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Neuropathology and Applied Neurobiology Oct 2023
Topics: Humans; Cobblestone Lissencephaly; Brain; Lissencephaly
PubMed: 37766395
DOI: 10.1111/nan.12939 -
Development (Cambridge, England) Sep 2023Cortical folding is a highly regulated process involving amplification of neuroprogenitor cells, increased neurogenesis and migration of neurons along the tangential...
Cortical folding is a highly regulated process involving amplification of neuroprogenitor cells, increased neurogenesis and migration of neurons along the tangential axis. A new paper in Development investigates the signalling processes behind cortical folding in mice, which have a smooth brain surface (lissencephaly) that evolved from the loss of folding present in gyrencephalic (folded cortex) mammals. To hear more about the story behind the paper, we caught up with the first author Matt Matrongolo and his supervisor Max Tischfield, Assistant Professor at Rutgers, The State University of New Jersey.
Topics: Humans; Animals; Mice; Neurogenesis; Neurons; Research Personnel; Mammals
PubMed: 37747267
DOI: 10.1242/dev.202286 -
Journal of Shoulder and Elbow Surgery Feb 2024A double cortical button technique for ulnar collateral ligament reconstruction (UCLR) has advantages including significant control over graft tensioning, less concern...
BACKGROUND AND HYPOTHESIS
A double cortical button technique for ulnar collateral ligament reconstruction (UCLR) has advantages including significant control over graft tensioning, less concern about graft length, and minimized risk of bone tunnel fracture compared with traditional UCLR techniques. This double cortical button technique was recently found to be noninferior in mechanical performance to the traditional docking technique regarding joint strength, joint stiffness, and graft strain. However, clinical outcomes have not been compared between these UCLR techniques. Therefore, the purpose of this study was to determine whether baseball players who underwent UCLR with a double cortical button (double button) technique have similar return-to-sport (RTS) outcomes to baseball players who underwent UCLR with the traditional docking (docking) technique.
MATERIALS AND METHODS
Baseball players who underwent primary UCLR from 2011 to 2020 across 2 institutions were identified. Included patients were contacted to complete a follow-up survey evaluating reoperations, RTS, and functional outcome scores. Functional outcome surveys include the Kerlan-Jobe Orthopaedic Clinic score, the Conway-Jobe score, the Andrews-Timmerman elbow score, and the Single Assessment Numeric Evaluation score.
RESULTS
Overall, 78 male baseball players (age: 18.9 ± 2.4 years) with an average follow-up of 3.1 ± 2.4 years were evaluated, with 73 of the players being baseball pitchers. Players in the double button group more frequently received palmaris longus autografts (78% vs. 30%) and less frequently received gracilis autografts (22% vs. 58%) compared with players in the docking group (P = .001); however, all other demographic factors were similar between the groups. All players in the double button group were able to RTS in 11.1 ± 2.6 months, whereas 96% of players in the docking group were able to RTS in 13.5 ± 3.4 months (P > .05). All postoperative outcomes and patient-reported outcomes were statistically similar between the groups and remained similar after isolating pitchers only and after separating partial-thickness from full-thickness UCL tears (all P > .05).
CONCLUSION
RTS and other postoperative outcomes may be similar between baseball players who underwent UCLR with the double button technique and the docking technique. Although future research may be necessary to strengthen clinical recommendations, these findings provide the first clinical outcomes in light of a recent cadaveric study finding similar elbow strength, joint stiffness, and graft strain compared with the docking technique.
Topics: Humans; Male; Adolescent; Young Adult; Adult; Baseball; Return to Sport; Ulnar Collateral Ligament Reconstruction; Collateral Ligament, Ulnar; Elbow; Elbow Joint; Collateral Ligaments; Classical Lissencephalies and Subcortical Band Heterotopias
PubMed: 37689100
DOI: 10.1016/j.jse.2023.07.045 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Sep 2023To explore the clinical characteristics and genetic basis for a child with X-linked lissencephaly with abnormal genitalia (XLAG).
OBJECTIVE
To explore the clinical characteristics and genetic basis for a child with X-linked lissencephaly with abnormal genitalia (XLAG).
METHODS
A child with XLAG who had presented at the Third Affiliated Hospital of Zhengzhou University in May 2021 was selected as the study subject. Peripheral blood samples of the child and his parents were collected and subjected to high-throughput sequencing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the result was analyzed by using bioinformatic software.
RESULTS
The child was found to have harbored a hemizygous c.945_948del variant in exon 2 of the ARX gene, which as a frameshifting variant has resulted in a truncated protein. His mother was found to be heterozygous for the variant, whilst his father was of wild type. The variant was unreported previously.
CONCLUSION
The hemizygous c.945_948del variant of the ARX gene probably underlay the XLAG in this patient. Above finding has provided a basis for the diagnosis and genetic counseling for this family.
Topics: Humans; Child; Classical Lissencephalies and Subcortical Band Heterotopias; Exons; Computational Biology; Genetic Counseling; Genitalia; Transcription Factors; Homeodomain Proteins
PubMed: 37643961
DOI: 10.3760/cma.j.cn511374-20220603-00380 -
American Journal of Medical Genetics.... Dec 2023Lissencephaly type 10 is a recently reported condition characterized by posterior predominant abnormalities in gyration with associated seizures, developmental delays or... (Review)
Review
Lissencephaly type 10 is a recently reported condition characterized by posterior predominant abnormalities in gyration with associated seizures, developmental delays or intellectual disability. We report a boy who presented at 5 years of age with epilepsy and developmental delays. His family history was notable for epilepsy in two prior generations associated with variable developmental and cognitive impact. Exome sequencing identified a novel missense variant in CEP85L [NM_001042475.2; c.196A>G, p.(Thr66Ala)] which segregated in four affected family members across three generations. Brain imaging of the proband demonstrated a posterior lissencephaly pattern with pachygyria, while other affected family members demonstrated a similar subcortical band heterotopia. This report expands the phenotypic spectrum of this rare disorder by describing a novel variant in CEP85L in a family with variable clinical and neuroimaging findings.
Topics: Male; Humans; Lissencephaly; Classical Lissencephalies and Subcortical Band Heterotopias; Brain; Mutation, Missense; Epilepsy; Cytoskeletal Proteins; Oncogene Proteins, Fusion
PubMed: 37621218
DOI: 10.1002/ajmg.a.63380 -
The Neuroscientist : a Review Journal... Aug 2023The cerebral cortex develops through a carefully conscripted series of cellular and molecular events that culminate in the production of highly specialized neuronal and... (Review)
Review
The cerebral cortex develops through a carefully conscripted series of cellular and molecular events that culminate in the production of highly specialized neuronal and glial cells. During development, cortical neurons and glia acquire a precise cellular arrangement and architecture to support higher-order cognitive functioning. Decades of study using rodent models, naturally gyrencephalic animal models, human pathology specimens, and, recently, human cerebral organoids, reveal that rodents recapitulate some but not all the cellular and molecular features of human cortices. Whereas rodent cortices are smooth-surfaced or lissencephalic, larger mammals, including humans and nonhuman primates, have highly folded/gyrencephalic cortices that accommodate an expansion in neuronal mass and increase in surface area. Several genes have evolved to drive cortical gyrification, arising from gene duplications or de novo origins, or by alterations to the structure/function of ancestral genes or their gene regulatory regions. Primary cortical folds arise in stereotypical locations, prefigured by a molecular "blueprint" that is set up by several signaling pathways (e.g., Notch, Fgf, Wnt, PI3K, Shh) and influenced by the extracellular matrix. Mutations that affect neural progenitor cell proliferation and/or neurogenesis, predominantly of upper-layer neurons, perturb cortical gyrification. Below we review the molecular drivers of cortical folding and their roles in disease.
PubMed: 37621149
DOI: 10.1177/10738584231190839 -
Nature Structural & Molecular Biology Sep 2023Cytoplasmic dynein-1 transports intracellular cargo towards microtubule minus ends. Dynein is autoinhibited and undergoes conformational changes to form an active...
Cytoplasmic dynein-1 transports intracellular cargo towards microtubule minus ends. Dynein is autoinhibited and undergoes conformational changes to form an active complex that consists of one or two dynein dimers, the dynactin complex, and activating adapter(s). The Lissencephaly 1 gene, LIS1, is genetically linked to the dynein pathway from fungi to mammals and is mutated in people with the neurodevelopmental disease lissencephaly. Lis1 is required for active dynein complexes to form, but how it enables this is unclear. Here, we present a structure of two yeast dynein motor domains with two Lis1 dimers wedged in-between. The contact sites between dynein and Lis1 in this structure, termed 'Chi,' are required for Lis1's regulation of dynein in Saccharomyces cerevisiae in vivo and the formation of active human dynein-dynactin-activating adapter complexes in vitro. We propose that this structure represents an intermediate in dynein's activation pathway, revealing how Lis1 relieves dynein's autoinhibited state.
Topics: Animals; Humans; Cytoplasmic Dyneins; Dyneins; Classical Lissencephalies and Subcortical Band Heterotopias; Biological Transport; Cytoskeleton; Dynactin Complex; Oligonucleotides; Mammals
PubMed: 37620585
DOI: 10.1038/s41594-023-01069-6 -
BioRxiv : the Preprint Server For... Aug 2023PRDM16 is a dynamic transcriptional regulator of various stem cell niches, including adipocytic, hematopoietic, cardiac progenitors, and neural stem cells. PRDM16 has...
PRDM16 is a dynamic transcriptional regulator of various stem cell niches, including adipocytic, hematopoietic, cardiac progenitors, and neural stem cells. PRDM16 has been suggested to contribute to 1p36 deletion syndrome, one of the most prevalent subtelomeric microdeletion syndromes. We report a patient with a de novo nonsense mutation in the PRDM16 coding sequence, accompanied by lissencephaly and microcephaly features. Human stem cells were genetically modified to mimic this mutation, generating cortical organoids that exhibited altered cell cycle dynamics. RNA sequencing of cortical organoids at day 32 unveiled changes in cell adhesion and WNT-signaling pathways. ChIP-seq of PRDM16 identified binding sites in postmortem human fetal cortex, indicating the conservation of PRDM16 binding to developmental genes in mice and humans, potentially at enhancer sites. A shared motif between PRDM16 and LHX2 was identified and further examined through comparison with LHX2 ChIP-seq data from mice. These results suggested a collaborative partnership between PRDM16 and LHX2 in regulating a common set of genes and pathways in cortical radial glia cells, possibly via their synergistic involvement in cortical development.
PubMed: 37609127
DOI: 10.1101/2023.08.12.553065 -
Development (Cambridge, England) Sep 2023Secondary lissencephaly evolved in mice due to effects on neurogenesis and the tangential distribution of neurons. Signaling pathways that help maintain lissencephaly...
Secondary lissencephaly evolved in mice due to effects on neurogenesis and the tangential distribution of neurons. Signaling pathways that help maintain lissencephaly are still poorly understood. We show that inactivating Twist1 in the primitive meninges causes cortical folding in mice. Cell proliferation in the meninges is reduced, causing loss of arachnoid fibroblasts that express Raldh2, an enzyme required for retinoic acid synthesis. Regionalized loss of Raldh2 in the dorsolateral meninges is first detected when folding begins. The ventricular zone expands and the forebrain lengthens at this time due to expansion of apical radial glia. As the cortex expands, regionalized differences in the levels of neurogenesis are coupled with changes to the tangential distribution of neurons. Consequentially, cortical growth at and adjacent to the midline accelerates with respect to more dorsolateral regions, resulting in cortical buckling and folding. Maternal retinoic acid supplementation suppresses cortical folding by normalizing forebrain length, neurogenesis and the tangential distribution of neurons. These results suggest that Twist1 and balanced retinoic acid signaling from the meninges are required to maintain normal levels of neurogenesis and lissencephaly in mice.
Topics: Animals; Mice; Cerebral Cortex; Lissencephaly; Meninges; Neurogenesis; Neurons; Tretinoin
PubMed: 37590085
DOI: 10.1242/dev.201381 -
International Journal of Developmental... Nov 2023Cortical development depends on neuronal migration of both excitatory and inhibitory interneurons. Neuronal migration disorders (NMDs) are conditions characterised by... (Review)
Review
Cortical development depends on neuronal migration of both excitatory and inhibitory interneurons. Neuronal migration disorders (NMDs) are conditions characterised by anatomical cortical defects leading to varying degrees of neurocognitive impairment, developmental delay and seizures. Refractory epilepsy affects 15 million people worldwide, and it is thought that cortical developmental disorders are responsible for 25% of childhood cases. However, little is known about the epidemiology of these disorders, nor are their aetiologies fully understood, though many are associated with sporadic genetic mutations. In this review, we aim to highlight X-linked NMDs including lissencephaly, periventricular nodular heterotopia and polymicrogyria because of their mostly familial inheritance pattern. We focus on the most prominent genes responsible: including DCX, ARX, FLNA, FMR1, L1CAM, SRPX2, DDX3X, NSHDL, CUL4B and OFD1, outlining what is known about their prevalence among NMDs, and the underlying pathophysiology. X-linked disorders are important to recognise clinically, as females often have milder phenotypes. Consequently, there is a greater chance they survive to reproductive age and risk passing the mutations down. Effective genetic screening is important to prevent and treat these conditions, and for this, we need to know gene mutations and have a clear understanding of the function of the genes involved. This review summarises the knowledge base and provides clear direction for future work by both scientists and clinicians alike.
Topics: Female; Humans; Epilepsy; Sex Factors; Genetic Testing; Mutation; Malformations of Cortical Development, Group II; Fragile X Mental Retardation Protein; Cullin Proteins
PubMed: 37574439
DOI: 10.1002/jdn.10290