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Epilepsy & Behavior Reports 2024Type 1 lissencephaly is a brain malformation characterized by agyria and pachygyria and is known to be caused by congenital infections and genetic variations. Here we...
Type 1 lissencephaly is a brain malformation characterized by agyria and pachygyria and is known to be caused by congenital infections and genetic variations. Here we present a case of a 4-month-old female with new onset infantile epileptic spasms syndrome (IESS) with initial etiology concerned for congenital cytomegalovirus (cCMV) due to a positive urine CMV PCR and maternal viral syndrome during pregnancy. Her brain MRI was significant for type 1 lissencephaly without other radiographical features of cCMV. The patient initially responded to high dose Prednisolone but had relapse of spasms at 9-month-old and required an ACTH course. She later developed generalized tonic seizures and focal impaired awareness seizures. Subsequent whole exome sequencing (WES) trio revealed a (c.405G > A, p.W135*) heterozygous nonsense variant which is pathogenic and thus solved the diagnostic puzzle. This case demonstrates that the absence of cCMV stigmata should raise concern for alternative etiology in cases of lissencephaly and the importance of genetic evaluation for subsequent management and family counseling.
PubMed: 38617375
DOI: 10.1016/j.ebr.2024.100664 -
Oxford Open Neuroscience 2024PRDM16 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 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: 38595939
DOI: 10.1093/oons/kvae001 -
Science (New York, N.Y.) Mar 2024Cytoplasmic dynein is a microtubule motor vital for cellular organization and division. It functions as a ~4-megadalton complex containing its cofactor dynactin and a...
Cytoplasmic dynein is a microtubule motor vital for cellular organization and division. It functions as a ~4-megadalton complex containing its cofactor dynactin and a cargo-specific coiled-coil adaptor. However, how dynein and dynactin recognize diverse adaptors, how they interact with each other during complex formation, and the role of critical regulators such as lissencephaly-1 (LIS1) protein (LIS1) remain unclear. In this study, we determined the cryo-electron microscopy structure of dynein-dynactin on microtubules with LIS1 and the lysosomal adaptor JIP3. This structure reveals the molecular basis of interactions occurring during dynein activation. We show how JIP3 activates dynein despite its atypical architecture. Unexpectedly, LIS1 binds dynactin's p150 subunit, tethering it along the length of dynein. Our data suggest that LIS1 and p150 constrain dynein-dynactin to ensure efficient complex formation.
Topics: Cryoelectron Microscopy; Dynactin Complex; Dyneins; Microtubule-Associated Proteins; Microtubules; Protein Binding; Humans; HeLa Cells; 1-Alkyl-2-acetylglycerophosphocholine Esterase; Nerve Tissue Proteins; Adaptor Proteins, Signal Transducing; WD40 Repeats; Protein Interaction Mapping
PubMed: 38547289
DOI: 10.1126/science.adk8544 -
Georgian Medical News Jan 2024Pediatric neuroimaging presents a unique set of challenges, primarily stemming from the intricacies of normal myelination processes occurring within the initial two...
Pediatric neuroimaging presents a unique set of challenges, primarily stemming from the intricacies of normal myelination processes occurring within the initial two years of life. This complexity is particularly pronounced in the context of pediatric epilepsy, where a substantial proportion of neuroimaging cases appears normal, especially in instances of idiopathic or provoked seizures. Nevertheless, abnormalities in neuroimaging tend to manifest in cases of acute or remote symptomatic seizures. Notably, the etiological landscape of seizures in children diverges significantly from that observed in adults, with neurodevelopmental, neurometabolic, and neuro-infectious factors emerging as predominant contributors. This multicentric study, conducted between November 2021 and November 2023, spanned diverse hospitals across various states in India. Encompassing children from birth to 12 years of age experiencing acute and remote symptomatic seizures, the study meticulously documented clinical and demographic profiles. Exclusion criteria were applied, excluding typical febrile seizures and idiopathic epilepsy syndromes to ensure a focused analysis. The study encompassed a total of 109 cases, revealing a spectrum of neuroimaging findings. Noteworthy among these were cortical malformations, including focal cortical dysplasia (12 cases), tuberous sclerosis (6 cases), polymicrogyria (3 cases), hemimegalencephaly (1 case), lissencephaly (1 case), schizencephaly (2 cases), heterotopias (3 cases), cavernous hemangioma (1 case), and AV malformation (1 case). Additionally, neoplastic lesions (6 cases), neurocysticercosis (5 cases), tuberculoma (4 cases), hippocampal sclerosis (3 cases), post-hypoxic and cerebrovascular accident gliosis (3 cases), leukodystrophies (2 cases), and non-lesional cases (58 cases) were documented. Pediatric neuroimaging in symptomatic seizures may present with normal findings, influenced by interpreter bias and the non-uniform availability of 3T MRI across different medical centers. The diverse causative factors for symptomatic seizures underscore the impact of demographic features, including the endemicity of specific infections and birth injuries, on the observed variability across medical centers. These findings underscore the imperative for a comprehensive understanding and standardization in pediatric neuroimaging practices.
Topics: Child; Child, Preschool; Humans; Infant; Infant, Newborn; Epilepsy; India; Magnetic Resonance Imaging; Neuroimaging; Stroke
PubMed: 38501627
DOI: No ID Found -
BioRxiv : the Preprint Server For... Feb 2024Doublecortin (DCX) is a microtubule-associated protein critical for brain development. Although most highly expressed in the developing central nervous system, the...
Doublecortin (DCX) is a microtubule-associated protein critical for brain development. Although most highly expressed in the developing central nervous system, the molecular function of DCX in neuron morphogenesis remains unknown and controversial. We demonstrate that DCX function is intimately linked to its microtubule-binding activity. By using human induced pluripotent stem cell (hiPSC)- derived cortical i Neurons genome engineered to express mEmerald-tagged DCX from the endogenous locus, we find that DCX-MT interactions become highly polarized very early during neuron morphogenesis. DCX becomes enriched only on straight microtubules in advancing growth cones with approximately 120 DCX molecules bound per micrometer of growth cone microtubule. At a similar saturation, microtubule-bound DCX molecules begin to impede lysosome transport, and thus can potentially control growth cone organelle entry. In addition, by comparing control, DCX-mEmerald and knockout DCX -/Y i Neurons, we find that DCX stabilizes microtubules in the growth cone peripheral domain by reducing the microtubule catastrophe frequency and the depolymerization rate. DCX -/Y i Neuron morphogenesis was inhibited in soft microenvironments that mimic the viscoelasticity of brain tissue and DCX -/Y neurites failed to grow toward brain-derived neurotrophic factor (BDNF) gradients. Together with high resolution traction force microscopy data, we propose a model in which DCX-decorated, rigid growth cone microtubules provide intracellular mechanical resistance to actomyosin generated contractile forces in soft physiological environments in which weak and transient adhesion-mediated forces in the growth cone periphery may be insufficient for productive growth cone advance. These data provide a new mechanistic understanding of how DCX mutations cause lissencephaly-spectrum brain malformations by impacting growth cone dynamics during neuron morphogenesis in physiological environments.
PubMed: 38464100
DOI: 10.1101/2024.02.28.582626 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Mar 2024To explore the clinical characteristics and genetic basis for a child with global developmental delay and autism. (Review)
Review
OBJECTIVE
To explore the clinical characteristics and genetic basis for a child with global developmental delay and autism.
METHODS
A child who had presented at West China Second University Hospital of Sichuan University on April 13, 2021 was selected as the study subject. Clinical manifestations, laboratory examination and result of genetic testing were analyzed.
RESULTS
The main symptoms of the child had included cognitive, language and motor delay, autism and epilepsy. Electroencephalogram revealed multiple focal discharges in both waking and sleeping stages, with the remarkable one seen at the sleeping stage. Cranial MRI showed pachygyria and local cortical thickening, Whole exome sequencing (WES) revealed that the child has harbored a heterozygous c.1589_1595dup (p.Gly533Leufs*143) frameshifting variant in the TBR1 gene (OMIM 604616). Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic (PS2+PVS1_Supporting+PM2_Supporting). After treated with levetiracetam and rehabilitation training, the child did not have seizure in the past 5 months, and his motor development has also significantly improved.
CONCLUSION
The c.1589_1595dup variant of the TBR1 gene probably underlay the disease in this patient.
Topics: Child; Humans; Autistic Disorder; China; Developmental Disabilities; Electroencephalography; Genetic Testing; T-Box Domain Proteins
PubMed: 38448025
DOI: 10.3760/cma.j.cn511374-20220328-00208 -
Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations.Brain Communications 2024This study aimed to determine the diagnostic yield of singleton exome sequencing and subsequent research-based trio exome analysis in children with a spectrum of brain...
This study aimed to determine the diagnostic yield of singleton exome sequencing and subsequent research-based trio exome analysis in children with a spectrum of brain malformations seen commonly in clinical practice. We recruited children ≤ 18 years old with a brain malformation diagnosed by magnetic resonance imaging and consistent with an established list of known genetic causes. Patients were ascertained nationally from eight tertiary paediatric centres as part of the Australian Genomics Brain Malformation Flagship. Chromosome microarray was required for all children, and those with pathogenic copy number changes were excluded. Cytomegalovirus polymerase chain reaction on neonatal blood spots was performed on all children with polymicrogyria with positive patients excluded. Singleton exome sequencing was performed through a diagnostic laboratory and analysed using a clinical exome sequencing pipeline. Undiagnosed patients were followed up in a research setting, including reanalysis of the singleton exome data and subsequent trio exome sequencing. A total of 102 children were recruited. Ten malformation subtypes were identified with the commonest being polymicrogyria (36%), pontocerebellar hypoplasia (14%), periventricular nodular heterotopia (11%), tubulinopathy (10%), lissencephaly (10%) and cortical dysplasia (9%). The overall diagnostic yield for the clinical singleton exome sequencing was 36%, which increased to 43% after research follow-up. The main source of increased diagnostic yield was the reanalysis of the singleton exome data to include newly discovered gene-disease associations. One additional diagnosis was made by trio exome sequencing. The highest phenotype-based diagnostic yields were for cobblestone malformation, tubulinopathy and lissencephaly and the lowest for cortical dysplasia and polymicrogyria. Pathogenic variants were identified in 32 genes, with variants in 6/32 genes occurring in more than one patient. The most frequent genetic diagnosis was pathogenic variants in . This study shows that over 40% of patients with common brain malformations have a genetic aetiology identified by exome sequencing. Periodic reanalysis of exome data to include newly identified genes was of greater value in increasing diagnostic yield than the expansion to trio exome. This study highlights the genetic and phenotypic heterogeneity of brain malformations, the importance of a multidisciplinary approach to diagnosis and the large number of patients that remain without a genetic diagnosis despite clinical exome sequencing and research reanalysis.
PubMed: 38444904
DOI: 10.1093/braincomms/fcae056 -
FASEB Journal : Official Publication of... Mar 2024NUDC (nuclear distribution protein C) is a mitotic protein involved in nuclear migration and cytokinesis across species. Considered a cytoplasmic dynein (henceforth...
NUDC (nuclear distribution protein C) is a mitotic protein involved in nuclear migration and cytokinesis across species. Considered a cytoplasmic dynein (henceforth dynein) cofactor, NUDC was shown to associate with the dynein motor complex during neuronal migration. NUDC is also expressed in postmitotic vertebrate rod photoreceptors where its function is unknown. Here, we examined the role of NUDC in postmitotic rod photoreceptors by studying the consequences of a conditional NUDC knockout in mouse rods (rNudC ). Loss of NUDC in rods led to complete photoreceptor cell death at 6 weeks of age. By 3 weeks of age, rNudC function was diminished, and rhodopsin and mitochondria were mislocalized, consistent with dynein inhibition. Levels of outer segment proteins were reduced, but LIS1 (lissencephaly protein 1), a well-characterized dynein cofactor, was unaffected. Transmission electron microscopy revealed ultrastructural defects within the rods of rNudC by 3 weeks of age. We investigated whether NUDC interacts with the actin modulator cofilin 1 (CFL1) and found that in rods, CFL1 is localized in close proximity to NUDC. In addition to its potential role in dynein trafficking within rods, loss of NUDC also resulted in increased levels of phosphorylated CFL1 (pCFL1), which would purportedly prevent depolymerization of actin. The absence of NUDC also induced an inflammatory response in Müller glia and microglia across the neural retina by 3 weeks of age. Taken together, our data illustrate the critical role of NUDC in actin cytoskeletal maintenance and dynein-mediated protein trafficking in a postmitotic rod photoreceptor.
Topics: Animals; Mice; Actins; Biological Transport; Cell Death; Dyneins; Retinal Rod Photoreceptor Cells
PubMed: 38441532
DOI: 10.1096/fj.202301641RR -
BMJ Case Reports Feb 2024The coexistence of an arteriovenous fistula (AVF) and neuronal migration abnormalities is a rare phenomenon. The underlying pathophysiology responsible for these...
The coexistence of an arteriovenous fistula (AVF) and neuronal migration abnormalities is a rare phenomenon. The underlying pathophysiology responsible for these anomalies remains elusive. Neuronal architectural irregularities arise from complex neuronal formation, migration and organisation dysfunctions. Isolated cases of these associations are rarely described in the literature. Here, we present an unusual case involving the coexistence of a pial AVF and a pachygyria-polymicrogyria complex in an early childhood boy. We have provided a detailed description of the neuroimaging characteristics and the therapeutic embolisation in this case, along with follow-up. Additionally, we conduct a comprehensive review of potential hypotheses about the association, referencing prior case reports. The presence of an aberrant blood supply or deviant venous drainage from the developing cortex may contribute to a variety of neuronal migration anomalies.
Topics: Male; Humans; Child, Preschool; Intracranial Arteriovenous Malformations; Polymicrogyria; Embolization, Therapeutic; Arteriovenous Fistula
PubMed: 38423569
DOI: 10.1136/bcr-2023-258820 -
Stem Cell Research Apr 2024Subcortical band heterotopia (SHB) is a rare severe brain developmental malformation caused by deficient neuronal migration during the development of cerebral cortex....
Subcortical band heterotopia (SHB) is a rare severe brain developmental malformation caused by deficient neuronal migration during the development of cerebral cortex. Here, a human induced pluripotent stem cell (iPSCs) line was established from a 4-year-1-month-old girl with SHB carrying a heterozygous mutation (c.568A > G, p.K190E) in DCX. The generated iPSC line showed the ability to differentiate into three lineages in vitro and was confirmed by pluripotency markers and the original gene mutation.
Topics: Female; Humans; Infant; Classical Lissencephalies and Subcortical Band Heterotopias; Induced Pluripotent Stem Cells; Mutation; Heterozygote; Cerebral Cortex
PubMed: 38402847
DOI: 10.1016/j.scr.2024.103356