
Brain ; 140(10): 2597-2609, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28969387

RESUMO

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.


Assuntos
Fibroblastos/citologia , Microcefalia/genética , Microcefalia/patologia , Mitose/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Células-Tronco Neurais/citologia , Animais , Animais Geneticamente Modificados , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Células Cultivadas , Pré-Escolar , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Feminino , Fibroblastos/patologia , Regulação da Expressão Gênica/genética , Humanos , Antígeno Ki-67/metabolismo , Masculino , Microcefalia/diagnóstico por imagem , Células-Tronco Neurais/patologia , Interferência de RNA/fisiologia , Adulto Jovem
6.
J Neuropathol Exp Neurol ; 76(3): 195-205, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28395088

RESUMO

Dyneins play a critical role in a wide variety of cellular functions such as the movement of organelles and numerous aspects of mitosis, making it central player in neocortical neurogenesis and migration. Recently, cytoplasmic dynein-1, heavy chain-1 (DYNC1H1) mutations have been found to cause a wide spectrum of brain cortical malformations. We report on the detailed neuropathological features of brain lesions from 2 fetuses aged 36 and 22 weeks of gestation (WG), respectively, carrying de novo DYNC1H1 mutations, p.Arg2720Lys and p.Val3951Ala and presenting the most severe phenotype reported to date. Analysis using the Dictyostelium discoideum dynein motor crystal structure showed that the mutations are both predicted to have deleterious consequences on the function of the motor domain. Both fetuses showed a similar macroscopic and histological brain malformative complex associating bilateral fronto-parietal polymicrogyria (PMG), dysgenesis of the corpus callosum and of the cortico-spinal tracts, along with brainstem and cerebellar abnormalities. Both exhibited extremely severe disrupted cortical lamination. Immunohistochemical studies provided the evidence for defects in cell proliferation and postmitotic neuroblast ability to exit from the subventricular zone resulting in a failure of radial migration toward the cortical plate, thus providing new insights for the understanding of the pathophysiology in these cortical malformations.


Assuntos
Encéfalo/anormalidades , Encéfalo/patologia , Dineínas do Citoplasma/genética , Mutação/genética , Fenótipo , Adulto , Técnicas de Cultura de Células , Feminino , Feto , Humanos , Neuropatologia , Gravidez , Estrutura Secundária de Proteína
7.
Am J Med Genet A ; 173(3): 706-711, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28168853

RESUMO

EPG5-related Vici syndrome is a rare multisystem autosomal recessive disorder characterized by corpus callosum agenesis (ACC), hypopigmentation, cataracts, acquired microcephaly, failure to thrive, cardiomyopathy and profound developmental delay, and immunodeficiency. We report here the first case of prenatally diagnosed Vici syndrome with delayed gyration associated with ACC. Trio based exome sequencing allowed the identification of a compound heterozygous mutation in the EPG5 gene. Our patient subsequently demonstrated severe developmental delay, hypopigmentation, progressive microcephaly, and failure to thrive which led to suspicion of the diagnosis. Her MRI demonstrated ACC with frontoparietal polymicrogyria, severe hypomyelination, and pontocerebellar atrophy. This prenatal presentation of malformations of cortical development in combination with ACC expands the EPG5-related phenotypic spectrum. Our report supports the idea that EPG5-related Vici syndrome is both a neurodevelopmental and neurodegenerative disorder. © 2017 Wiley Periodicals, Inc.


Assuntos
Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/genética , Mutação , Fenótipo , Polimicrogiria/diagnóstico , Polimicrogiria/genética , Proteínas/genética , Exoma , Feminino , Estudos de Associação Genética , Testes Genéticos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imagem por Ressonância Magnética , Masculino , Gravidez , Diagnóstico Pré-Natal , Ultrassonografia
9.
Neurogenetics ; 18(2): 73-79, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27747449

RESUMO

Kinesins play a critical role in the organization and dynamics of the microtubule cytoskeleton, making them central players in neuronal proliferation, neuronal migration, and postmigrational development. Recently, KIF2A mutations were identified in cortical malformation syndromes associated with microcephaly. Here, we detected two de novo p.Ser317Asn and p.His321Pro mutations in KIF2A in two patients with lissencephaly and microcephaly. In parallel, we re-evaluated the two previously reported cases showing de novo mutations of the same residues. The identification of mutations only in the residues Ser317 and His321 suggests these are hotspots for de novo mutations. Both mutations lead to a classic form of lissencephaly, with a posterior to anterior gradient, almost indistinguishable from LIS1-related lissencephaly. However, three fourths of patients also showed variable congenital and postnatal microcephaly, up to -5 SD. Located in the motor domain of the KIF2A protein, the Ser317 and His321 alterations are expected to disrupt binding or hydrolysis of ATP and consequently the MT depolymerizing activity. This report also establishes that KIF2A mutations represent significant causes of classic lissencephaly with microcephaly.


Assuntos
Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Cinesina/genética , Mutação de Sentido Incorreto , Adolescente , Análise Mutacional de DNA , Feminino , Frequência do Gene , Humanos , Lactente , Lisencefalia/genética , Masculino , Polimorfismo de Nucleotídeo Único
10.
Eur J Med Genet ; 59(4): 249-56, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26732629

RESUMO

Tubulinopathies are increasingly emerging major causes underlying complex cerebral malformations, particularly in case of microlissencephaly often associated with hypoplastic or absent corticospinal tracts. Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. We report on an early foetal case with FADS and microlissencephaly due to TUBB2B mutation. Neuropathological examination disclosed virtually absent cortical lamination, foci of neuronal overmigration into the leptomeningeal spaces, corpus callosum agenesis, cerebellar and brainstem hypoplasia and extremely severe hypoplasia of the spinal cord with no anterior and posterior horns and almost no motoneurons. At the cellular level, the p.Cys239Phe TUBB2B mutant leads to tubulin heterodimerization impairment, decreased ability to incorporate into the cytoskeleton, microtubule dynamics alteration, with an accelerated rate of depolymerization. To our knowledge, this is the first case of microlissencephaly to be reported presenting with a so severe and early form of FADS, highlighting the importance of tubulin mutation screening in the context of FADS with microlissencephaly.


Assuntos
Artrogripose/genética , Malformações do Desenvolvimento Cortical/genética , Microcefalia/genética , Tubulina (Proteína)/genética , Adulto , Artrogripose/fisiopatologia , Cerebelo/fisiopatologia , Feminino , Feto , Humanos , Malformações do Desenvolvimento Cortical/fisiopatologia , Microcefalia/fisiopatologia , Neurônios Motores/patologia , Mutação , Medula Espinal/fisiopatologia , Tubulina (Proteína)/deficiência
12.
Eur J Med Genet ; 58(8): 416-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26188271

RESUMO

Heterozygous ACTG1 mutations are responsible for Baraitser-Winter cerebrofrontofacial syndrome which cortical malformation is characterized by pachygyria with frontal to occipital gradient of severity. We identified by whole exome sequencing in a cohort of 12 patients with prenatally diagnosed microlissencephaly, 2 foetal cases with missense mutations in the ACTG1 gene and in one case of living patient with typical Baraitser-Winter syndrome. Both foetuses and child exhibited microcephaly and facial dysmorphism consisting of microretrognatism, hypertelorism and low-set ears. Brain malformations included lissencephaly with an immature cortical plate, dysmorphic (2/3) or absent corpus callosum and vermian hypoplasia (2/3). Our results highlight the powerful diagnostic value of exome sequencing for patients with microlissencephaly, that may expand the malformation spectrum of ACTG1-related Baraitser-Winter cerebrofrontofacial syndrome and may suggest that ACTG1 could be added to the list of genes for assessing microlissencephaly.


Assuntos
Anormalidades Múltiplas/genética , Actinas/genética , Anormalidades Craniofaciais/genética , Microcefalia/genética , Mutação de Sentido Incorreto , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Aborto Eugênico , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Criança , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/patologia , Exoma , Éxons , Feminino , Feto , Expressão Gênica , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons , Masculino , Microcefalia/diagnóstico , Microcefalia/patologia
13.
Orphanet J Rare Dis ; 9: 72, 2014 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-24886560

RESUMO

Joubert syndrome is a clinically and genetically heterogeneous ciliopathy characterized by a typical cerebellar and brainstem malformation (the "molar tooth sign"), and variable multiorgan involvement. To date, 24 genes have been found mutated in Joubert syndrome, of which 13 also cause Meckel syndrome, a lethal ciliopathy with kidney, liver and skeletal involvement. Here we describe four patients with mild Joubert phenotypes who carry pathogenic mutations in either MKS1 or B9D1, two genes previously implicated only in Meckel syndrome.


Assuntos
Doenças Cerebelares/genética , Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Mutação , Doenças Renais Policísticas/genética , Proteínas/genética , Retina/anormalidades , Anormalidades Múltiplas , Adulto , Doenças Cerebelares/patologia , Cerebelo/anormalidades , Criança , Pré-Escolar , Transtornos da Motilidade Ciliar/patologia , Encefalocele/patologia , Anormalidades do Olho/patologia , Feminino , Humanos , Doenças Renais Císticas/patologia , Imagem por Ressonância Magnética , Masculino , Doenças Renais Policísticas/patologia , Retina/patologia , Retinite Pigmentosa , Índice de Gravidade de Doença
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