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Journal of Human Genetics Feb 2018
Topics: Calcinosis; Humans; Mutation; Occludin; Polymicrogyria
PubMed: 29192239
DOI: 10.1038/s10038-017-0390-y -
Journal of Pediatric Neurosciences 2017Encephalocranial lipomatosis is a rare disorder that characteristically involves ectomesodermal tissues such as skin, eye, and the central nervous system. Here, we...
Encephalocranial lipomatosis is a rare disorder that characteristically involves ectomesodermal tissues such as skin, eye, and the central nervous system. Here, we report a 3-year-old girl presented with developmental delay, seizures, limbal dermoid, and weakness of right lower limb. Imaging revealed hemiatrophy, arachnoid cyst, and polymicrogyria. The constellation of clinical finding and imaging leads to the diagnosis.
PubMed: 28553398
DOI: 10.4103/jpn.JPN_130_16 -
Brain & Development Mar 2015The tubulin gene family is mainly expressed in post-mitotic neurons during cortical development with a specific spatial and temporal expression pattern. Members of this... (Review)
Review
The tubulin gene family is mainly expressed in post-mitotic neurons during cortical development with a specific spatial and temporal expression pattern. Members of this family encode dimeric proteins consisting of two closely related subunits (α and β), representing the major constituents of microtubules. Tubulin genes play a crucial role in the mechanisms of the Central Nervous System development such as neuronal migration and axonal guidance (axon outgrowth and maintenance). Different mutations in α/β-tubulin genes (TUBA1A, TUBA8, TUBB2A, TUBB4A, TUBB2B, TUBB3, and TUBB) might alter the dynamic properties and functions of microtubules in several ways, effecting a reduction in the number of functional tubulin heterodimers and causing alterations in GTP binding and disruptions of the binding of other proteins to microtubules (motor proteins and other microtubule interacting proteins). In recent years an increasing number of brain malformations has been associated with mutations in tubulin genes: malformations of cortical development such as lissencephaly and various grades of gyral disorganization, focal or diffuse polymicrogyria and open or closed-lips schizencephaly as likely consequences of an altered neuronal migration process; abnormalities or agenesis of the midline commissural structures (anterior commissure, corpus callosum and fornix), hypoplasia of the oculomotor and optic nerves, dysmorphisms of the hind-brain as expression of axon guidance disorders. Dysmorphisms of the basal ganglia (fusion between the caudate nucleus and putamen with absence of the anterior limb of the internal capsule) and hippocampi were also observed. A rare form of leukoencephalopathy characterized by hypomyelination with atrophy of the basal ganglia an cerebellum (H-ABC) was also recently described. The present review, describing the structural and functional features of tubulin genes, aims to revise the main cerebral associated malformations and related clinical aspects, suggesting a genotype-phenotype correlation.
Topics: Brain; Humans; Nervous System Malformations; Tubulin
PubMed: 25008804
DOI: 10.1016/j.braindev.2014.06.002 -
Soft Matter Feb 2021The characteristically folded surface of the human brain is critical for brain function and allows for higher cognitive abilities. Recent mostly computational research...
The characteristically folded surface of the human brain is critical for brain function and allows for higher cognitive abilities. Recent mostly computational research advances have shown that mechanical instabilities play a crucial role during early brain development and cortical folding. However, it is difficult to investigate such mechanisms in vivo. To experimentally gain deeper insights into the physical mechanisms that underlie the development of brain shape, we use a setup of swelling polymers. We investigate the influence of cortical thickness and the stiffness ratio between cortex and subcortex on the resulting surface pattern by taking the initially smooth fetal brain geometry at week 22 into consideration. The gel specimens possess a two-layered structure accounting for gray and white matter tissue and yield complex surface morphologies that well resemble patterns in the human brain. The results are in good agreement with analytical predictions. Through the variation of cortical thickness and stiffness, it is possible to reproduce cortical malformations such as polymicrogyria and lissencephaly. The results suggest that wrinkling with subsequent transition into folding is the driving instability mechanism during brain development. In addition, the experiments provide valuable insights towards the distinction between wrinkling and creasing instabilities. Taken together, the presented swelling experiments impressively demonstrate the purely physical aspects of brain shape and constitute a valuable tool to advance our understanding of human brain development.
Topics: Brain; Humans; Magnetic Resonance Imaging; Polymers
PubMed: 33480902
DOI: 10.1039/d0sm02209h -
Pediatric Neurology Sep 2021In 2018, I was honored to receive the Bernard Sachs Award for a lifetime of work expanding knowledge of diverse neurodevelopmental disorders. Summarizing work over more... (Review)
Review
In 2018, I was honored to receive the Bernard Sachs Award for a lifetime of work expanding knowledge of diverse neurodevelopmental disorders. Summarizing work over more than 30 years is difficult but is an opportunity to chronicle the dramatic changes in the medical and scientific world that have transformed the field of Child Neurology over this time, as reflected in my own work. Here I have chosen to highlight five broad themes of my research beginning with my interest in descriptive terms that drive wider understanding and my choice for the title of this review. From there I will go on to contrast the state of knowledge as I entered the field with the state of knowledge today for four human brain malformations-lissencephaly, megalencephaly, cerebellar malformations, and polymicrogyria. For all, the changes have been dramatic.
Topics: Awards and Prizes; Cerebellar Diseases; Child; Humans; Lissencephaly; Megalencephaly; Polymicrogyria; Terminology as Topic
PubMed: 34330614
DOI: 10.1016/j.pediatrneurol.2021.05.006 -
Molecular Neurobiology Jul 2023Tubulins are the highly conserved subunit of microtubules which involve in various fundamental functions including brain development. Microtubules help in neuronal... (Review)
Review
Tubulins are the highly conserved subunit of microtubules which involve in various fundamental functions including brain development. Microtubules help in neuronal proliferation, migration, differentiation, cargo transport along the axons, synapse formation, and many more. Tubulin gene family consisting of multiple isotypes, their differential expression and varied post translational modifications create a whole new level of complexity and diversity in accomplishing manifold neuronal functions. The studies on the relation between tubulin genes and brain development opened a new avenue to understand the role of each tubulin isotype in neurodevelopment. Mutations in tubulin genes are reported to cause brain development defects especially cortical malformations, referred as tubulinopathies. There is an increased need to understand the molecular correlation between various tubulin mutations and the associated brain pathology. Recently, mutations in tubulin isotypes (TUBA1A, TUBB, TUBB1, TUBB2A, TUBB2B, TUBB3, and TUBG1) have been linked to cause various neurodevelopmental defects like lissencephaly, microcephaly, cortical dysplasia, polymicrogyria, schizencephaly, subcortical band heterotopia, periventricular heterotopia, corpus callosum agenesis, and cerebellar hypoplasia. This review summarizes on the microtubule dynamics, their role in neurodevelopment, tubulin isotypes, post translational modifications, and the role of tubulin mutations in causing specific neurodevelopmental defects. A comprehensive list containing all the reported tubulin pathogenic variants associated with brain developmental defects has been prepared to give a bird's eye view on the broad range of tubulin functions.
Topics: Humans; Tubulin; Brain; Microcephaly; Mutation; Malformations of Cortical Development; Microtubules; Brain Diseases
PubMed: 36943622
DOI: 10.1007/s12035-023-03302-1 -
Brain Communications 2021Polymicrogyria is a malformation of cortical development characterized by overfolding and abnormal lamination of the cerebral cortex. Manifestations include epilepsy,...
Polymicrogyria is a malformation of cortical development characterized by overfolding and abnormal lamination of the cerebral cortex. Manifestations include epilepsy, speech disturbance and motor and cognitive disability. Causes include acquired prenatal insults and inherited and genetic variants. The proportion of patients with polymicrogyria and a causative germline or mosaic variant is not known. The aim of this study was to identify the monogenic causes of polymicrogyria in a heterogeneous cohort of patients reflective of specialized referral services. Patients with polymicrogyria were recruited from two clinical centres in Australia and Belgium. Patients with evidence of congenital cytomegalovirus infection or causative chromosomal copy number variants were excluded. One hundred and twenty-three patients were tested using deep sequencing gene panels including known and candidate genes for malformations of cortical development. Causative and potentially causative variants were identified and correlated with phenotypic features. Pathogenic or likely pathogenic variants were identified in 25/123 (20.3%) patients. A candidate variant was identified for an additional patient but could not be confirmed as , and therefore it was classified as being of uncertain significance with high clinical relevance. Of the 22 dominant variants identified, 5 were mosaic with allele fractions less than 0.33 and the lowest allele fraction 0.09. The most common causative genes were and . The other eleven causative genes were , , and . A genetic cause was more likely to be identified in the presence of an abnormal head size or additional brain malformations suggestive of a tubulinopathy, such as dysmorphic basal ganglia. A gene panel test provides greater sequencing depth and sensitivity for mosaic variants than whole exome or genome sequencing but is limited to the genes included, potentially missing variants in newly discovered genes. The diagnostic yield of 20.3% indicates that polymicrogyria may be associated with genes not yet known to be associated with brain malformations, brain-specific somatic mutations or non-genetic causes.
PubMed: 33604570
DOI: 10.1093/braincomms/fcaa221 -
Cerebral Cortex (New York, N.Y. : 1991) Mar 2018Polymicrogyria is a malformation of cortical folding and layering underlying different cognitive and neurological manifestations. The polymicrogyric cortex has...
Polymicrogyria is a malformation of cortical folding and layering underlying different cognitive and neurological manifestations. The polymicrogyric cortex has heterogeneous morphofunctional patterns, qualitatively described at magnetic resonance imaging (MRI) by variable severity gradients and functional activations. We investigated the link between abnormal cortical folding and cortical function in order to improve surgical planning for patients with polymicrogyria and intractable epilepsy. We performed structural and functional MRI on 14 patients with perisylvian polymicrogyria and adopted surface-based methods to detect alterations of cortical thickness (CT) and local gyrification index (LGI) compared with normal cortex (30 age-matched subjects). We quantitatively assessed the grade of anatomic disruption of the polymicrogyric cortex and defined its relationship with decreased cortical function. We observed a good matching between visual analysis and morphometric measurements. CT maps revealed sparse clusters of thickening, while LGI maps disclosed circumscribed regions of maximal alteration with a uniformly decreasing centrifugal gradient. In polymicrogyric areas in which gyral and sulcal patterns were preserved, functional activation maintained the expected location, but was reduced in extent. Morphofunctional correlations, evaluated along cortico-cortical paths between maximum morphologic alterations and significant activations, identified an interindividual threshold for LGI (z-value = -1.09) beyond which functional activations were no longer identifiable.
Topics: Brain Mapping; Case-Control Studies; Female; Functional Laterality; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Oxygen; Polymicrogyria
PubMed: 28334078
DOI: 10.1093/cercor/bhx036 -
Developmental Medicine and Child... Oct 2019We aimed to systematically review the speech production, language, and oral function phenotype of bilateral perisylvian polymicrogyria (BPP), and examine the correlation...
AIM
We aimed to systematically review the speech production, language, and oral function phenotype of bilateral perisylvian polymicrogyria (BPP), and examine the correlation between the topography of polymicrogyria and the severity of speech, language, and oral functional impairment.
METHOD
A systematic search of MEDLINE, Embase, and PubMed databases was completed on 26th October 2017 using Medical Subject Heading terms synonymous with BPP and speech, language, or oral motor impairment. In total, 2411 papers were identified and 48 met inclusion criteria.
RESULTS
Expressive and receptive language impairment and oral structural and functional deficits are frequent in BPP. Expressive deficits are frequently more severe than receptive. Only one study used formal assessments to demonstrate the presence of speech disorder, namely dysarthria. Seven studies reported an association between diffuse BPP and more severe language impairment.
INTERPRETATION
Findings confirmed that language deficits are common in BPP, though assessment of the specific speech phenotype is limited. The paucity of high quality studies detailing the specific communication phenotype of BPP highlights the need for further investigation. Improving understanding of this phenotype will inform the development of targeted therapies and lead to better long-term outcomes.
WHAT THIS PAPER ADDS
Speech, language, and oral functional impairments are common in individuals with bilateral perisylvian polymicrogyria. Posterior polymicrogyria is associated with a less severe language impairment than anterior polymicrogyria. Deeper investigation of speech is needed to understand implicated networks in this malformation.
Topics: Abnormalities, Multiple; Humans; Intellectual Disability; Language; Language Development Disorders; Malformations of Cortical Development; Phenotype; Severity of Illness Index; Speech
PubMed: 30680716
DOI: 10.1111/dmcn.14153 -
Seizure Oct 2023To evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting.
PURPOSE
To evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting.
METHODS
In this retrospective observational study, we included PwE with epilepsy who received a prescription for CBD between 01.03.2019 and 30.11.2022 and had a follow-up period ≥ 3 months. Participants were evaluated at baseline and after 3, 6, and 12 months. "Responders" were defined as individuals experiencing a reduction in seizure frequency > 30% but < 80% compared to baseline, while "super responders" were those with a reduction ≥ 80%. Adverse events were recorded to assess safety.
RESULTS
Forty-two PwE were included (mean age 36.1 ± 10.9 years; 14 females). In 24 patients CBD was prescribed on-label (Lennox-Gastaut syndrome, n = 18; Dravet syndrome, n = 5; tuberous sclerosis, n = 1), while 18 patients were treated off-label (ring chromosome 20 syndrome, n = 1; ring chromosome 17 syndrome, n = 1; Lafora disease, n = 3; Unverricht-Lundborg disease, n = 1; polymicrogyria, n = 2; febrile infection-related epilepsy syndrome, n = 1; non-lesional focal epilepsy, n = 2; developmental and/or epileptic encephalopathy of unknown etiology n = 6). The mean number of concomitant antiseizure medications was 3.4 (≥2 for all patients). At 3 months, 10 subjects (23%) were "responders" and 12 (29%) were "super-responders". Efficacy was sustained at 6 and 12 months of follow-up. Twenty-two patients (52.3%) developed AEs, with drowsiness (36.5%) and diarrhea (9.8%) being the most common. The retention rate was 85.7%, 78.6%, and 71.4% at 3, 6, and 12 months, respectively.
CONCLUSIONS
In this monocentric real-world study, CBD was a safe and effective therapeutic option for highly drug-resistant patients, leading to a dramatic reduction in seizure frequency in over one-fourth of them, including off-label indications.
PubMed: 37506564
DOI: 10.1016/j.seizure.2023.07.009