scholarly journals Mouse Models Characterize GNAO1 Encephalopathy as a Neurodevelopmental Disorder Leading to Motor Anomalies: from a Severe G203R to a Milder C215Y Mutation

2021 ◽  
Author(s):  
Denis Silachev ◽  
Alexey Koval ◽  
Mikhail Savitsky ◽  
Guru Padmasola ◽  
Charles Quairiaux ◽  
...  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Late Onset ◽  
Wide Spectrum ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Epileptic Seizures ◽  
Motor Dysfunction ◽  
Neuronal Precursor Cells

Abstract GNAO1 encephalopathy characterized by a wide spectrum of neurological deficiencies in pediatric patients originates from de novo heterozygous mutations in the gene encoding Gαo, the major neuronal G protein. Efficient treatments and even the proper understanding of the underlying etiology are currently lacking for this dominant disease. Adequate animal models of GNAO1 encephalopathy are urgently needed. Here we describe establishment and characterization of mouse models of the disease based on two point mutations in GNAO1 with different clinical manifestations. One of them is G203R leading to the early-onset epileptic seizures, motor dysfunction, developmental delay and intellectual disability. The other is C215Y producing much milder clinical outcomes, mostly – late-onset motor hyperactivity. The resultant mouse models show distinct phenotypes: severe neonatal lethality in GNAO1[G203R]/+ mice vs. normal vitality in GNAO1[C215Y]/+. The latter model further revealed strong hyperactivity and hyperlocomotion in a panel of behavioral assays, without signs of epilepsy, recapitulating the patients’ manifestations. Importantly, despite these differences the two models similarly revealed prenatal brain developmental anomalies, such as enlarged lateral ventricles and decreased numbers of neuronal precursor cells in the cortex. Thus, our work unveils GNAO1 encephalopathy as to a large extent neurodevelopmental malady. We expect that this understanding and the tools we established will be instrumental for future therapeutic developments.

scholarly journals Genotypes and Phenotypes of MEF2C Haploinsufficiency Syndrome: New Cases and Novel Point Mutations

2021 ◽  
Vol 9 ◽  
Author(s):  
Lin Wan ◽  
Xinting Liu ◽  
Linyan Hu ◽  
Huimin Chen ◽  
Yulin Sun ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Poor Performance ◽  
Genetic Alterations ◽  
Mendelian Inheritance ◽  
Whole Exome ◽  
Patients With Epilepsy ◽  
Free Status

Aim: MEF2C haploinsufficiency syndrome (MCHS) is a severe neurodevelopmental disorder. We describe the clinical phenotypes and genotypes of seven patients with MCHS to enhance the understanding of clinical manifestations and genetic alterations associated with MCHS.Method: Seven patients (6 females and 1 male, aged between 2 years 5 months and 6 years) who had MEF2C mutations, and their parents underwent trio-based whole-exome sequencing; subsequently, their clinical features were assessed. A literature review of patients with MCHS was performed by searching the PubMed and Online Mendelian Inheritance in Man databases.Results: Seven mutations were identified, of which six were unreported in the past; of the reported cases, five patients had de novo mutations but two had an undefined inheritance pattern. All patients presented delays in developmental milestones, severe intellectual disabilities and lack of speech. Six patients exhibited infantile hypotonia, five patients experienced stereotypic movements and were unable to walk, four patients exhibited poor eye contact indicative of autism and two showed poor performance. While six patients experienced seizure, five among them became seizure free after receiving anti-seizure medicine. Three patients showed a regression in their development, whereas the mothers of two patients exhibited mosaicism but were healthy without any abovementioned symptoms.Interpretation: Regression was not a common phenomenon but occurred in MCHS. The prognosis of MCHS patients with epilepsy was good, but most patients can achieve a seizure-free status. Healthy people may have low-level mosaicism and carry a pathogenic MEF2C mutation.

Cyclin-Dependent Kinase-Like 5 (CDKL5) Mutation Screening in Rett Syndrome and Related Disorders

2010 ◽  
Vol 13 (2) ◽  
pp. 168-178 ◽  
Author(s):  
Rose White ◽  
Gladys Ho ◽  
Swetlana Schmidt ◽  
Ingrid E. Scheffer ◽  
Alexandra Fischer ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Early Onset ◽  
De Novo ◽  
Wide Spectrum ◽  
Neurodevelopmental Disorder ◽  
Mutation Screening ◽  
Clinical Manifestations ◽  
Epileptic Encephalopathy ◽  
Cyclin Dependent Kinase ◽  
Aicardi Syndrome

AbstractRett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n = 102), males with X-linked mental retardation (n = 9), patients with West syndrome (n = 52), patients with autism (n = 59), patients with epileptic encephalopathy (n = 33), patients with Aicardi syndrome (n = 7) and other patients with intellectual disability with or without seizures (n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.

scholarly journals KCND3-Related Neurological Disorders: From Old to Emerging Clinical Phenotypes

2020 ◽  
Vol 21 (16) ◽  
pp. 5802
Author(s):  
Luca Pollini ◽  
Serena Galosi ◽  
Manuela Tolve ◽  
Caterina Caputi ◽  
Carla Carducci ◽  
...  
Keyword(s):  
Movement Disorders ◽  
Early Onset ◽  
Neurological Disorder ◽  
De Novo ◽  
Age Of Onset ◽  
Late Onset ◽  
Wide Spectrum ◽  
Neurodevelopmental Disorder ◽  
Clinical Phenotypes ◽  
K Current

KCND3 encodes the voltage-gated potassium ion channel subfamily D member 3, a six trans-membrane protein (Kv4.3), involved in the transient outward K+ current. KCND3 defect causes both cardiological and neurological syndromes. From a neurological perspective, Kv4.3 defect has been associated to SCA type 19/22, a complex neurological disorder encompassing a wide spectrum of clinical features beside ataxia. To better define the phenotypic spectrum and course of KCND3-related neurological disorder, we review the clinical presentation and evolution in 68 reported cases. We delineated two main clinical phenotypes according to the age of onset. Neurodevelopmental disorder with epilepsy and/or movement disorders with ataxia later in the disease course characterized the early onset forms, while a prominent ataxic syndrome with possible cognitive decline, movement disorders, and peripheral neuropathy were observed in the late onset forms. Furthermore, we described a 37-year-old patient with a de novo KCND3 variant [c.901T>C (p.Ser301Pro)], previously reported in dbSNP as rs79821338, and a clinical phenotype paradigmatic of the early onset forms with neurodevelopmental disorder, epilepsy, parkinsonism-dystonia, and ataxia in adulthood, further expanding the clinical spectrum of this condition.

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

Epileptic Encephalopathy, Myoclonus–Dystonia, and Premature Pubarche in Siblings with a Novel C-Terminal Truncating Mutation in ATRX Gene

2019 ◽  
Vol 50 (05) ◽  
pp. 327-331 ◽  
Author(s):  
Thea Giacomini ◽  
Maria Stella Vari ◽  
Sara Janis ◽  
Giulia Prato ◽  
Livia Pisciotta ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Epileptic Seizures ◽  
Epileptic Encephalopathy ◽  
Recessive Mutations ◽  
Truncating Mutation ◽  
Alpha Thalassemia ◽  
Male Patients ◽  
Myoclonus Dystonia

AbstractThe X-linked alpha thalassemia mental retardation (ATR-X) syndrome is a genetic disorder caused by X-linked recessive mutations in ATRX gene, related to a wide spectrum of clinical manifestations, such as alpha thalassemia, developmental delay, genital abnormalities, and gastrointestinal disorders. Patients with ATR-X syndrome can suffer from different types of epileptic seizures, but a severe epileptic encephalopathy pattern has not been described to date. We describe, for the first time, two brothers with genetically confirmed ATR-X syndrome who presented with drug-resistant epileptic encephalopathy, with tonic and polimorphic seizures reported in the elder brother and epileptic spasms in the younger brother. Moreover, both brothers showed a peculiar movement disorder with myoclonus–dystonia, worsened during periods of distress or pain. These cases expand the clinical spectrum of ATR-X syndrome and open new opportunities for the molecular diagnosis of ATRX mutations in male patients with severe epileptic encephalopathies and movement disorders.

scholarly journals Translational animal models of autism and neurodevelopmental disorders

2012 ◽  
Vol 14 (3) ◽  
pp. 293-305 ◽  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Restricted Interests ◽  
Homologous Genes ◽  
Biological Outcomes

Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics.

scholarly journals Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

2019 ◽  
Author(s):  
Casandra L. Larrivee ◽  
Huijie Feng ◽  
Josiah A. Quinn ◽  
Vincent S. Shaw ◽  
Jeffrey R. Leipprandt ◽  
...  
Keyword(s):  
Mouse Model ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Clinical Manifestations ◽  
Brain Regions ◽  
Psychomotor Development ◽  
Nucleotide Exchange ◽  
Involuntary Movements ◽  
Gait Abnormality ◽  
The Brain

AbstractNeurodevelopmental disorder with involuntary movements (NEDIM, OMIM: 617493) is a severe, early onset neurological condition characterized by a delay in psychomotor development, hypotonia, and hyperkinetic involuntary movements. Heterozygous de novo mutations in the GNAO1 gene cause NEDIM. Gαo, the gene product of GNAO1, is the alpha subunit of Go, a member of the heterotrimeric Gi/o family of G-proteins. Go is found abundantly throughout the brain but the pathophysiological mechanisms linking Gαo functions to clinical manifestations of GNAO1-related disorders are still poorly understood. One of the most common mutant alleles among the GNAO1 encephalopathies is the c.626G>A or p.Arg209His (R209H) mutation. We developed heterozygous knock-in Gnao1+/R209H mutant mice using CRISPR/Cas9 methodology to assess whether a mouse model could replicate aspects of the NEDIM clinical pattern. Mice carrying the R209H mutation exhibited increased locomotor activity and a modest gait abnormality at 8-12 weeks. In contrast to mice carrying other mutations in Gnao1, the Gnao1+/R209H mice did not show enhanced seizure susceptibility. Levels of protein expression in multiple brain regions were unchanged from WT mice but the nucleotide exchange rate of mutant R209H Gαo was 9 times faster than WT. The atypical neuroleptic risperidone has shown efficacy in a patient with the R209H mutation. It also alleviated the hyperlocomotion phenotype observed in our mouse model but suppressed locomotion in WT mice as well. In this study, we show that Gnao1+/R209H mice mirror elements of the patient phenotype and respond to an approved pharmacological agent.

scholarly journals Childhood epileptic seizures imitating migraine and encephalitis

2012 ◽  
Vol 140 (9-10) ◽  
pp. 558-562
Author(s):  
Ruzica Kravljanac ◽  
Milena Djuric
Keyword(s):  
Antiepileptic Drugs ◽  
Clinical Presentation ◽  
Late Onset ◽  
Clinical Manifestations ◽  
Epileptic Seizures ◽  
Childhood Epilepsy ◽  
Visual Hallucinations ◽  
Seizure Recurrence ◽  
Acute Therapy ◽  
Epileptic Discharges

Introduction. Paroxismal events can resemble epileptic seizures, however, some epileptic seizures, especially benign occipital childhood epilepsies can imitate migraine, cycling vomiting or encephalitis. Objective. The aim of this study was evaluation of clinical and electroencephalographic (EEG) features and outcome in children with benign occipital childhood epilepsies. Methods. Investigation included 18 patients with benign occipital childhood epilepsies hospitalized in the period from 2007 to 2010. The diagnosis was based on clinical and EEG characteristics of seizures, while treatment included acute therapy for seizures and chronic antiepileptic drugs. Prognosis was analyzed in terms of neurological outcome and seizure recurrence rate. Results. Benign occipital childhood epilepsy with early onset was diagnosed in 15 children. Vegetative symptoms, mostly ictal vomiting (13), eye deviation and loss of consciousness (13) dominated in the clinical presentation. The most frequent EEG findings showed occipital epileptic discharges. Benign occipital childhood epilepsy with late onset was diagnosed in three cases. Seizures were manifested by visual hallucinations, headache and secondary generalized convulsions. All three patients were administered chronic antiepileptic drugs and had good outcome. Conclusion. In our patients, clinical manifestations of benign occipital epilepsies had some similarities with clinical features of migraine and encephalitis. It could explain misdiagnosis in some of them. Knowledge about main features and differences between each of these disorders is crucial for making appropriate diagnosis.

scholarly journals Pathogenic variants in SMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features

2020 ◽  
Author(s):  
Dong Li ◽  
Qin Wang ◽  
Naihua N. Gong ◽  
Alina Kurolap ◽  
Hagit Baris Feldman ◽  
...  
Keyword(s):  
De Novo ◽  
Brain Size ◽  
Wide Spectrum ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Wild Type ◽  
Chromatin Remodeler ◽  
Mild Developmental Delay ◽  
Pathogenic Variants ◽  
Facial Dysmorphia

Intellectual disability (ID) encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for over 50% of the patients remains elusive. We describe mutations in SMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a novel neurodevelopmental disorder, identifying twelve individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature, and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 Drosophila ortholog Iswi led to smaller body size, reduced dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology and abnormal locomotor function. Iswi loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that SMARCA5 pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.

scholarly journals The Novel KIF1A Missense Variant (R169T) Strongly Reduces Microtubule Stimulated ATPase Activity and Is Associated With NESCAV Syndrome

2021 ◽  
Vol 15 ◽  
Author(s):  
Cinthia Aguilera ◽  
Stefan Hümmer ◽  
Marc Masanas ◽  
Elisabeth Gabau ◽  
Miriam Guitart ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Clinical Features ◽  
De Novo ◽  
Wide Spectrum ◽  
Neurodevelopmental Disorder ◽  
Spastic Paraparesis ◽  
Cerebellar Atrophy ◽  
Missense Variant ◽  
Motor Domain ◽  
Anterograde Transport

KIF1A is a microtubule-dependent motor protein responsible for fast anterograde transport of synaptic vesicle precursors in neurons. Pathogenic variants in KIF1A have been associated with a wide spectrum of neurological disorders. Here, we report a patient presenting a severe neurodevelopmental disorder carrying a novel de novo missense variant p.Arg169Thr (R169T) in the KIF1A motor domain. The clinical features present in our patient match with those reported for NESCAV syndrome including severe developmental delay, spastic paraparesis, motor sensory neuropathy, bilateral optic nerve atrophy, progressive cerebellar atrophy, epilepsy, ataxia, and hypotonia. Here, we demonstrate that the microtubule-stimulated ATPase activity of the KIF1A is strongly reduced in the motor domain of the R169T variant. Supporting this, in silico structural modeling suggests that this variant impairs the interaction of the KIF1A motor domain with microtubules. The characterization of the molecular effect of the R169T variant on the KIF1A protein together with the presence of the typical clinical features indicates its causal pathogenic effect.

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