Megalencephaly and hemimegalencephaly: Breakthroughs in molecular etiology

Mirzaa, Ghayda; Poduri, Annapurna

doi:10.1002/ajmg.c.31401

Cited by 107 publications

(88 citation statements)

References 65 publications

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“…As the fairy tale goes Goldilocks selects the porridge that is Bjust right.^As introduced above the overall correlation of human brain size (volume) with IQ is positive, consistently shown to hover somewhere from .2 to .5 (Lange et al 2010;Taki et al 2012;Toga and Thompson 2005;Willerman et al 1991). However, as is well known in the pediatric literature brain growth that is either too small (microcephaly) or too large (macrocephaly) is associated with intellectual deficits and developmental disorders (Fombonne et al 1999;Mirzaa and Poduri 2014;von der Hagen et al 2014). The normalcy development as reflected in Fig.…”

Section: Size-function Rulementioning

confidence: 91%

Structural Image Analysis of the Brain in Neuropsychology Using Magnetic Resonance Imaging (MRI) Techniques

Bigler

2015

Neuropsychol Rev

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Magnetic resonance imaging (MRI) of the brain provides exceptional image quality for visualization and neuroanatomical classification of brain structure. A variety of image analysis techniques provide both qualitative as well as quantitative methods to relate brain structure with neuropsychological outcome and are reviewed herein. Of particular importance are more automated methods that permit analysis of a broad spectrum of anatomical measures including volume, thickness and shape. The challenge for neuropsychology is which metric to use, for which disorder and the timing of when image analysis methods are applied to assess brain structure and pathology. A basic overview is provided as to the anatomical and pathoanatomical relations of different MRI sequences in assessing normal and abnormal findings. Some interpretive guidelines are offered including factors related to similarity and symmetry of typical brain development along with size-normalcy features of brain anatomy related to function. The review concludes with a detailed example of various quantitative techniques applied to analyzing brain structure for neuropsychological outcome studies in traumatic brain injury.

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Section: Size-function Rulementioning

confidence: 91%

Structural Image Analysis of the Brain in Neuropsychology Using Magnetic Resonance Imaging (MRI) Techniques

Bigler

2015

Neuropsychol Rev

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“…These mutations are typically not found in the blood and are only present in the affected cortex [9,10,114,120]. In addition to somatic mutations, de novo germline mutations in this same pathway, involving PIK3R2, CCND2, and AKT3 genes, have been found with megalencephalypolymycrogyria-polydactyl-hydrocephalus (MPPH) syndrome [11].…”

Section: (D) Genetic Generalized Epilepsiesmentioning

confidence: 98%

The Genetics of the Epilepsies

Achkar

Olson

Poduri

et al. 2015

Curr Neurol Neurosci Rep

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While genetic causes of epilepsy have been hypothesized from the time of Hippocrates, the advent of new genetic technologies has played a tremendous role in elucidating a growing number of specific genetic causes for the epilepsies. This progress has contributed vastly to our recognition of the epilepsies as a diverse group of disorders, the genetic mechanisms of which are heterogeneous. Genotype-phenotype correlation, however, is not always clear. Nonetheless, the developments in genetic diagnosis raise the promise of a future of personalized medicine. Multiple genetic tests are now available, but there is no one test for all possible genetic mutations, and the balance between cost and benefit must be weighed. A genetic diagnosis, however, can provide valuable information regarding comorbidities, prognosis, and even treatment, as well as allow for genetic counseling. In this review, we will discuss the genetic mechanisms of the epilepsies as well as the specifics of particular genetic epilepsy syndromes. We will include an overview of the available genetic testing methods, the application of clinical knowledge into the selection of genetic testing, genotype-phenotype correlations of epileptic disorders, and therapeutic advances as well as a discussion of the importance of genetic counseling.

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“…Many human mutations, which activate the PI3K-AKT-mTOR pathway (PTEN is an upstream phosphatase inhibitor) have been implicated in megalencephaly, hemimegalencephaly, and polymicrogyria (4). Genetic rodent models have provided limited insight to the pathogenesis of cortical migration disorders as rodents have a naturally lissencephalic cortex and many cerebral overgrowth models have mild phenotypes in rodents while causing severe disease in humans.…”

Section: Commentarymentioning

confidence: 99%

You Have Brains in Your Head, You Have Organoids in Your Dish, you Can Steer Yourself in any Direction you Wish

Thodeson¹,

Hsieh²

2017

Epilepsy Curr

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An expansion of the cerebral neocortex is thought to be the foundation for the unique intellectual abilities of humans. It has been suggested that an increase in the proliferative potential of neural progenitors (NPs) underlies the expansion of the cortex and its convoluted appearance. Here we show that increasing NP proliferation induces expansion and folding in an in vitro model of human corticogenesis. Deletion of PTEN stimulates proliferation and generates significantly larger and substantially folded cerebral organoids. This genetic modification allows sustained cell cycle reentry, expansion of the progenitor population, and delayed neuronal differentiation, all key features of the developing human cortex. In contrast, Pten deletion in mouse organoids does not lead to folding. Finally, we utilized the expanded cerebral organoids to show that infection with Zika virus impairs cortical growth and folding. Our study provides new insights into the mechanisms regulating the structure and organization of the human cortex. Classical lissencephaly is a genetic neurological disorder associated with mental retardation and intractable epilepsy, and Miller-Dieker syndrome (MDS) is the most severe form of the disease. In this study, to investigate the effects of MDS on human progenitor subtypes that control neuronal output and influence brain topology, we analyzed cerebral organoids derived from control and MDS-induced pluripotent stem cells (iPSCs) using time-lapse imaging, immunostaining, and single-cell RNA sequencing. We saw a cell migration defect that was rescued when we corrected the MDS causative chromosomal deletion and severe apoptosis of the founder neuroepithelial stem cells, accompanied by increased horizontal cell divisions. We also identified a mitotic defect in outer radial glia, a progenitor subtype that is largely absent from lissencephalic rodents but critical for human neocortical expansion. Our study, therefore, deepens our understanding of MDS cellular pathogenesis and highlights the broad utility of cerebral organoids for modeling humanneurodevelopmental disorders. The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the Ca V 1.2 calcium Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia Assembly of F...

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Megalencephaly and hemimegalencephaly: Breakthroughs in molecular etiology

Cited by 107 publications

References 65 publications

Structural Image Analysis of the Brain in Neuropsychology Using Magnetic Resonance Imaging (MRI) Techniques

Structural Image Analysis of the Brain in Neuropsychology Using Magnetic Resonance Imaging (MRI) Techniques

The Genetics of the Epilepsies

You Have Brains in Your Head, You Have Organoids in Your Dish, you Can Steer Yourself in any Direction you Wish

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