186 results on '"Lissencephaly"'
Search Results
2. Novel homozygous LAMB1 in‐frame deletion in a pediatric patient with brain anomalies and cerebrovascular event.
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Toutouna, Louiza, Beck‐Woedl, Stefanie, Feige, Ursula, Glaeser, Birgitta, Komlosi, Katalin, Eckenweiler, Matthias, Luetzen, Niklas, Haack, Tobias B., Fischer, Judith, Bader, Ingrid, and Tzschach, Andreas
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Biallelic pathogenic variants in LAMB1 have been associated with autosomal recessive lissencephaly 5 (OMIM 615191), which is characterized by brain malformations (cobblestone lissencephaly, hydrocephalus), developmental delay, and epilepsy. Pathogenic variants in LAMB1 are rare, with only 11 pathogenic variants and 11 patients reported to date. Here, we report on a 6‐year‐old patient from a consanguineous family with profound developmental delay, microcephaly, and a history of a perinatal cerebrovascular event. Brain magnetic resonance imaging (MRI) showed cerebellar cystic defects, signal intensity abnormalities, and a hypoplastic corpus callosum. Trio‐exome analysis revealed a homozygous in‐frame deletion of Exons 23 and 24 of LAMB1 affecting 104 amino acids including the epidermal growth factor (EGF)‐like units 11 and 12 in Domain III. To our knowledge, this is the first reported in‐frame deletion in LAMB1. Our findings broaden the clinical and molecular spectrum of LAMB1‐associated syndromes. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Schizencephaly diagnosed after an episode of seizure during labor: A case report.
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Paudel, Kusum, Prasad, Tanisha, Gyawali, Prashant, Nepal, Gaurav, and Jaiswal, Vikash
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SEIZURES (Medicine) , *CEREBRAL cortex , *DIAGNOSIS , *CRANIOFACIAL abnormalities - Abstract
Schizencephaly, an extremely rare anomaly of the cortex, is characterized by abnormal clefts in the cerebral cortex. Very often, this condition is diagnosed early in the childhood period but few instances exist in literature where schizencephaly‐associated seizures and hemiparesis have presented later in life too. Here, we report a rare case scenario of a lady in her late 30s who initially presented to us with obstetric concerns wherein schizencephaly remained an incidental finding despite the significantly large cortical cleft along with lobar holoprosencephaly and lissencephaly. [ABSTRACT FROM AUTHOR]
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- 2023
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4. Stem cell‐based region‐specific brain organoids: Novel models to understand neurodevelopmental defects.
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The study of human brain development and neurodevelopmental defects has remained challenging so far due to unique, specific, and complex underlying processes. Recent advances in the technologies and protocols of in vitro human brain organoid development have led to immense possibilities of understanding these processes. Human brain organoids are stem‐cell derived three‐dimensional in vitro tissues that resemble the developing fetal brain. Major advances in stem cell techniques pioneering the development of in vitro human brain development include reprogramming human somatic cells into induced pluripotent cells (iPSCs) followed by the targeted differentiation of iPSCs into the cells of three embryonic germ cell layers. The neural progenitor cells produced by the directed differentiation of iPSCs undergo some level of self‐organization to generate in vitro human brain like tissue. A three‐dimensional differentiation approach applied to create region‐specific brain organoids has successfully led to develop highly specialized cortical, forebrain, pallium, and subpallium in vitro human brain organoid models. These stem cell‐based brain organoids are novel models to study human brain development, neurodevelopmental defects, chemical toxicity testing, and drug repurposing screening. This review focuses on the fundamentals of brain organoid development and applications. The novel applications of using cortical organoids in understanding the mechanisms of Zika virus‐induced microcephaly, congenital microcephaly, and lissencephaly are also discussed. [ABSTRACT FROM AUTHOR]
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- 2022
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5. Novel finding of lissencephaly and severe osteopenia in a Chinese patient with SATB2‐associated syndrome and a brief review of literature.
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Lo, Hui‐Yin, Ng, Wai‐Fu, Fong, Nai‐Chung, Lui, Choi‐Yu Dilys, and Lam, Ching‐Wan
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SATB2‐associated syndrome (SAS) is a rare disorder characterized by developmental delay, behavioral problems, and craniofacial anomalies in particular dental and palatal abnormalities. We describe the clinical course, genetic and autopsy findings in a Chinese boy with global developmental delay, hypotonia, epilepsy, recurrent fractures and osteopenia. Brain magnetic resonance imaging showed pachygyria, white matter hypoplasia and hypogenesis of the corpus callosum. Whole‐exome sequencing identified a novel heterozygous missense variant c.1555G>A p.(Glu519Lys) in the SATB2 gene. Unfortunately, he died at 26 months of bronchiolitis and pneumonia. Autopsy revealed pachygyria which was more severe anteriorly, dilated lateral and third ventricles and partial agenesis of the corpus callosum. Histology showed features compatible with two‐layered lissencephaly. The bone showed disordered lamination and bone matrix. Although SATB2 has been shown to be involved in the regulation of neuronal migration in the developing brain, lissencephaly has not been reported so far. This could represent a more severe phenotype of SAS. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Novel lissencephaly‐associated DCX variants in the C‐terminal DCX domain affect microtubule binding and dynamics.
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Lin, Jun‐Ru, Cheng, Ju‐Fang, Liu, Yo‐Tsen, Hsu, Ting‐Rong, Lin, Kao‐Min, Chen, Chien, Lin, Chia‐Ling, Tsai, Meng‐Han, and Tsai, Jin‐Wu
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MICROTUBULES , *X chromosome , *MISSENSE mutation , *NEURAL development , *CELL growth , *TUBULINS - Abstract
Objective: Pathogenic variants in DCX on the X chromosome lead to lissencephaly and subcortical band heterotopia (SBH), brain malformations caused by neuronal migration defects. Its product doublecortin (DCX) binds to microtubules to modulate microtubule polymerization. How pathogenic DCX variants affect these activities remains not fully investigated. Methods: DCX variants were identified using whole exome and Sanger sequencing from six families with lissencephaly/SBH. We examined how these variants affect DCX functions using microtubule binding, regrowth, and colocalization assays. Results: We found novel DCX variants p.Val177AlafsTer31 and p.Gly188Trp, as well as reported variants p.Arg196His, p.Lys202Met, and p.Thr203Ala. Incidentally, all of the missense variants were clustered on the C‐terminal DCX domain. The microtubule binding ability was significantly decreased in p.Val177AlafsTer31, p.Gly188Trp, p.Lys202Met, and previously reported p.Asp262Gly variants. Furthermore, expression of p.Val177AlafsTer31, p.Gly188Trp, p.Arg196His, p.Lys202Met, and p.Asp262Gly variants hindered microtubule growth in cells. There were also decreases in the colocalization of p.Val177AlafsTer31, p.Thr203Ala, and p.Asp262Gly variants to microtubules. Significance: Our results indicate that these variants in the C‐terminal DCX domain altered microtubule binding and dynamics, which may underlie neuronal migration defects during brain development. [ABSTRACT FROM AUTHOR]
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- 2022
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7. A comparative study of pre‐alpha islands in the entorhinal cortex from selected primates and in lissencephaly.
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Schön, Michael, Nosanova, Anastasia, Jacob, Christian, Kraus, Johann Michael, Kestler, Hans A., Mayer, Benjamin, Feldengut, Simone, Amunts, Katrin, Del Tredici, Kelly, Boeckers, Tobias M., and Braak, Heiko
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The entorhinal cortex (EC) is the main interface between the sensory association areas of the neocortex and the hippocampus. It is crucial for the evaluation and processing of sensory data for long‐term memory consolidation and shows damage in many brain diseases, for example, neurodegenerative diseases, such as Alzheimer's disease and developmental disorders. The pre‐alpha layer of the EC in humans (layer II) displays a remarkable distribution of neurons in islands. These cellular islands give rise to a portion of the perforant path—the major reciprocal data stream for neocortical information into the hippocampal formation. However, the functional relevance of the morphological appearance of the pre‐alpha layer in cellular islands and the precise timing of their initial appearance during primate evolution are largely unknown. Here, we conducted a comparative study of the EC from 38 nonhuman primates and Homo sapiens and found a strong relationship between gyrification index (GI) and the presence of the pre‐alpha cellular islands. The formation of cellular islands also correlated with brain and body weight as well as neopallial volume. In the two human lissencephalic cases, the cellular islands in the pre‐alpha layer were lacking. These findings emphasize the relationship between cortical folding and island formation in the EC from an evolutionary perspective and suggest a role in the pathomechanism of developmental brain disorders. [ABSTRACT FROM AUTHOR]
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- 2022
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8. A prenatal case of lissencephaly with cerebellar hypoplasia: New mutation in RELN gene.
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Balza, Claire, Garofalo, Giulia, Cos, Teresa, Désir, Julie, Kang, Xin, Keymolen, Kathelijn, Soblet, Julie, Van Berkel, Kim, Vilain, Catheline, Ben Abbou, Wafa, and Cassart, Marie
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GENETIC mutation , *PRENATAL diagnosis - Abstract
Reelinopathies cause a distinctive lissencephaly type associated with cerebellar hypoplasia. To help further management, we wanted to report here the first prenatal diagnosis due to a homozygous inherited reelinopathy. [ABSTRACT FROM AUTHOR]
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- 2021
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9. Neuropathology of genetically defined malformations of cortical development—A systematic literature review.
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Brock, Stefanie, Cools, Filip, and Jansen, Anna C.
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HUMAN abnormalities , *GENETIC variation , *HISTOPATHOLOGY , *CORPUS callosum - Abstract
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: Eighty‐one 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 are available only for a small number of genes. As each genetic cause might lead to unique histopathological features of MCD, standardised thorough neuropathological assessment and reporting should be encouraged. Histological features can help improve the understanding of the pathogenesis of MCD and generate hypotheses with impact on further research directions. [ABSTRACT FROM AUTHOR]
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- 2021
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10. Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3.
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Maiko Hatano, Hiroko Fukushima, Tatsuyuki Ohto, Yuichi Ueno, Saki Saeki, Takashi Enokizono, Ryuta Tanaka, Mai Tanaka, Kazuo Imagawa, Yu Kanai, Mitsuhiro Kato, Hiroshi Shiraku, Hisato Suzuki, Tomoko Uehara, Toshiki Takenouchi, Kenjiro Kosaki, and Hidetoshi Takada
- Abstract
Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation. Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction. Here, we report an 8‐year‐old boy with CDCBM3 showing a typical, but relatively mild, clinical presentation of CDCBM3 features. Whole‐exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298C>A [p.(Ser433Tyr)]. To our knowledge, the mutation has never been reported previously. The variant was located distal to the nucleotide binding domain (NBD), in which previously‐reported variants in CDCBM3 patients have been located. The computational structural analysis showed the p.433 forms the pocket with NBD. Variants in KIF2A have been reported in the NBD for CDCBM3, in the kinesin motor 3 domain, but not in the NBD in epilepsy, and outside of the kinesin motor domain in autism spectrum syndrome, respectively. Our patient has a variant, that is not in the NBD but at the pocket with the NBD, resulting in a clinical features of CDCBM3 with mild symptoms. The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies. We can call this spectrum “KIF2A syndrome” with variable severity. [ABSTRACT FROM AUTHOR]
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- 2021
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11. Zika virus infection: A correlation between prenatal ultrasonographic and postmortem neuropathologic changes.
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Gutiérrez Sánchez, Luz A., Sandoval Martínez, Diana K., Díaz‐Martínez, Luis A., and Becerra Mojica, Carlos H.
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ZIKA virus infections , *AUTOPSY , *POSTMORTEM changes , *CORPUS callosum , *CENTRAL nervous system , *ZIKA virus - Abstract
This study presents a correlation between prenatal ultrasonographic images and neuropathologic findings of postmortem tissue samples from five confirmed cases of perinatal Zika virus (ZIKV) infection belonging to the cohort of the ZEN Initiative in Bucaramanga, Colombia. Deaths occurred between June 2016 and March 2017. Mothers consulted with ZIKV infection clinical manifestations or fetal central nervous system (CNS) abnormalities or both. A detailed ultrasound scan and neurosonographic protocol was performed by maternal fetal specialists. Perinatal autopsies were performed following the Colombian National Health Institute's ZIKV protocol. The autopsies were from two fetal deaths, and three early neonatal deaths. Gestational age was between 262/7 and 382/7 weeks. Two cases were classified as mild microcephaly. Few findings by ultrasound and pathology were found in case 1 because it was a late infection; the other cases presented findings corresponding to congenital Zika syndrome: craniofacial malformations, cerebellar hypoplasia, anomalies of the corpus callosum and ventriculomegaly, all confirmed in autopsy specimens. By ultrasonography, hyperechogenicities were seen in several brain structures, which correspond to cortical and periventricular calcifications, subependymal glial reactivity and perivascular rings. The ultrasound and pathological findings show a wide spectrum of CNS anomalies that confirm the neurotropic effect of the ZIKV, recognizing the neuroimaging findings of this disease (unilateral ventriculomegaly, alterations in the corpus callosum and cerebellum, and calcifications) are highly suggestive of ZIKV infection. [ABSTRACT FROM AUTHOR]
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- 2019
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12. Domain swap in the C‐terminal ubiquitin‐like domain of human doublecortin.
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Rufer, Arne C., Kusznir, Eric, Burger, Dominique, Stihle, Martine, Ruf, Armin, and Rudolph, Markus G.
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C-terminal binding proteins , *UBIQUITIN , *LISSENCEPHALY - Abstract
Doublecortin, a microtubule‐associated protein that is only produced during neurogenesis, cooperatively binds to microtubules and stimulates microtubule polymerization and cross‐linking by unknown mechanisms. A domain swap is observed in the crystal structure of the C‐terminal domain of doublecortin. As determined by analytical ultracentrifugation, an open conformation is also present in solution. At higher concentrations, higher‐order oligomers of the domain are formed. The domain swap and additional interfaces observed in the crystal lattice can explain the formation of doublecortin tetramers or multimers, in line with the analytical ultracentrifugation data. Taken together, the domain swap offers a mechanism for the observed cooperative binding of doublecortin to microtubules. Doublecortin‐induced cross‐linking of microtubules can be explained by the same mechanism. The effect of several mutations leading to lissencephaly and double‐cortex syndrome can be traced to the domain swap and the proposed self‐association of doublecortin. [ABSTRACT FROM AUTHOR]
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- 2018
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13. Disruption of YWHAE gene at 17p13.3 causes learning disabilities and brain abnormalities.
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Noor, A., Bogatan, S., Watkins, N., Meschino, W. S., and Stavropoulos, D. J.
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LEARNING disabilities , *BRAIN abnormalities , *LISSENCEPHALY , *DELETION mutation , *NEUROLOGICAL disorders - Abstract
There is a broad phenotypic spectrum of patients with 17p13.3 deletions. One of the most prominent feature is lissencephaly caused by haploinsufficiency of the gene PAFAH1B1. The deletion of this gene and those distal to it, results in Miller‐Dieker syndrome, however there have been many reports of patients with haploinsufficiency of the distal genes alone. The deletions of these genes including YWHAE CRK and TUSC5 have been studied extensively and YWHAE has been postulated to be the cause of neurological abnormalities. The patients with deletions of the Miller‐Dieker syndrome distal region present with variable clinical features including brain abnormalities, growth retardation, developmental delay, facial dysmorphisms and seizures. While there have been many patients reported to have deletions involving the YWHAE gene along with other genes, here we present the first detailed clinical description of a patient with deletion of YWHAE alone, allowing a more accurate characterization of the pathogenicity of YWHAE haploinsufficiency. The patient reported here demonstrated brain abnormalities, learning disabilities, and seizures supporting the role of YWHAE in these features. We review the literature and use this case report to better characterize and further confirm the genotype‐phenotype relationship of the genes within the critical region of Miller‐Dieker Syndrome. [ABSTRACT FROM AUTHOR]
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- 2018
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14. Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated with lissencephaly.
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Harel, Tamar, Hacohen, Nuphar, Shaag, Avraham, Gomori, Moshe, Singer, Amihood, Elpeleg, Orly, and Meiner, Vardiella
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Lissencephaly is a severe malformation of cortical development, most often attributed to abnormalities in neuronal migration. It is associated with a severe prognosis including developmental delay, intellectual disability, and seizures. Lissencephaly can be reliably diagnosed during late gestation by neurosonography or fetal magnetic resonance imaging (MRI). We report two sibling male fetuses who were diagnosed with delayed cortical sulcation highly suggestive of lissencephaly during late pregnancy. After receiving genetic counseling, the parents elected to terminate the pregnancies based on the neuroradiological findings and the associated severe prognosis. Whole exome sequencing (WES) of an affected fetus, and subsequent Sanger sequencing of the second fetus, revealed a homozygous frameshift variant in CRADD, which encodes an adaptor protein that interacts with PIDD and caspase-2 to initiate apoptosis. Biallelic variants in this gene have been recently reported to cause 'thin' lissencephaly and intellectual disability. Interestingly, the allegedly healthy father was also found to be homozygous for the variant, prompting evaluation by brain MRI which revealed hypogyration. This study underscores the phenotypic variability of pathogenic variants in CRADD and the challenges of prenatal genetic counseling. [ABSTRACT FROM AUTHOR]
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- 2017
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15. Interneuronopathies and their role in early life epilepsies and neurodevelopmental disorders.
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Katsarou, Anna-Maria, Moshé, Solomon L., and Galanopoulou, Aristea S.
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- 2017
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16. Lissencephaly: Expanded imaging and clinical classification.
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Di Donato, Nataliya, Chiari, Sara, Mirzaa, Ghayda M., Aldinger, Kimberly, Parrini, Elena, Olds, Carissa, Barkovich, A. James, Guerrini, Renzo, and Dobyns, William B.
- Abstract
Lissencephaly ('smooth brain,' LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The LIS spectrum includes agyria, pachygyria, and subcortical band heterotopia. Our first classification of LIS and subcortical band heterotopia (SBH) was developed to distinguish between the first two genetic causes of LIS-LIS1 (PAFAH1B1) and DCX. However, progress in molecular genetics has led to identification of 19 LIS-associated genes, leaving the existing classification system insufficient to distinguish the increasingly diverse patterns of LIS. To address this challenge, we reviewed clinical, imaging and molecular data on 188 patients with LIS-SBH ascertained during the last 5 years, and reviewed selected archival data on another ∼1,400 patients. Using these data plus published reports, we constructed a new imaging based classification system with 21 recognizable patterns that reliably predict the most likely causative genes. These patterns do not correlate consistently with the clinical outcome, leading us to also develop a new scale useful for predicting clinical severity and outcome. Taken together, our work provides new tools that should prove useful for clinical management and genetic counselling of patients with LIS-SBH (imaging and severity based classifications), and guidance for prioritizing and interpreting genetic testing results (imaging based- classification). [ABSTRACT FROM AUTHOR]
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- 2017
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17. A novel recurrent LIS1 splice site mutation in classic lissencephaly.
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Philbert, Marion, Maillard, Camille, Cavallin, Mara, Goldenberg, Alice, Masson, Cecile, Boddaert, Nathalie, El Morjani, Adrienne, Steffann, Julie, Chelly, Jamel, Gerard, Xavier, and Bahi‐Buisson, Nadia
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- 2017
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18. A likely pathogenic ACTG1 variant in a child showing partial phenotypic overlap with Baraitser-Winter syndrome.
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Graziani L, Cinnirella G, Ferradini V, Conte C, Bascio FL, Bengala M, Sangiuolo F, and Novelli G
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- Female, Humans, Actins genetics, Mutation, Missense, Phenotype, Child, Preschool, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Abnormalities, Multiple pathology, Epilepsy, Intellectual Disability diagnosis, Intellectual Disability genetics, Lissencephaly, Microcephaly diagnosis, Microcephaly genetics, Nervous System Malformations
- Abstract
Baraitser-Winter syndrome (BRWS) is a rare autosomal dominant disease (AD) caused by heterozygous variants in ACTB (BRWS1) or ACTG1 (BRWS2) genes. BRWS features developmental delay/intellectual disability of variable degree and craniofacial dysmorphisms. Brain abnormalities (especially pachygyria), microcephaly, epilepsy, as well as hearing impairment, cardiovascular and genitourinary abnormalities may be present. We report on a 4-year-old female, who was addressed to our institution because of psychomotor delay associated with microcephaly and dysmorphic features, short stature, mild bilateral sensorineural hearing loss, mild cardiac septal hypertrophy, and abdominal swelling. Clinical exome sequencing detected a c.617G>A p.(Arg206Gln) de novo variant in ACTG1 gene. Such variant has been previously reported in association with a form of AD nonsyndromic sensorineural progressive hearing loss and we classified it as likely pathogenic according to ACMG/AMP criteria, despite our patient's phenotype only partially overlapped BWRS2. Our finding supports the extreme variability of the ACTG1-related disorders, ranging from classical BRWS2 to nuanced clinical expressions not fitting the original description, and occasionally featuring previously undescribed clinical findings., (© 2023 Wiley Periodicals LLC.)
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- 2023
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19. RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.
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Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M.‐A., Mayer, M., Rodriguez, D., and Burglen, L.
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NEURODEGENERATION , *FETAL development , *CEREBELLUM , *BRAIN stem , *CEREBELLAR ataxia , *REELIN - Abstract
Pontocerebellar hypoplasias ( PCH) are characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. We report five patients referred for PCH, showing atypical clinical and magnetic resonance imaging ( MRI) features suggestive of defects in the Reelin pathway. We screened for mutations in RELN or VLDLR and compared the phenotype of these patients with that of previously reported patients. All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities. Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation. The four other patients had a milder phenotype consistent with CARMQ1 (cerebellar ataxia and mental retardation with or without quadrupedal locomotion). These patients showed mild simplification or thickening of cortical gyration and had VLDLR mutations. Reelin signaling regulates neuronal migration in the developing mammalian brain. VLDLR is a key component of the Reelin pathway. Our patients had a very small and dysplatic cerebellar vermis that should suggest the involvement of these genes. Moreover, differences in clinical severity, involvement of the cerebellar hemispheres, together with the severity of the neocortical defect, enables RELN-mutated patients to be distinguished from VLDLR-mutated patients. [ABSTRACT FROM AUTHOR]
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- 2016
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20. Expanding the phenotype of RTTN variations: a new family with primary microcephaly, severe growth failure, brain malformations and dermatitis.
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Grandone, A., Torella, A., Santoro, C., Giugliano, T., del Vecchio Blanco, F., Mutarelli, M., Cirillo, M., Cirillo, G., Piluso, G., Capristo, C., Festa, A., Marzuillo, P., Miraglia del Giudice, E., Perrone, L., and Nigro, V.
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MICROCEPHALY , *DEVELOPMENTAL biology , *DWARFISM , *SKIN inflammation , *BRAIN imaging , *MAGNETIC resonance imaging - Abstract
Primary autosomal recessive microcephaly ( MCPH) is a developmental disorder characterized by prenatal onset of abnormal brain growth. MCPH occurs both alone and as part of a broad range of neurodevelopmental syndromes with or without cortical malformations and growth retardation. Here we report a consanguineous Moroccan family with two siblings affected by severe primary microcephaly, failure to thrive, congenital dermatitis and severe developmental delay. Brain magnetic resonance imaging showed lissencephaly of frontal lobes and periventricular heterotopia of the gray matter. We performed both Comparative Genomic Hybridization array and whole exome sequencing ( WES) analyses of the kindred. No quantitative defects were detected. However, WES identified a new homozygous missense variation in the penultimate nucleotide of exon 23 of RTTN gene (c. 2953A>G; pArg985Gly). cDNA sequencing revealed two abnormal spliced products, one lacking only exon 23 and the other lacking exons 22 and 23 (out-of-frame). RTTN is a protein involved in cilia structure and function. Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism ( PD). We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN-associated diseases and ciliary dysfunction. [ABSTRACT FROM AUTHOR]
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- 2016
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21. A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A.
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Tian, Guoling, Cristancho, Ana G., Dubbs, Holly A., Liu, Grant T., Cowan, Nicholas J., and Goldberg, Ethan M.
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NEURAL development , *LISSENCEPHALY , *MICROTUBULES , *HETERODIMERS , *GENETIC mutation , *GENETIC overexpression - Abstract
Background Microtubules are dynamic polymers of α/ β tubulin heterodimers that play a critical role in cerebral cortical development, by regulating neuronal migration, differentiation, and morphogenesis. Mutations in genes that encode either α- or β-tubulin or a spectrum of proteins involved in the regulation of microtubule dynamics lead to clinically devastating malformations of cortical development, including lissencephaly. Methods This is a single case report or a patient with lissencephaly, developmental delay, nystagmus, persistent hyperplastic primary vitreous, and infantile spasms, and undertook a neurogenetic workup. We include studies of mutant function in Escherichia coli and HeLa cells. Results The patient was found to have a novel de novo mutation in kinesin family member 2A ( KIF2A). This mutation results in a substitution of isoleucine at a highly conserved threonine residue within the ATP-binding domain. The KIF2A p.Thr320Ile mutant protein exhibited abnormal solubility, and KIF2A p.Thr320Ile overexpression in cultured cells led to the formation of aberrant microtubule networks. Conclusion Findings support the pathogenic link between KIF2A mutation and lissencephaly, and expand the range of presentation to include infantile spasms and congenital anomalies. [ABSTRACT FROM AUTHOR]
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- 2016
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22. Update on the ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome.
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Di Donato, Nataliya, Kuechler, Alma, Vergano, Samantha, Heinritz, Wolfram, Bodurtha, Joann, Merchant, Sabiha R., Breningstall, Galen, Ladda, Roger, Sell, Susan, Altmüller, Janine, Bögershausen, Nina, Timms, Andrew E., Hackmann, Karl, Schrock, Evelin, Collins, Sarah, Olds, Carissa, Rump, Andreas, and Dobyns, William B.
- Abstract
Baraitser-Winter cerebrofrontofacial syndrome is caused by heterozygous missense mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1. Recently, we characterized the large cohort of 41 patients presenting with this condition. Our series contained 34 patients with mutations in ACTB and only nine with ACTG1 mutations. Here, we report on seven unrelated patients with six mutations in ACTG1-four novel and two previously reported. Only one of seven patients was clinically diagnosed with this disorder and underwent ACTB/ACTG1 targeted sequencing, four patients were screened as a part of the large lissencephaly cohort and two were tested with exome sequencing. Retrospectively, facial features were compatible with the diagnosis but significantly milder than previously reported in four patients, and non-specific in one. The pattern of malformations of cortical development was highly similar in four of six patients with available MRI images and encompassed frontal predominant pachygyria merging with the posterior predominant band heterotopia. Two remaining patients showed mild involvement consistent with bilaterally simplified gyration over the frontal lobes. Taken together, we expand the clinical spectrum of the ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome demonstrating the mild end of the facial and brain manifestations. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2016
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23. First-trimester intrauterine Zika virus infection and brain pathology: prenatal and postnatal neuroimaging findings.
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Werner, Heron, Sodré, Danielle, Hygino, Celso, Guedes, Bianca, Fazecas, Tatiana, Nogueira, Renata, Daltro, Pedro, Tonni, Gabriele, Lopes, Jorge, and Araujo Júnior, Edward
- Subjects
BRAIN diseases ,BRAIN ,CEREBRAL ventricles ,COMMUNICABLE diseases ,COMPUTED tomography ,FETAL ultrasonic imaging ,HYDROCEPHALUS ,MAGNETIC resonance imaging ,NEURORADIOLOGY ,PREGNANCY complications ,FIRST trimester of pregnancy ,LISSENCEPHALY ,THREE-dimensional imaging ,THREE-dimensional printing ,CRANIOFACIAL abnormalities ,CALCINOSIS - Abstract
What's Already Known about this Topic?Intrauterine Zika virus infection has been associated with several malformations of the central nervous system, mainly microcephaly. What does this Study Add?We present a case of congenital Zika virus infection in which perinatal brain pathology was investigated using multiple diagnostic procedures. Maternal serology for Zika virus was positive when performed at 31 weeks, but the onset of clinical symptoms was at 10 weeks, indicating that early pregnancy infection may result in a long viral shedding and result in severe brain malformations that become detectable only later in pregnancy. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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24. DMRTA2 ( DMRT5) is mutated in a novel cortical brain malformation.
- Author
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Urquhart, J.E., Beaman, G., Byers, H., Roberts, N.A., Chervinsky, E., O'Sullivan, J., Pilz, D., Fry, A., Williams, S.G., Bhaskar, S.S., Khayat, M., Simanovsky, N., Shachar, I.B., Shalev, S.A., and Newman, W.G.
- Subjects
- *
GENETIC mutation , *LISSENCEPHALY , *BRAIN abnormalities , *GENES , *TRANSCRIPTION factors , *GENETICS - Abstract
Lissencephaly is a phenotypically and genetically heterogeneous group of cortical brain malformations due to abnormal neuronal migration. The identification of many causative genes has increased the understanding of normal brain development. A consanguineous family was ascertained with three siblings affected by a severe prenatal neurodevelopmental disorder characterised by fronto-parietal pachygyria, agenesis of the corpus callosum and progressive severe microcephaly. Autozygosity mapping and exome sequencing identified a homozygous novel single base pair deletion, c.1197delT in DMRTA2, predicted to result in a frameshift variant p.( Pro400Leufs*33). DMRTA2 encodes doublesex and mab-3-related transcription factor a2, a transcription factor key to the development of the dorsal telencephalon. Data from murine and zebrafish knockout models are consistent with the variant of DMTRA2 ( DMRT5) as responsible for the cortical brain phenotype. Our study suggests that loss of function of DMRTA2 leads to a novel disorder of cortical development. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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25. A syndrome of microcephaly, short stature, polysyndactyly, and dental anomalies caused by a homozygous KATNB1 mutation.
- Author
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Yigit, Gökhan, Wieczorek, Dagmar, Bögershausen, Nina, Beleggia, Filippo, Möller‐Hartmann, Claudia, Altmüller, Janine, Thiele, Holger, Nürnberg, Peter, and Wollnik, Bernd
- Abstract
Using whole-exome sequencing, we identified a homozygous acceptor splice-site mutation in intron 6 of the KATNB1 gene in a patient from a consanguineous Turkish family who presented with congenital microcephaly, lissencephaly, short stature, polysyndactyly, and dental abnormalities. cDNA analysis revealed complete loss of the natural acceptor splice-site resulting either in the usage of an alternative, exonic acceptor splice-site inducing a frame-shift and premature protein truncation or, to a minor extent, in complete skipping of exon 7. Both effects most likely lead to complete loss of KATNB1 function. Homozygous and compound heterozygous mutations in KATNB1 have very recently been described as a cause of microcephaly with brain malformations and seizures. We extend the KATNB1 associated phenotype by describing a syndrome characterized by primordial dwarfism, lissencephaly, polysyndactyly, and dental anomalies, which is caused by a homozygous truncating KATNB1 mutation. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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26. Prenatal diagnosis of cobblestone lissencephaly associated with Walker-Warburg syndrome based on a specific sonographic pattern.
- Author
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Lacalm, A., Nadaud, B., Massoud, M., Putoux, A., Gaucherand, P., and Guibaud, L.
- Subjects
- *
PRENATAL diagnosis , *LISSENCEPHALY , *GENETIC disorder diagnosis , *ULTRASONIC imaging , *PATHOLOGY , *FETAL ultrasonic imaging , *NERVOUS system abnormalities , *FIRST trimester of pregnancy , *SECOND trimester of pregnancy , *ULTRASONIC encephalography - Abstract
We report a specific sonographic cerebral pattern of cobblestone lissencephaly (CL) that has not been described previously. This pattern was encountered in four index cases and allowed prenatal diagnosis of CL associated with Walker-Warburg syndrome. The pattern included both an outer echogenic band with reduced pericerebral space, corresponding to an infra- and supratentorial extracortical layer of neuroglial overmigration on pathological examination, and a 'Z'-shaped appearance of the brainstem. This pattern was found as early as 14 weeks' gestation in one of our cases. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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27. Discrete domains of gene expression in germinal layers distinguish the development of gyrencephaly.
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de Juan Romero, Camino, Bruder, Carl, Tomasello, Ugo, Sanz‐Anquela, José Miguel, and Borrell, Víctor
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- *
GENE expression , *GERMINAL layers , *CEREBRAL cortex , *TRANSCRIPTION factors , *FERRET - Abstract
Gyrencephalic species develop folds in the cerebral cortex in a stereotypic manner, but the genetic mechanisms underlying this patterning process are unknown. We present a large-scale transcriptomic analysis of individual germinal layers in the developing cortex of the gyrencephalic ferret, comparing between regions prospective of fold and fissure. We find unique transcriptional signatures in each germinal compartment, where thousands of genes are differentially expressed between regions, including ~80% of genes mutated in human cortical malformations. These regional differences emerge from the existence of discrete domains of gene expression, which occur at multiple locations across the developing cortex of ferret and human, but not the lissencephalic mouse. Complex expression patterns emerge late during development and map the eventual location of folds or fissures. Protomaps of gene expression within germinal layers may contribute to define cortical folds or functional areas, but our findings demonstrate that they distinguish the development of gyrencephalic cortices. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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28. Miller-Dieker Syndrome with unbalanced translocation 45, X, psu dic(17;Y)(p13;p11.32) detected by fluorescence in situ hybridization and G-banding analysis using high resolution banding technique.
- Author
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Mishima, Takashi, Watari, Michiko, Iwaki, Yutaka, Nagai, Takumi, Kawamata-Nakamura, Miho, Kobayashi, Yukako, Fujieda, Satoko, Oikawa, Mamoru, Takahashi, Nobuhiro, Keira, Mitsuaki, Yoshida, Hiroshi, and Tonoki, Hidefumi
- Abstract
Lissencephaly is one of the central nervous system anomalies of Miller-Dieker Syndrome (MDS). Fetuses with lissencephaly have an abnormal smooth brain with fewer folds and grooves that will be detected by ultrasounds or fetal magnetic resonance imaging (MRI) after 30 weeks of gestation. We report a fetus with lissencephaly diagnosed as Miller-Dieker Syndrome postnatally. G banded chromosome analysis revealed 45,X,psu dic(17;Y)(p13;p11.32).ish dic (17;Y)(LIS1-,RARA+, SRY+, DYZ3+) by G-banding analysis using high resolution banding technique. Fetal delayed cortical development will be the findings to perform further investigations including fluorescence in situ hybridization analysis for MDS, a 17p13.3 microdeletion syndrome, pre/postnatally. This will be the first case of MDS with unbalanced translocation between deleted short arm of chromosome 17 and Y chromosome. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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29. Severe presentation of WDR62 mutation: Is there a role for modifying genetic factors?
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Poulton, Cathryn J., Schot, Rachel, Seufert, Katja, Lequin, Maarten H., Accogli, Andrea, Annunzio, Giuseppe D', Villard, Laurent, Philip, Nicole, de Coo, René, Catsman‐Berrevoets, Coriene, Grasshoff, Ute, Kattentidt‐Mouravieva, Anja, Calf, Hans, de Vreugt‐Gronloh, Erika, van Unen, Leontine, Verheijen, Frans W., Galjart, Niels, Morris‐Rosendahl, Deborah J., and Mancini, Grazia M. S.
- Abstract
Mutations in WDR62 are associated with primary microcephaly; however, they have been reported with wide phenotypic variability. We report on six individuals with novel WDR62 mutations who illustrate this variability and describe three in greater detail. Of the three, one lacks neuromotor development and has severe pachygyria on MRI, another has only delayed speech and motor development and moderate polymicrogyria, and the third has an intermediate phenotype. We observed a rare copy number change of unknown significance, a 17q25qter duplication, in the first severely affected individual. The 17q25 duplication included an interesting candidate gene, tubulin cofactor D ( TBCD), crucial in microtubule assembly and disassembly. Sequencing of the non-duplicated allele showed a TBCD missense mutation, predicted to cause a deleterious p.Phe1121Val substitution. Sequencing of a cohort of five patients with WDR62 mutations, including one with an identical mutation and different phenotype, plus 12 individuals with diagnosis of microlissencephaly and another individual with mild intellectual disability (ID) and a 17q25 duplication, did not reveal TBCD mutations. However, immunostaining with tubulin antibodies of cells from patients with both WDR62 and TBCD mutation showed abnormal tubulin network when compared to controls and cells with only the WDR62 mutation. Therefore, we propose that genetic factors contribute to modify the severity of the WDR62 phenotype and, although based on suggestive evidence, TBCD could function as one of such factors. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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30. A novel inverted 17p13.3 microduplication disrupting PAFAH1B1 ( LIS1) in a girl with syndromic lissencephaly.
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Classen, Sabrina, Goecke, Timm, Drechsler, Matthias, Betz, Beate, Nickel, Natalie, Beier, Manfred, Schaper, Jörg, Karenfort, Michael, and Royer‐Pokora, Brigitte
- Abstract
We describe a female patient with mild lissencephaly (pachygyria), severe intellectual disability, and facial dysmorphisms with an inverted 1.4 Mb microduplication of chromosome 17p13.3. The 17p13.3 microduplication syndrome is associated with mild intellectual disabiltiy and contains, among others, the PAFAH1B1 ( LIS1) gene, whereas microdeletions of the same segment cause Miller-Dieker syndrome (MDS) with severe to profound retardation. The duplication identified in our patient encompasses 29 genes, including CRK and YWHAE. The proximal breakpoint of the duplication is located in the first intron of the PAFAH1B1 gene. Analysis of total RNA showed that only one PAFAH1B1 allele is expressed. Therefore, this patient has a unique alteration: a duplication including YWHAE and CRK and haploinsufficiency of PAFAH1B1. Overexpression of YWHAE is associated with macrosomia, mild developmental delay, autism and facial dysmorphisms, and deletion of PAFAH1B1 alone leads to isolated lissencephaly (ILS). The patient described here shares features with MDS, but she is affected to a lesser degree. Her facial features are similar to MDS, and she has manifestations seen in other cases with YWHAE duplication. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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31. A de novo ACTB gene pathogenic variant in identical twins with phenotypic variation for hydrops and jejunal atresia.
- Author
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Sibbin K, Yap P, Nyaga D, Heller R, Evans S, Strachan K, Alburaiky S, Nguyen HMA, Hermann-Le Denmat S, Ganley ARD, O'Sullivan JM, and Bloomfield FH
- Subjects
- Actins genetics, Actins metabolism, Biological Variation, Population, Craniofacial Abnormalities, Edema, Epilepsy, Facies, Humans, Intellectual Disability, Lissencephaly, Saccharomyces cerevisiae metabolism, Intestinal Atresia diagnosis, Intestinal Atresia genetics, Twins, Monozygotic genetics
- Abstract
The beta-actin gene (ACTB) encodes a ubiquitous cytoskeletal protein, essential for embryonic development in humans. De novo heterozygous missense variants in the ACTB are implicated in causing Baraitser-Winter cerebrofrontofacial syndrome (BWCFFS; MIM#243310). ACTB pathogenic variants are rarely associated with intestinal malformations. We report on a rare case of monozygotic twins presenting with proximal small bowel atresia and hydrops in one, and apple-peel bowel atresia and laryngeal dysgenesis in the other. The twin with hydrops could not be resuscitated. Intensive and surgical care was provided to the surviving twin. Rapid trio genome sequencing identified a de novo missense variant in ACTB (NM_00101.3:c.1043C>T; p.(Ser348Leu)) that guided the care plan. The identical variant subsequently was identified in the demised twin. To characterize the functional effect, the variant was recreated as a pseudoheterozygote in a haploid wild-type S. cerevisiae strain. There was an obvious growth defect of the yACT1
S348L/WT pseudoheterozygote compared to a yACT1WT/WT strain when grown at 22°C but not when grown at 30°C, consistent with the yACT1 S348L variant having a functional defect that is dominant over the wild-type allele. The functional results provide supporting evidence that the Ser348Leu variant is likely to be a pathogenic variant, including being associated with intestinal malformations in BWCFFS, and can demonstrate variable expressivity within monozygotic twins., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)- Published
- 2022
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32. A 14-year-old girl with lissencephaly and craniofacial dysmorphism.
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Sasaki, Atsushi, Shioda, Kei, Homma, Taku, Fukatsu, Ryo, and Koide, Hiroyoshi
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- *
CASE studies , *CHILDHOOD epilepsy , *SYNDROMES , *HUMAN chromosome abnormalities , *DIAGNOSTIC use of fluorescence in situ hybridization , *DIFFERENTIAL diagnosis , *LISSENCEPHALY , *DIAGNOSIS - Abstract
The article presents a case study of a patient born at 38 weeks gestation who was admitted to the hospital due to epilepsy at two months and died at the age of 14 with the diagnosis of Miller-Dieker syndrome (MDS). It says that fluorescence in situ hybridization (FISH) for chromosomal testing was conducted which revealed a deletion in the MDS region. It discusses the two categories of lissencephaly and the differential diagnosis of MDS.
- Published
- 2012
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33. Sonographic assessment of normal and abnormal patterns of fetal cerebral lamination.
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Pugash, D., Hendson, G., Dunham, C. P., Dewar, K., Money, D. M., and Prayer, D.
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ULTRASONIC imaging , *MAGNETIC resonance imaging , *BRAIN abnormalities , *DIAGNOSTIC imaging , *BRAIN imaging - Abstract
ABSTRACT Objectives Prenatal development of the brain is characterized by gestational age-specific changes in the laminar structure of the brain parenchyma before 30 gestational weeks. Cerebral lamination patterns of normal fetal brain development have been described histologically, by postmortem in-vitro magnetic resonance imaging ( MRI) and by in-vivo fetal MRI. The purpose of this study was to evaluate the sonographic appearance of laminar organization of the cerebral wall in normal and abnormal brain development. Methods This was a retrospective study of ultrasound findings in 92 normal fetuses and 68 fetuses with abnormal cerebral lamination patterns for gestational age, at 17-38 weeks' gestation. We investigated the visibility of the subplate zone relative to the intermediate zone and correlated characteristic sonographic findings of cerebral lamination with gestational age in order to evaluate transient structures. Results In the normal cohort, the subplate zone-intermediate zone interface was identified as early as 17 weeks, and in all 57 fetuses examined up to 28 weeks. In all of these fetuses, the subplate zone appeared anechoic and the intermediate zone appeared homogeneously more echogenic than did the subplate zone. In the 22 fetuses between 28 and 34 weeks, there was a transition period when lamination disappeared in a variable fashion. The subplate zone-intermediate zone interface was not identified in any fetus after 34 weeks ( n = 13). There were three patterns of abnormal cerebral lamination: (1) no normal laminar pattern before 28 weeks ( n = 32), in association with severe ventriculomegaly, diffuse ischemia, microcephaly, teratogen exposure or lissencephaly; (2) focal disruption of lamination before 28 weeks ( n = 24), associated with hemorrhage, porencephaly, stroke, migrational abnormalities, thanatophoric dysplasia, meningomyelocele or encephalocele; (3) increased prominence and echogenicity of the intermediate zone before 28 weeks and/or persistence of a laminar pattern beyond 33 weeks ( n = 10), associated with Type 1 lissencephaly or CMV infection. There was a mixed focal/diffuse pattern in two fetuses. In CMV infection, the earliest indication of the infection was focal heterogeneity and increased echogenicity of the intermediate zone, which predated the development of microcephaly, ventriculomegaly and intracranial calcification. Conclusions The fetal subplate and intermediate zones can be demonstrated reliably on routine sonography before 28 weeks and disappear after 34 weeks. These findings represent normal gestational age-dependent transient laminar patterns of cerebral development and are consistent with histological studies. Abnormal fetal cerebral lamination patterns for gestational age are also visible on sonography, and may indicate abnormal brain development. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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34. Developmental Dynamics of PAFAH1B Subunits During Mouse Brain Development.
- Author
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Escamez, Teresa, Bahamonde, Olga, Tabares-Seisdedos, Rafael, Vieta, Eduard, Martinez, Salvador, and Echevarria, Diego
- Abstract
Platelet-activating factor (PAF) mediates an array of biological processes in the mammalian central nervous system as a bioactive lipid messenger in synaptic function and dysfunction (plasticity, memory, and neurodegeneration). The intracellular enzyme that deacetylates the PAF (PAFAH1B) is composed of a tetramer of two catalytic subunits, ALPHA1 (PAFAH1B3) and ALPHA2 (PAFAH1B2), and a regulatory dimer of LIS1 (PAFAH1B1). We have investigated the mouse PAFAH1B subunit genes during brain development in normal mice and in mice with a hypomorphic allele for Lis1 (Lis1/sLis1; Cahana et al. [2001] Proc Natl Acad Sci U S A 98:6429–6434). We have analyzed quantitatively (by means of real-time polymerase chain reaction) and qualitatively (by in situ hybridization techniques) the amounts and expression patterns of their transcription in developing and postnatal brain, focusing mainly on differences in two laminated encephalic regions, the forebrain (telencephalon) and hindbrain (cerebellum) separately. The results revealed significant differences in cDNA content between these two brain subdivisions but, more importantly, between the LIS1 complex subunits. In addition, we found significant spatial differences in gene expression patterns. Comparison of results obtained with Lis1/sLis1 analysis also revealed significant temporal and spatial differences in Alpha1 and Lis1 expression levels. Thus, small changes in the amount of the Lis1 gene may differentially regulate expression of Alpha1 and Alpha2, depending on the brain region, which suggests different roles for each LIS1 complex subunit during neural differentiation and neural migration. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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35. A unique role of dynein and nud family proteins in corticogenesis.
- Author
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Toba, Shiori and Hirotsune, Shinji
- Subjects
- *
DYNEIN , *CELL proliferation , *PROTEIN synthesis , *EPILEPSY , *NEURODEGENERATION - Abstract
Heterozygous LIS1 mutations are the most common cause of human lissencephaly, a human neuronal migration defect, and DCX mutations are the most common cause of X-linked lissencephaly. Lissencephaly is characterized by a smooth cerebral surface, thick cortex and dilated lateral ventricles associated with mental retardation and seizures due to defective neuronal migration. Lissencephaly due to the heterozygous loss of the gene LIS1 is a good example of a haploinsufficiency disorder. LIS1 was deleted or mutated in a large proportion of patients with lissencephaly in a heterozygous fashion. A series of studies discovered that LIS1 is an essential regulator of cytoplasmic dynein. Notably, the role of LIS1 in regulating dynein activity is highly conserved among eukaryotes. In particular, we reported that LIS1 and NDEL1 are essential for dynein transport to the plus-end of microtubules by kinesin, which is essential to maintain the proper distribution of cytoplasmic dynein within the cell. In addition, we report that mNUDC (mammalian NUDC) interacts with kinesin-1 and is required for the anterograde transport of a cytoplasmic dynein complex by kinesin-1. A microtubule organization and motor proteins are further modulated by post-translational modifications, including phosphorylation and palmitoylation. These modifications share a common pathway with mitotic cell division. For example, Aurora-A is activated during neurite elongation, and phosphorylates NDEL1, which facilitates microtubule extension into neurite processes. Elucidations of molecular pathways involving neuronal migrations provide us a chance to design a novel strategy for neurological disorder due to defective neuronal migration. For example, inhibition of calpain protects LIS1 from proteolysis resulting in the augmentation of LIS1 levels, which leads to rescue of the phenotypes that are observed in Lis1+/− mice. Endeavoring to address the regulation of the microtubule network and motor proteins will help in understanding not only corticogenesis but neurodegenerative disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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36. How the brain folds: a new genetic mechanism involving a laminin gene.
- Author
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Kumar, RA
- Subjects
- *
JUVENILE diseases , *LISSENCEPHALY , *MAGNETIC resonance imaging of the brain , *STEM cells , *NEURONS - Abstract
Recessive LAMC3 mutations cause malformations of occipital cortical development Barak et al. (2011) Nature Genetics 43(6): 590-594. Epub 15 May 2011 [ABSTRACT FROM AUTHOR]
- Published
- 2011
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37. The Japanese Society of Neuropathology.
- Subjects
- *
NEUROLOGICAL disorders , *FUNCTIONAL genomics , *DYNEIN , *LISSENCEPHALY , *BRAIN abnormalities ,ABSTRACTS - Abstract
The article presents abstracts on neuropathology which include "Functional Genomics: Phenotypic screening of large gene sets to identify genes that promote nerve regeneration," by Vance Lemmon, "A unique role of motor proteins and their friends in corticogenesis: landscape of cytoplasmic dynein and nud family proteins," by S. Hirotsune and "Genotype-phenotype correlation of brain malformations," by M. Kato.
- Published
- 2011
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38. A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay, and ambiguous genitalia in males and neuropsychiatric disorders in females.
- Author
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Ekşioğlu, Yaman Z., Pong, Amanda W., and Takeoka, Masanori
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- *
HOMEOBOX genes , *EPILEPSY risk factors , *CHILDREN'S hospitals , *INTELLECTUAL disabilities , *GENITALIA abnormality complications , *LISSENCEPHALY , *DIAGNOSIS , *GENETICS - Abstract
ARX, the aristaless-related homeobox gene, is implicated in cerebral, testicular, and pancreatic development. ARX mutations are associated with various forms of epilepsy, developmental delay, and ambiguous genitalia in humans. A mouse model that recapitulates X-linked lissencephaly with ambiguous genitalia (XLAG) is far from elucidating the substrate for phenotypes that different ARX mutations cause. Moreover, despite phenotypic pleomorphism associated with X-linked dominant ARX mutations, heterozygous female carriers have not been thoroughly studied. Reviewing records of patients with ARX mutations, infantile epilepsies, and psychomotor retardation, we analyzed a family harboring a novel ARX mutation with different phenotypes in males and females, including Ohtahara syndrome. Children's Hospital Boston patient records were retrospectively screened for patients with infantile epileptic encephalopathies who underwent ARX sequencing based on clinical suspicion. Identified families were analyzed for genetic and neuropsychiatric phenomena. The proband was a male with Ohtahara syndrome, ambiguous genitalia, psychomotor delay, and central nervous system dysgenesis due to a novel ARX mutation in exon 5, causing a frameshift in the aristaless domain. Heterozygous females demonstrated neurocognitive/psychiatric phenomena including learning difficulties, anxiety, depression, and schizophrenia. This is the first reported case of Ohtahara syndrome with abnormal genital and psychomotor development in the setting of this novel ARX mutation in exon 5. Based on the unique phenotype of the proband and on the presence of heterozygous females with neurocognitive/psychiatric ailments, this study describes the potential roles for ARX mutations in epilepsy and neuropsychiatric disease, underscoring the importance of ARX in interneuron development, cerebral electrical activity, cognition, and behavior. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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39. Long-term follow-up of type 1 lissencephaly: survival is related to neuroimaging abnormalities.
- Author
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DE WIT, MARIE-CLAIRE Y., DE RIJK-VAN ANDEL, JOJANNEKE, HALLEY, DICKY J., PODDIGHE, PINO J., ARTS, WILLEM FRANS M., DE COO, IRENAEUS F. M., and MANCINI, GRAZIA M. S.
- Subjects
- *
GENETICS , *PATIENTS , *LISSENCEPHALY , *INTELLECTUAL disabilities - Abstract
Aim: To evaluate survival, clinical, and genetic characteristics of all patients with classic or type 1 lissencephaly born between 1972 and 1990 in the Netherlands, who at the time were enrolled in an observational study.Method: We re-evaluated 24 patients (11 males, 13 females) for long-term follow-up and survival information.Results: Mean length of follow-up was 14 years (SD 9 y 8 mo). Eleven patients were alive at follow-up. All patients showed severe intellectual disability, intractable epilepsy, and complete dependency on care. Life expectancy was related to the severity of the lissencephaly on neuroimaging. Molecular analysis of the LIS1 gene was not possible at the time of the original study and was now requested by eight parents. This revealed a pathogenic nonsense mutation or deletion in seven patients.Interpretation: Our study provides information about the long-term course of lissencephaly and the relationship between lissencephaly severity and prognosis. It also shows that renewed attention to genetic counselling remains valued by families of patients with a severe congenital neurological disease. [ABSTRACT FROM AUTHOR]- Published
- 2011
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40. Abnormal development of the human cerebral cortex.
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Squier, Waney and Jansen, Anna
- Subjects
- *
CEREBRAL cortex , *FETAL brain abnormalities , *HUMAN abnormalities , *NEURAL development , *GENETICS - Abstract
This review presents an overview of human cortical malformation based on the insights gained from examination of human fetal brains. Examination at early stages of fetal brain development allows the identification of the specific pathways which are disrupted in human cortical malformation. Detailed examination of human fetal brains in parallel with studies of genetics and animal models is leading to new concepts of cortical malformations. Here we review a range of human cortical malformations based on a simple classification according to the developmental process thought to be disrupted: neuroblast proliferation, undermigration, overmigration, cortical maturation and destructive lesions. A single case example of a dated intrauterine injury illustrates the spectrum of malformations which may result at a single period in development. The recommended methods of examination of human fetal brain are described together with some of their pitfalls. Detailed neuropathological observations indicate the need for caution in the classification of malformations; radiological findings and pathology of the mature brain do not reflect the specific disruptive pathways of cortical malformations. While many insults may lead to the same pattern of malformation, a single insult can lead to multiple patterns of malformation. Our detailed studies of the human fetal brain suggest that the interface between the meninges and the radial glial end feet may be an intriguing new focus of interest in understanding cortical development. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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41. Detection of cytomegalovirus in preserved umbilical cord from a boy with autistic disorder.
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Kawatani, Masao, Nakai, Akio, Okuno, Takashi, Kobata, Ritsuyo, Moriuchi, Masako, Moriuchi, Hiroyuki, Tsukahara, Hirokazu, and Mayumi, Mitsufumi
- Subjects
- *
CASE studies , *AUTISM in children , *CYTOMEGALOVIRUS diseases , *GENETIC disorders , *LISSENCEPHALY , *MAGNETIC resonance imaging of the brain - Abstract
The article presents a case study of a Japanese boy by healthy and non-consanguineous parents at the nth week of gestation. He was admitted because of a sudden onset of right-sided hemiconvulsions. During his infancy, he was suspected of deafness due to slight social smiles, eye contact, and rare response to name calls. Magnetic resonance imaging showed a focal pachygyria and lissencephaly in the left centro-temporal regions. Moreover, a congenital cytomegalovirus infection (CMV) was suspected.
- Published
- 2010
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42. Genetic malformations of the human frontal lobe.
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Amrom, Dina and Walsh, Christopher A.
- Subjects
- *
FRONTAL lobe diseases , *HUMAN abnormalities , *GENETIC disorders , *LISSENCEPHALY , *NEURONS - Abstract
The article offers information on the genetically determined human frontal lobe malformations. It states that polymicrogyria is a malformation that can range from mild forms localized to a single gyrus, to one or more lobes. It mentions that malformations showing an interior to posterior gradient severity includes various types of lissencephaly (LIS) which is caused by deficient neuronal migration.
- Published
- 2010
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43. The clinical patterns and molecular genetics of lissencephaly and subcortical band heterotopia.
- Author
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Dobyns, William B.
- Subjects
- *
MOLECULAR genetics , *LISSENCEPHALY , *CEREBRAL cortex abnormalities , *NEURONS , *GENES - Abstract
The article presents information on the molecular genetics and clinical patterns of lissencephaly (LIS) and subcortical band heterotopia. It is stated that LIS and the related malformation subcortical band heterotopia are classic malformations associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. It mentions that first casual LIS gene was reported in 1993 and to date, there are six different genes including ARX, DCX, LISI.
- Published
- 2010
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44. Phenotypic and molecular characterization of a novel DCX deletion and a review of the literature.
- Author
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Chou, A., Boerkoel, C., du Souich, C., and Rupps, R.
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- *
LISSENCEPHALY , *BRAIN abnormalities , *LEARNING problems , *MAGNETIC resonance imaging , *NEUROSCIENCES , *GENETICS - Abstract
The article focuses on the features and genetic aspects of classical lissencephaly. Classical lissencephaly is a neuronal migration disorder and magnetic resonance imaging revealed its physical and genetic components. One patient is reported with the condition that occurred after an uncomplicated pregnancy. Analysis shows indications that the condition is associated to problems with the genetic and molecular function in the brain.
- Published
- 2009
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45. An 11-month-old boy with intractable epilepsy from birth.
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Itoh, Masayuki
- Subjects
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LISSENCEPHALY , *DEVELOPMENTAL disabilities , *X-linked intellectual disabilities , *GENETIC mutation , *INFANTS , *AUTOPSY - Abstract
The article provides information on a study about an 11-month-old boy who had an x-linked lissencephaly with abnormal genitalia (XLAG) caused by aristaless-related homeobox (ARX) gene mutation. It discusses that XLAG is a disease which is limited to male infants and shows neonatal onset of intractable epilepsy, micropenis, cryptorchidism and hypothalamic dysfunction. Information regarding the autopsy findings after two hours of his death due to central respiratory failure is discussed.
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- 2009
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46. Neuronal migration disorders: clinical, neuroradiologic and genetics aspects.
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Spalice, Alberto, Parisi, Pasquale, Nicita, Francesco, Pizzardi, Giorgia, Del Balzo, Francesca, and Iannetti, Paola
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NEURORADIOLOGY , *GENETICS , *LISSENCEPHALY , *PATHOLOGY , *CEREBRAL sulci , *DYSPLASIA , *BRAIN diseases , *EPILEPSY , *ETIOLOGY of diseases - Abstract
Disorders of neuronal migration are a heterogeneous group of disorders of nervous system development. One of the most frequent disorders is lissencephaly, characterized by a paucity of normal gyri and sulci resulting in a ‘smooth brain’. There are two pathologic subtypes: classical and cobblestone. Six different genes could be responsible for this entity (LIS1, DCX, TUBA1A, VLDLR, ARX, RELN), although co-delection of YWHAE gene with LIS1 could result in Miller–Dieker Syndrome. Heterotopia is defined as a cluster of normal neurons in abnormal locations, and divided into three main groups: periventricular nodular heterotopia, subcortical heterotopia and marginal glioneural heterotopia. Genetically, heterotopia is related to Filamin A ( FLNA) or ADP-ribosylation factor guanine exchange factor 2 ( ARFGEF2) genes mutations. Polymicrogyria is described as an augmentation of small circonvolutions separated by shallow enlarged sulci; bilateral frontoparietal form is characterized by bilateral, symmetric polymicrogyria in the frontoparietal regions. Bilateral perisylvian polymicrogyria results in a clinical syndrome manifested by mild mental retardation, epilepsy and pseudobulbar palsy. Gene mutations linked to this disorder are SRPX2, PAX6, TBR2, KIAA1279, RAB3GAP1 and COL18A1. Schizencephaly, consisting in a cleft of cerebral hemisphere connecting extra-axial subaracnoid spaces and ventricles, is another important disorder of neuronal migration whose clinical characteristics are extremely variable. EMX2 gene could be implicated in its genesis. Focal cortical dysplasia is characterized by three different types of altered cortical laminations, and represents one of most severe cause of epilepsy in children. TSC1 gene could play a role in its etiology. Conclusion: This review reports the main clinical, genetical and neuroradiological aspects of these disorders. It is hoped that accumulating data of the development mechanisms underlying the expanded network formation in the brain will lead to the development of therapeutic options for neuronal migration disorders. [ABSTRACT FROM AUTHOR]
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- 2009
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47. Refining the phenotype of α-1a Tubulin ( TUBA1A) mutation in patients with classical lissencephaly.
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Morris-Rosendahl, D. J., Najm, J., Lachmeijer, A. M. A., Sztriha, L., Martins, M., Kuechler, A., Haug, V., Zeschnigk, C., Martin, P., Santos, M., Vasconcelos, C., Omran, H., Kraus, U., Van der Knaap, M. S., Schuierer, G., Kutsche, K., and Uyanik, G.
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GENETIC mutation , *LISSENCEPHALY , *PHENOTYPES , *GENES , *HUMAN chromosome abnormality diagnosis , *GENETICS ,CORPUS callosum abnormalities - Abstract
Mutations in the α-1a Tubulin ( TUBA1A) gene have recently been found to cause cortical malformations resemblant of classical lissencephaly but with a specific combination of features. To date, TUBA1A mutations have been described in five patients and three foetuses. Our aims were to establish how common TUBA1A mutations are in patients with lissencephaly and to contribute to defining the phenotype associated with TUBA1A mutation. We performed mutation analysis in the TUBA1A gene in 46 patients with classical lissencephaly. In 44 of the patients, mutations in the LIS1 and/or DCX genes had previously been excluded; in 2 patients, mutation analysis was only performed in TUBA1A based on magnetic resonance imaging (MRI) findings. We identified three new mutations and one recurrent mutation in five patients with variable patterns of lissencephaly on brain MRI. Four of the five patients had congenital microcephaly, and all had dysgenesis of the corpus callosum and cerebellar hypoplasia, and variable cortical malformations, including subtle subcortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule. We estimate the frequency of mutation in TUBA1A gene in patients with classical lissencephaly to be approximately 4%, and although not as common as mutations in the LIS1 or DCX genes, mutation analysis in TUBA1A should be included in the molecular genetic diagnosis of classical lissencephaly, particularly in patients with the combination of features highlighted in this paper. [ABSTRACT FROM AUTHOR]
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- 2008
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48. LIS1 and NDEL1 coordinate the plus-end-directed transport of cytoplasmic dynein.
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Yamada, Masami, Toba, Shiori, Yoshida, Yuko, Haratani, Koji, Mori, Daisuke, Yano, Yoshihisa, Mimori-Kiyosue, Yuko, Nakamura, Takeshi, Itoh, Kyoko, Fushiki, Shinji, Setou, Mitsutoshi, Wynshaw-Boris, Anthony, Torisawa, Takayuki, Toyoshima, Yoko Y, and Hirotsune, Shinji
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DYNEIN , *BRAIN abnormalities , *INTELLECTUAL disabilities , *CYTOPLASMIC filaments , *MICROTUBULES - Abstract
LIS1 was first identified as a gene mutated in human classical lissencephaly sequence. LIS1 is required for dynein activity, but the underlying mechanism is poorly understood. Here, we demonstrate that LIS1 suppresses the motility of cytoplasmic dynein on microtubules (MTs), whereas NDEL1 releases the blocking effect of LIS1 on cytoplasmic dynein. We demonstrate that LIS1, cytoplasmic dynein and MT fragments co-migrate anterogradely. When LIS1 function was suppressed by a blocking antibody, anterograde movement of cytoplasmic dynein was severely impaired. Immunoprecipitation assay indicated that cytoplasmic dynein forms a complex with LIS1, tubulins and kinesin-1. In contrast, immunoabsorption of LIS1 resulted in disappearance of co-precipitated tubulins and kinesin. Thus, we propose a novel model of the regulation of cytoplasmic dynein by LIS1, in which LIS1 mediates anterograde transport of cytoplasmic dynein to the plus end of cytoskeletal MTs as a dynein–LIS1 complex on transportable MTs, which is a possibility supported by our data. [ABSTRACT FROM AUTHOR]
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- 2008
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49. Differential activation of mononuclear phagocytes in cerebellar malformation associated with Walker–Warburg syndrome.
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Ulfig, Norbert, Steinbrecher, Alice, Stoltenburg-Didinger, Gisela, and Rezaie, Payam
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LISSENCEPHALY , *NEUROMUSCULAR diseases , *PHAGOCYTES , *BRAIN abnormalities , *IMMUNE system - Abstract
Walker–Warburg syndrome (WWS) is an autosomal recessive disorder with alterations affecting the CNS that are characteristic of type-II lissencephaly and dysplasia/hypoplasia of the cerebellum. Other than these features, WWS is typically also accompanied by muscular dystrophy and abnormalities affecting the eyes. There is at present little information on the state of microglial and mononuclear phagocytic cell responses within the brain in WWS. In this case report, we present evidence for focal and differential activation of mononuclear phagocytes specifically confined to the dysplastic cerebellum of an infant at 5 months of age, diagnosed with WWS. [ABSTRACT FROM AUTHOR]
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- 2008
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50. Bilateral periventricular nodular heterotopia and lissencephaly in an infant with unbalanced t(12;17)(q24.31; p13.3) translocation.
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Grosso, Salvatore, Fichera, Marco, Galesi, Ornella, Luciano, Daniela, Pucci, Lucia, Giardini, Francesca, Berardi, Rosario, and Balestri, Paolo
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BRAIN research , *BRAIN diseases , *INFANTS , *INFANT diseases , *LISSENCEPHALY , *NODULAR disease , *GENETIC disorders - Abstract
Periventricular nodular heterotopia and Miller-Dieker syndrome are two different disorders of brain development. Miller-Dieker syndrome exhibits classical lissencephaly and is related to defects in the lissencephaly gene ( LIS1). Periventricular nodular heterotopia is characterized by aggregates of grey matter adjacent to the lateral ventricle and is mainly linked to mutations in the Filamin A (FLNA) gene. We describe a male infant presenting with facial dysmorphisms resembling those of Miller-Dieker syndrome, neuromotor delay, and drug - resistant infantile spasms. Magnetic resonance imaging of the brain showed periventricular nodular heterotopia overlaid by classical lissencephaly with complete agyria. Cytogenetic and molecular investigations detected a maternally inherited unbalanced translocation involving chromosome arms 17p and 12q. This resulted in partial monosomy of 17p13.3→pter and partial trisomy of 12q24.3→qter No mutation was found in the FLNA gene. The patient died at the age of 22 months from respiratory insufficiency during an infection of the lower respiratory tract. Our observation extends the list of the overlying cortical malformations associated with periventricular nodular heterotopia. It remains to be established whether this peculiar neuronal migration disorder represents a phenotype totally linked to 17q13.3 deletion or results from a combination of gene defects at 17q13.3 and 12q24.3. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
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