Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects

Brain ◽  
2021 ◽  
Author(s):  
Srinivasarao Repudi ◽  
Daniel J Steinberg ◽  
Nimrod Elazar ◽  
Vanessa L Breton ◽  
Mark S Aquilino ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Intractable Epilepsy ◽  
Premature Death ◽  
Molecular Evidence ◽  
Null Mutation ◽  
Neuronal Function ◽  
Mouse Cortex ◽  
Underlying Mechanisms ◽  
Biallelic Mutations ◽  
Brain Hyperexcitability

Abstract WOREE syndrome caused by human germline biallelic mutations in WWOX is a neurodevelopmental disorder characterized by intractable epilepsy, severe developmental delay, ataxia and premature death at the age of 2–4 years. The underlying mechanisms of WWOX actions are poorly understood. In the current study, we show that specific neuronal deletion of murine Wwox produces phenotypes typical of the Wwox-null mutation leading to brain hyperexcitability, intractable epilepsy, ataxia and postnatal lethality. A significant decrease in transcript levels of genes involved in myelination was observed in mouse cortex and hippocampus. Wwox-mutant mice exhibited reduced maturation of oligodendrocytes, reduced myelinated axons and impaired axonal conductivity. Brain hyperexcitability and hypomyelination were also revealed in human brain organoids with a WWOX deletion. These findings provide cellular and molecular evidence for myelination defects and hyperexcitability in the WOREE syndrome linked to neuronal function of WWOX.

scholarly journals Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes

2021 ◽  
Author(s):  
Srinivasarao Repudi ◽  
Irina Kustanovich ◽  
Sara Abu-Swai ◽  
Shani Stern ◽  
Rami I. Aqeilan
Keyword(s):  
Gene Therapy ◽  
Autosomal Recessive ◽  
Viral Vector ◽  
Intractable Epilepsy ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
The Central Nervous System ◽  
Biallelic Mutations ◽  
Brain Hyperexcitability ◽  
Wwox Gene

AbstractWW domain-containing oxidoreductase (WWOX) is an emerging neural gene regulating homeostasis of the central nervous system. Germline biallelic mutations in WWOX cause WWOX-related epileptic encephalopathy (WOREE) syndrome and spinocerebellar ataxia, and autosomal recessive 12 (SCAR12), two devastating neurodevelopmental disorders with highly heterogenous clinical outcomes, the most common being severe epileptic encephalopathy and profound global developmental delay. We recently demonstrated that neuronal ablation of murine Wwox recapitulates phenotypes of Wwox-null mice leading to intractable epilepsy, hypomyelination and postnatal lethality. Here, we designed and produced an adeno-associated viral vector harboring murine Wwox or human WWOX cDNA and driven by the human neuronal Synapsin I promoter (AAV-SynI-WWOX). Testing the efficacy of AAV-SynI-WWOX delivery in Wwox null mice demonstrated that specific neuronal restoration of WWOX expression rescued brain hyperexcitability and seizures, hypoglycemia, and myelination deficits as well as the premature lethality of Wwox-null mice. These findings provide a proof-of-concept for WWOX gene therapy as a promising approach to curing children with WOREE and SCAR12.

Question-and-Answer Forum

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S4) ◽  
pp. 13-13
Keyword(s):  
Functional Disability ◽  
Neuroprotective Effect ◽  
Neurodevelopmental Disorder ◽  
Historical Context ◽  
Brain Diseases ◽  
Delayed Treatment ◽  
Disease States ◽  
At Risk Children ◽  
Underlying Mechanisms ◽  
The Impact

AbstractSchizophrenia is a neurodevelopmental disorder associated with persistent symptomatology, severe functional disability, and residual morbidity characteristic of neurodegenerative brain diseases. The illness begins with genetic susceptibility and generally expresses itself after puberty through subtle changes that begin during the prodromal stage. Symptoms get progressively worse and tend to become more resistant to treatment with each relapse. Evidence for a neuroprotective effect of some forms of early treatment is beginning to emerge. While the underlying mechanisms remain uncertain, atypical antipsychotics may counteract some of the progressive deteriorative effects by enhancing synaptic plasticity and cellular resilience. However, identifying and treating patients in the earliest disease states presents methodological challenges as there is no consensus on the best methods of intervention and differences in at-risk children are not readily detectable or substantial enough to predict which ones will develop schizophrenia.In this expert roundtable supplement, Jeffrey A. Lieberman, MD, reviews the historical context of progressive deterioration in schizophrenia. Next, Diana O. Perkins, MD, MPH, reviews some of the challenges to early identification of illness as well as the impact of early versus delayed treatment. Finally, L. Fredrik Jarskog, MD, focuses on the neurobiology of functional progression in schizophrenia as well as pharmacology and the potential for neuroprotection.

scholarly journals Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations

2020 ◽  
Vol 6 (1) ◽  
pp. e387 ◽  
Author(s):  
Annalisa Vetro ◽  
Tiziana Pisano ◽  
Silvia Chiaro ◽  
Elena Procopio ◽  
Azzurra Guerra ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Brain Mri ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Premature Death ◽  
Epileptic Encephalopathy ◽  
Whole Exome ◽  
Mri Scans ◽  
Severe Hypotonia ◽  
Profound Disability

ObjectiveTo describe clinical, biochemical, and molecular genetic findings in a large inbred family in which 4 children with a severe early-onset epileptic-dyskinetic encephalopathy, with suppression burst EEG, harbored homozygous mutations of phosphatidylinositol glycan anchor biosynthesis, class P (PIGP), a member of the large glycosylphosphatidylinositol (GPI) anchor biosynthesis gene family.MethodsWe studied clinical features, EEG, brain MRI scans, whole-exome sequencing (WES), and measured the expression of a subset of GPI-anchored proteins (GPI-APs) in circulating granulocytes using flow cytometry.ResultsThe 4 affected children exhibited a severe neurodevelopmental disorder featuring severe hypotonia with early dyskinesia progressing to quadriplegia, associated with infantile spasms, focal, tonic, and tonic-clonic seizures and a burst suppression EEG pattern. Two of the children died prematurely between age 2 and 12 years; the remaining 2 children are aged 2 years 7 months and 7 years 4 months. The homozygous c.384del variant of PIGP, present in the 4 patients, introduces a frame shift 6 codons before the expected stop signal and is predicted to result in the synthesis of a protein longer than the wild type, with impaired functionality. We demonstrated a reduced expression of the GPI-AP CD16 in the granulocytic membrane in affected individuals.ConclusionsPIGP mutations are consistently associated with an epileptic-dyskinetic encephalopathy with the features of early infantile epileptic encephalopathy with profound disability and premature death. CD16 is a valuable marker to support a genetic diagnosis of inherited GPI deficiencies.

scholarly journals Abundance and localization of human UBE3A protein isoforms

2020 ◽  
Vol 29 (18) ◽  
pp. 3021-3031 ◽  
Author(s):  
Carissa L Sirois ◽  
Judy E Bloom ◽  
James J Fink ◽  
Dea Gorka ◽  
Steffen Keller ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Embryonic Stem ◽  
Protein Isoforms ◽  
Wild Type ◽  
Neuronal Function ◽  
Ube3a Gene ◽  
Recent Case Study ◽  
The Individual ◽  
Human Isoforms

Abstract Loss of UBE3A expression, a gene regulated by genomic imprinting, causes Angelman syndrome (AS), a rare neurodevelopmental disorder. The UBE3A gene encodes an E3 ubiquitin ligase with three known protein isoforms in humans. Studies in mouse suggest that the human isoforms may have differences in localization and neuronal function. A recent case study reported mild AS phenotypes in individuals lacking one specific isoform. Here we have used CRISPR/Cas9 to generate isogenic human embryonic stem cells (hESCs) that lack the individual protein isoforms. We demonstrate that isoform 1 accounts for the majority of UBE3A protein in hESCs and neurons. We also show that UBE3A predominantly localizes to the cytoplasm in both wild type and isoform-null cells. Finally, we show that neurons lacking isoform 1 display a less severe electrophysiological AS phenotype.

scholarly journals Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder

2021 ◽  
Vol 7 (1) ◽  
pp. e551
Author(s):  
Jennifer M. Bain ◽  
Olivia Thornburg ◽  
Cheryl Pan ◽  
Donnielle Rome-Martin ◽  
Lia Boyle ◽  
...  
Keyword(s):  
Language Impairment ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Retrospective Chart Review ◽  
Premature Death ◽  
Parent Report ◽  
Autism Spectrum ◽  
Pathogenic Variants ◽  
Motor Problems ◽  
Cortical Visual Impairment

ObjectiveTo expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals.MethodsParticipants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures.ResultsWe expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2–38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition.ConclusionsThe spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.

scholarly journals AAV9 gene therapy restores lifespan and treats pathological and behavioral abnormalities in a mouse model of CLN8-Batten disease

2020 ◽  
Author(s):  
Tyler B. Johnson ◽  
Katherine A. White ◽  
Jacob T. Cain ◽  
Logan Langin ◽  
Melissa A. Pratt ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Batten Disease ◽  
Premature Death ◽  
Gene Therapy Vector ◽  
Behavioral Abnormalities ◽  
Endoplasmic Reticulum Protein ◽  
Biallelic Mutations ◽  
Brain And Spinal Cord

AbstractCLN8 disease is a rare form of neuronal ceroid lipofuscinosis caused by biallelic mutations in the CLN8 gene, which encodes a transmembrane endoplasmic reticulum protein involved in trafficking of lysosomal enzymes. CLN8 disease patients present with myoclonus, tonic-clonic seizures, and progressive declines in cognitive and motor function, with many cases resulting in premature death early in life. There are currently no treatments that can cure the disease or substantially slow disease progression. Using a mouse model of CLN8 disease, we tested the safety and efficacy of an intracerebroventricularly (ICV)-delivered self-complementary AAV9 (scAAV9) gene therapy vector driving expression of human CLN8. A single neonatal injection was safe and well-tolerated, resulting in robust transgene expression throughout the brain and spinal cord from 4 to 24 months, reducing histopathological and behavioral hallmarks of the disease and completely restoring lifespan from 10 months in untreated animals to beyond 24 months of age in treated animals. These results demonstrate, by far, the most successful rescue reported in an animal model of CLN8 disease, and supports gene therapy as a promising therapeutic strategy for this disorder.

scholarly journals Modeling Genetic Epileptic Encephalopathies using Brain Organoids

2020 ◽  
Author(s):  
Daniel J. Steinberg ◽  
Afifa Saleem ◽  
Srinivasa Rao Repudi ◽  
Ehud Banne ◽  
Muhammad Mahajnah ◽  
...  
Keyword(s):  
Es Cells ◽  
Premature Death ◽  
Epileptic Encephalopathy ◽  
Neural Population ◽  
Epileptic Encephalopathies ◽  
Intractable Seizures ◽  
Damage Response ◽  
Human Es Cells ◽  
Biallelic Mutations

SummaryEpileptic encephalopathies (EEs) are a group of disorders associated with intractable seizures, brain development and functional abnormalities, and in some cases, premature death. Pathogenic human germline biallelic mutations in tumor suppressor WW domain-containing oxidoreductase (WWOX) are associated with a relatively mild autosomal-recessive spinocerebellar ataxia-12 (SCAR12) and a more severe early infantile WWOX-related epileptic encephalopathy (WOREE). In this study, we generated an in-vitro model for EEs, using the devastating WOREE syndrome as a prototype, by establishing brain organoids from CRISPR-engineered human ES cells and from patient-derived iPSCs. Using these models, we discovered dramatic cellular and molecular CNS abnormalities, including neural population changes, cortical differentiation malfunctions, and Wnt-pathway and DNA-damage response impairment. Furthermore, we provide a proof-of-concept that ectopic WWOX expression could potentially rescue these phenotypes. Our findings underscore the utility of modeling childhood epileptic encephalopathies using brain organoids and their use as a unique platform to test possible therapeutic intervention strategies.

scholarly journals Cyclin-Dependent Kinase-Like 5 (CDKL5): Possible Cellular Signalling Targets and Involvement in CDKL5 Deficiency Disorder

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Syouichi Katayama ◽  
Noriyuki Sueyoshi ◽  
Tetsuya Inazu ◽  
Isamu Kameshita
Keyword(s):  
Catalytic Activity ◽  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Cyclin Dependent Kinase ◽  
Loss Of Function ◽  
Neuronal Function ◽  
Transcriptional Mapping ◽  
Target Molecules ◽  
New Treatment ◽  
The Relationship

Cyclin-dependent kinase-like 5 (CDKL5, also known as STK9) is a serine/threonine protein kinase originally identified in 1998 during a transcriptional mapping project of the human X chromosome. Thereafter, a mutation in CDKL5 was reported in individuals with the atypical Rett syndrome, a neurodevelopmental disorder, suggesting that CDKL5 plays an important regulatory role in neuronal function. The disease associated with CDKL5 mutation has recently been recognised as CDKL5 deficiency disorder (CDD) and has been distinguished from the Rett syndrome owing to its symptomatic manifestation. Because CDKL5 mutations identified in patients with CDD cause enzymatic loss of function, CDKL5 catalytic activity is likely strongly associated with the disease. Consequently, the exploration of CDKL5 substrate characteristics and regulatory mechanisms of its catalytic activity are important for identifying therapeutic target molecules and developing new treatment. In this review, we summarise recent findings on the phosphorylation of CDKL5 substrates and the mechanisms of CDKL5 phosphorylation and dephosphorylation. We also discuss the relationship between changes in the phosphorylation signalling pathways and the Cdkl5 knockout mouse phenotype and consider future prospects for the treatment of mental and neurological disease associated with CDKL5 mutations.

Atrial fibrillation after cardiopulmonary surgery

ESC CardioMed ◽  
2018 ◽  
pp. 2223-2227
Author(s):  
Rohan S. Wijesurendra ◽  
Barbara Casadei
Keyword(s):  
Atrial Fibrillation ◽  
Artery Bypass ◽  
Premature Death ◽  
Bypass Grafting ◽  
Prolonged Hospital Stay ◽  
Significant Morbidity ◽  
Increased Risk ◽  
Underlying Mechanisms ◽  
Prolonged Hospital ◽  
Consequent Increase

Postoperative atrial fibrillation (POAF) is a frequently noted complication following cardiopulmonary surgery, with a reported incidence of between 10% and 60%. Most studies have defined POAF as atrial fibrillation (or other atrial arrhythmia, such as atrial flutter) occurring between the procedure and hospital discharge; this definition is also adopted in this chapter, while recognizing that cardiopulmonary surgery is also associated with an increased incidence of atrial fibrillation in the longer term. POAF is an important condition, as it is associated with a prolonged hospital stay and consequent increase in medical costs, significant morbidity, including an increased risk of stroke, and has also been linked to an increased risk of premature death. Much recent work has focused on an improved understanding of the underlying mechanisms, and on trialling prophylactic therapies designed to reduce the incidence of POAF. Nevertheless, this condition remains a significant clinical challenge following cardiopulmonary surgery, particularly valvular intervention, coronary artery bypass grafting, and combined valvular/coronary cases.

VALPROIC ACID EXTENDS LIFESPAN OF THE ZEBRAFISH MODEL OF CLN2 DISEASE (LATE INFANTILE NEURONAL CEROID LIPOFUSCINOSIS)

2015 ◽  
Vol 86 (11) ◽  
pp. e4.153-e4
Author(s):  
Fahad Mahmood ◽  
Anselm Zdebik ◽  
Alexandra Au ◽  
Jennifer Cooke ◽  
Claire Russell
Keyword(s):  
Seizure Activity ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Epileptiform Activity ◽  
Intractable Epilepsy ◽  
Premature Death ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Lysosomal Storage ◽  
Zebrafish Model ◽  
Lysosomal Protease

CLN2 disease is a subtype of the neuronal ceroid lipofuscinoses (NCLs), a group of lysosomal storage disorders causing progressive, untreatable, neurodegeneration, intractable epilepsy and premature death in children. We have developed a permanent genetic zebrafish model of CLN2 disease due to a mutation in tpp1 encoding the lysosomal protease Tripeptidyl-peptidase-1 that replicates the neurodegenerative and storage phenotype. We hypothesize that CLN2 zebrafish display electrical and behavioural evidence of seizure activity that responds to established anti-convulsants and can further be used to develop novel therapeutic approaches.To validate the presence of seizures we performed single electrode electroencephalography showing CLN2 zebrafish had increased spiking activity vs wildtype with Fast-Fourier transform showing significantly increased amplitude about 2–4Hz. This was attenuated by Valproate (p=0.049), but not pentobarbitone. We also demonstrate that Valproate significantly reduces seizure-related movement bouts, thereby correlating movements and epileptiform activity. Lastly, we show exposure to Valproate significantly extends the lifespan of our zebrafish model with mortality between 3–6 days post-fertilization 8.33% in treated vs 33.3% in controls (p=0.01).The CLN2 zebrafish model thus displays electrical and behavioural seizure activity that can be attenuated by Valproate, with associated prolongation in survival. Moreover this model can utilize high-throughput in vivo screening assays to develop novel anti-convulsants.

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