scholarly journals Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

2022 ◽  
Author(s):  
Julian Schröter ◽  
Bernt Popp ◽  
Heiko Brennenstuhl ◽  
Jan H. Döring ◽  
Stephany H. Donze ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Early Onset ◽  
Neurodevelopmental Disorder ◽  
Motor Impairment ◽  
Case Series ◽  
Intractable Epilepsy ◽  
Global Developmental Delay ◽  
Protein Structure Analysis ◽  
Brain Malformations ◽  
Subcortical Band Heterotopia

AbstractTUBA1A tubulinopathy is a rare neurodevelopmental disorder associated with brain malformations as well as early-onset and intractable epilepsy. As pathomechanisms and genotype-phenotype correlations are not completely understood, we aimed to provide further insights into the phenotypic and genetic spectrum. We here present a multicenter case series of ten unrelated individuals from four European countries using systematic MRI re-evaluation, protein structure analysis, and prediction score modeling. In two cases, pregnancy was terminated due to brain malformations. Amongst the eight living individuals, the phenotypic range showed various severity. Global developmental delay and severe motor impairment with tetraparesis was present in 63% and 50% of the subjects, respectively. Epilepsy was observed in 75% of the cases, which showed infantile onset in 83% and a refractory course in 50%. One individual presented a novel TUBA1A-associated electroclinical phenotype with evolvement from early myoclonic encephalopathy to continuous spike-and-wave during sleep. Neuroradiological features comprised a heterogeneous spectrum of cortical and extracortical malformations including rare findings such as cobblestone lissencephaly and subcortical band heterotopia. Two individuals developed hydrocephalus with subsequent posterior infarction. We report four novel and five previously published TUBA1A missense variants whose resulting amino acid substitutions likely affect longitudinal, lateral, and motor protein interactions as well as GTP binding. Assessment of pathogenic and benign variant distributions in synopsis with prediction scores revealed sections of variant enrichment and intolerance to missense variation. We here extend the clinical, neuroradiological, and genetic spectrum of TUBA1A tubulinopathy and provide insights into residue-specific pathomechanisms and genotype-phenotype correlations.

scholarly journals Expanding the Phenotype of TUBB2A-Related Tubulinopathy: Three Cases of a Novel, Heterozygous TUBB2A Pathogenic Variant p.Gly98Arg

2020 ◽  
pp. 1-8
Author(s):  
Lindsey Schmidt ◽  
Karen E. Wain ◽  
Catherine Hajek ◽  
Juvianee I. Estrada-Veras ◽  
Maria J. Guillen Sacoto ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Case Series ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Cortical Dysplasia ◽  
Global Developmental Delay ◽  
Tubulin Genes ◽  
Pathogenic Variants ◽  
Brain Malformations ◽  
History Of

Tubulinopathies are a group of conditions caused by variants in 6 tubulin genes that present with a spectrum of brain malformations. One of these conditions is <i>TUBB2A</i>-related tubulinopathy. Currently, there are 9 reported individuals with pathogenic variants within the <i>TUBB2A</i> gene, with common manifestations including, but not limited to, global developmental delay, seizures, cortical dysplasia, and dysmorphic corpus callosum. We report 3 patients identified by exome and genome sequencing to have a novel, pathogenic, missense variant in <i>TUBB2A</i> (p.Gly98Arg). They presented similarly with intellectual disability, hypotonia, and global developmental delay and varied with respect to the type of cortical brain malformation, seizure history, diagnosis of autism spectrum disorder, and other features. This case series expands the natural history of <i>TUBB2A</i>-related tubulinopathy while describing the presentation of a novel, pathogenic, missense variant in 3 patients.

Case Series With Late-Onset Psychosis Hospitalized in a Geriatric Psychiatry Unit in Turkey: Experience in 9 Years

2003 ◽  
Vol 15 (1) ◽  
pp. 69-72 ◽  
Author(s):  
Yesne Alici-Evcimen ◽  
Turan Ertan ◽  
Engin Eker
Keyword(s):  
Early Onset ◽  
Late Onset ◽  
Case Series ◽  
Geriatric Psychiatry ◽  
Delusional Disorder ◽  
Early Onset Schizophrenia ◽  
Treatment Results ◽  
Thought Insertion ◽  
Psychiatry Department ◽  
Paranoid Psychosis

In this article we report the first series of Turkish inpatients with late-onset psychosis, and describe our 9-year experience at the only inpatient geriatric psychiatry department in Turkey. Among 420 patients hospitalized between 1993 and 2002, 27 were psychotic. In this group, eight patients were diagnosed as having late-onset schizophrenia (LOS) and six very-late-onset schizophrenia-like psychosis (VLOSLP). Five patients had early-onset schizophrenia and eight had delusional disorder. Females were more frequently seen in the group with LOS and the group with VLOSLP. Except for one patient with LOS, all patients with VLOSLP and LOS had paranoid psychosis. Nihilistic delusions, delusions of poverty or guilt, thought withdrawal, thought insertion, and thought broadcasting were not seen in any of the patients. Additionally, none of the LOS or VLOSLP patients showed erotomanic delusions. Grandiose and mystic delusions were not seen in those with VLOSLP. Treatment results and antipsychotic dosages at discharge were similar to those in previous reports from other cultures.

scholarly journals Association of early-onset epileptic encephalopathy with involuntary movements – Case series and literature review

2020 ◽  
pp. 100417
Author(s):  
Atsuko Arisaka ◽  
Mitsuko Nakashima ◽  
Satoko Kumada ◽  
Kenji Inoue ◽  
Hiroya Nishida ◽  
...  
Keyword(s):  
Literature Review ◽  
Early Onset ◽  
Case Series ◽  
Epileptic Encephalopathy ◽  
Involuntary Movements

scholarly journals Mental health of children with neurodevelopmental disorders during COVID-19: A brief report of family experiences from a low and middle income country

2021 ◽  
pp. 135910452110260
Author(s):  
Sowmyashree M Kaku
Keyword(s):  
Mental Health ◽  
Mental Health Professionals ◽  
Neurodevelopmental Disorder ◽  
Case Series ◽  
Ground Level ◽  
Middle Income ◽  
Middle Income Countries ◽  
Mental Health Difficulties ◽  
Similar Report ◽  
Low And Middle Income

COVID-19 has grossly impacted lives of people across the globe. In particular, children have also been affected due to closure of schools, therapy, and day care centers. Families have been challenged with new circumstances, and mental health professionals are coming up with novel ways to help these families who have children with mental health issues. This article describes experiences of families who have children with a diagnosed neurodevelopmental disorder with comorbid mental health difficulties and their ways of coping with the pandemic challenges. The series will throw light on ground level experiences of families during the pandemic, give insights into their ways of adapting, and brings out problem areas which healthcare professionals must work on, to design novel ways of care. The case series is novel and a similar report has probably not been presented from India or other low and middle income countries.

scholarly journals Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Ilaria Mannucci ◽  
Nghi D. P. Dang ◽  
Hannes Huber ◽  
Jaclyn B. Murry ◽  
Jeff Abramson ◽  
...  
Keyword(s):  
De Novo ◽  
Clinical Course ◽  
Neurodevelopmental Disorder ◽  
Global Developmental Delay ◽  
Helicase Activity ◽  
Speech Impairment ◽  
Human Phenotype ◽  
Missense Variants ◽  
The Impact ◽  
Global Translation

Abstract Background We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

scholarly journals Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novoGRIN2Amutation

Epilepsia ◽  
2014 ◽  
Vol 55 (7) ◽  
pp. e75-e79 ◽  
Author(s):  
Sunita Venkateswaran ◽  
Ken A. Myers ◽  
Amanda C. Smith ◽  
Chandree L. Beaulieu ◽  
Jeremy A. Schwartzentruber ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Intractable Epilepsy ◽  
Global Developmental Delay ◽  
Whole Exome

scholarly journals Direct and Collateral Alterations of Functional Cortical Circuits in a Rat Model of Subcortical Band Heterotopia

2018 ◽  
Vol 29 (10) ◽  
pp. 4253-4262 ◽  
Author(s):  
Vanessa Plantier ◽  
Françoise Watrin ◽  
Emmanuelle Buhler ◽  
Fanny Sandrine Martineau ◽  
Surajit Sahu ◽  
...  
Keyword(s):  
Barrel Cortex ◽  
Intractable Epilepsy ◽  
Pyramidal Cells ◽  
Cortical Region ◽  
Cortical Networks ◽  
Causative Gene ◽  
Double Cortex Syndrome ◽  
Subcortical Band Heterotopia ◽  
Migration Disorder ◽  
Band Heterotopia

Abstract Subcortical band heterotopia (SBH), also known as double-cortex syndrome, is a neuronal migration disorder characterized by an accumulation of neurons in a heterotopic band below the normotopic cortex. The majority of patients with SBH have mild to moderate intellectual disability and intractable epilepsy. However, it is still not clear how cortical networks are organized in SBH patients and how this abnormal organization contributes to improper brain function. In this study, cortical networks were investigated in the barrel cortex in an animal model of SBH induced by in utero knockdown of Dcx, main causative gene of this condition in human patients. When the SBH was localized below the Barrel Field (BF), layer (L) four projection to correctly positioned L2/3 pyramidal cells was weakened due to lower connectivity. Conversely, when the SBH was below an adjacent cortical region, the excitatory L4 to L2/3 projection was stronger due to increased L4 neuron excitability, synaptic strength and excitation/inhibition ratio of L4 to L2/3 connection. We propose that these developmental alterations contribute to the spectrum of clinical dysfunctions reported in patients with SBH.

scholarly journals Neurodevelopmental Trajectories and Clinical Profiles in a Sample of Children and Adolescents With Early- and Very-Early-Onset Schizophrenia

2021 ◽  
Vol 12 ◽  
Author(s):  
Maria Pontillo ◽  
Roberto Averna ◽  
Maria Cristina Tata ◽  
Fabrizia Chieppa ◽  
Maria Laura Pucciarini ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Neurodevelopmental Disorders ◽  
Early Onset ◽  
Social Role ◽  
Treatment Plan ◽  
Neurodevelopmental Disorder ◽  
Communication Disorders ◽  
Autism Spectrum ◽  
Early Onset Schizophrenia ◽  
Assessment And Treatment

Schizophrenia before the age of 18 years is usually divided into two categories. Early-onset schizophrenia (EOS) presents between the ages of 13 and 17 years, whereas very-early-onset schizophrenia (VEOS) presents at or before the age of 12 years. Previous studies have found that neurodevelopmental difficulties in social, motor, and linguistic domains are commonly observed in VEOS/EOS patients. Recent research has also shown a high prevalence of neurodevelopmental disorders (e.g., intellectual disability, communication disorders, autism spectrum disorder, neurodevelopmental motor disorders) in VEOS/EOS patients, indicating genetic overlap between these conditions. These findings lend support to the neurodevelopmental continuum model, which holds that childhood neurodevelopmental disorders and difficulties and psychiatric disorders (e.g., schizophrenia) fall on an etiological and neurodevelopmental continuum, and should not be considered discrete entities. Based on this literature, in this study we focused on the overlap between neurodevelopmental disorders and schizophrenia investigating, in a large sample (N = 230) of VEOS/EOS children and adolescents, the clinical differences, at the onset of psychosis, between VEOS/EOS with neurodevelopmental disorder or neurodevelopmental difficulties and VEOS/EOS with no diagnosed neurodevelopmental disorder or neurodevelopmental difficulties. The findings showed that, in children and adolescents with a neurodevelopmental disorder or neurodevelopmental difficulties, psychosis onset occurred at an earlier age, was associated with more severe functional impairment (e.g., global, social, role), and was characterized by positive symptoms (e.g., grandiose ideas, perceptual abnormalities, disorganized communication) and disorganized symptoms (e.g., odd behavior or appearance, bizarre thinking). Instead, in children and adolescents without a neurodevelopmental disorder or neurodevelopmental difficulties, psychosis onset was mainly characterized by negative symptomatology (e.g., social anhedonia, avolition, expression of emotion, experience of emotions and self, ideational richness). Given these differences, the presence of a neurodevelopmental disorder or neurodevelopmental difficulties should be carefully investigated and integrated early into the assessment and treatment plan for VEOS/EOS patients.

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