scholarly journals Acute encephalopathy after head trauma in a patient with a RHOBTB2 mutation

2020 ◽  
Vol 6 (3) ◽  
pp. e418
Author(s):  
Annemarie C.S. Knijnenburg ◽  
Joost Nicolai ◽  
Levinus A. Bok ◽  
Akin Bay ◽  
Alexander P.A. Stegmann ◽  
...  
Keyword(s):  
Head Trauma ◽  
De Novo ◽  
Brain Regions ◽  
Epileptic Activity ◽  
Epileptic Encephalopathy ◽  
Missense Mutations ◽  
Acute Encephalopathy ◽  
Severe Intellectual Disability ◽  
Eeg Abnormalities ◽  
Slow Activity

ObjectiveDe novo missense mutations in the RHOBTB2 gene have been described as causative for developmental and epileptic encephalopathy.MethodsThe clinical phenotype of this disorder includes early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorder. Three RHOBTB2 patients have been described with acute encephalopathy and febrile epileptic status. All showed severe EEG abnormalities during this episode and abnormal MRI with hemisphere swelling or reduced diffusion in various brain regions.ResultsWe describe the episode of acute encephalopathy after head trauma in a 5-year-old RHOBTB2 patient. At admission, Glasgow coma scale score was E4M4V1. EEG was severely abnormal showing a noncontinuous pattern with slow activity without epileptic activity indicating severe encephalopathy. A second EEG on day 8 was still severely slowed and showed focal delta activity frontotemporal in both hemispheres. Gradually, he recovered, and on day 11, he had regained his normal reactivity, behavior, and mood. Two months after discharge, EEG showed further decrease in slow activity and increase in normal electroencephalographic activity. After discharge, parents noted that he showed more hyperkinetic movements compared to before this period of encephalopathy. Follow-up MRI showed an increment of hippocampal atrophy. In addition, we summarize the clinical characteristics of a second RHOBTB2 patient with increase of focal periventricular atrophy and development of hemiparesis after epileptic status.ConclusionsAcute encephalopathy in RHOBTB2 patients can also be triggered by head trauma.

scholarly journals YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism

2021 ◽  
Vol 12 ◽  
Author(s):  
Xing-Guang Ye ◽  
Zhi-Gang Liu ◽  
Jie Wang ◽  
Jie-Min Dai ◽  
Pei-Xiu Qiao ◽  
...  
Keyword(s):  
Missense Mutation ◽  
De Novo ◽  
Febrile Seizures ◽  
Epileptic Encephalopathy ◽  
Myoclonic Epilepsy ◽  
Missense Mutations ◽  
Regional Effect ◽  
Diverse Range ◽  
Mild Phenotype ◽  
Truncating Mutation

YWHAG, which encodes an adapter protein 14-3-3γ, is highly expressed in the brain and regulates a diverse range of cell signaling pathways. Previously, eight YWHAG mutations have been identified in patients with epileptic encephalopathy (EE). In this study, using trios-based whole exome sequencing, we identified two novel YWHAG mutations in two unrelated families with childhood myoclonic epilepsy and/or febrile seizures (FS). The identified mutations included a heterozygous truncating mutation (c.124C>T/p.Arg42Ter) and a de novo missense mutation (c.373A>G/p.Lys125Glu). The two probands experienced daily myoclonic seizures that were recorded with ictal generalized polyspike-slow waves, but became seizure-free with simple valproate treatment. The other affected individuals presented FS. The truncating mutation was identified in the family with six individuals of mild phenotype, suggesting that YWHAG mutations of haploinsufficiency are relatively less pathogenic. Analysis on all missense mutations showed that nine mutations were located within 14-3-3γ binding groove and another mutation was located at residues critical for dimerization, indicating a molecular sub-regional effect. Mutation Arg132Cys, which was identified recurrently in five patients with EE, would have the strongest influence on binding affinity. 14-3-3γ dimers supports target proteins activity. Thus, a heterozygous missense mutation would lead to majority dimers being mutants; whereas a heterozygous truncating mutation would lead to only decreasing the number of wild-type dimer, being one of the explanations for phenotypical variation. This study suggests that YWHAG is potentially a candidate pathogenic gene of childhood myoclonic epilepsy and FS. The spectrum of epilepsy caused by YWHAG mutations potentially range from mild myoclonic epilepsy and FS to severe EE.

scholarly journals Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations

2017 ◽  
Vol 3 (6) ◽  
pp. e206 ◽  
Author(s):  
Carla Marini ◽  
Michele Romoli ◽  
Elena Parrini ◽  
Cinzia Costa ◽  
Davide Mei ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Focal Epilepsy ◽  
Brain Mri ◽  
Somatic Mosaicism ◽  
Epileptic Encephalopathy ◽  
Seizure Onset ◽  
Severe Intellectual Disability ◽  
The Mean

Objective:To describe electroclinical features and outcome of 6 patients harboring KCNB1 mutations.Methods:Clinical, EEG, neuropsychological, and brain MRI data analysis. Targeted next-generation sequencing of a 95 epilepsy gene panel.Results:The mean age at seizure onset was 11 months. The mean follow-up of 11.3 years documented that 4 patients following an infantile phase of frequent seizures became seizure free; the mean age at seizure offset was 4.25 years. Epilepsy phenotypes comprised West syndrome in 2 patients, infantile-onset unspecified generalized epilepsy, myoclonic and photosensitive eyelid myoclonia epilepsy resembling Jeavons syndrome, Lennox-Gastaut syndrome, and focal epilepsy with prolonged occipital or clonic seizures in each and every one. Five patients had developmental delay prior to seizure onset evolving into severe intellectual disability with absent speech and autistic traits in one and stereotypic hand movements with impulse control disorder in another. The patient with Jeavons syndrome evolved into moderate intellectual disability. Mutations were de novo, 4 missense and 2 nonsense, 5 were novel, and 1 resulted from somatic mosaicism.Conclusions:KCNB1-related manifestations include a spectrum of infantile-onset generalized or focal seizures whose combination leads to early infantile epileptic encephalopathy including West, Lennox-Gastaut, and Jeavons syndromes. Long-term follow-up highlights that following a stormy phase, seizures subside or cease and treatment may be eased or withdrawn. Cognitive and motor functions are almost always delayed prior to seizure onset and evolve into severe, persistent impairment. Thus, KCNB1 mutations are associated with diffuse brain dysfunction combining seizures, motor, and cognitive impairment.

scholarly journals De novo Mutations in NALCN Cause a Syndrome of Congenital Contractures of the Limbs and Face with Hypotonia, and Developmental Delay

2015 ◽  
Author(s):  
Jessica X Chong ◽  
Margaret J McMillin ◽  
Kathryn M Shively ◽  
Anita E Beck ◽  
Colby T Marvin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Developmental Delay ◽  
De Novo ◽  
Dominant Negative ◽  
Protein Domain ◽  
Dominant Negative Effect ◽  
Global Developmental Delay ◽  
Missense Mutations ◽  
Severe Intellectual Disability ◽  
Dominant Condition

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five simplex cases putatively diagnosed with “DA2A with severe neurological abnormalities” in which the proband had Congenital Contractures of the LImbs and FAce, Hypotonia, and global Developmental Delay often resulting in early death, a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in sodium leak channel, nonselective (NALCN) in four families with CLIFAHDD syndrome. Using molecular inversion probes to screen NALCN in a cohort of 202 DA cases as well as concurrent exome sequencing of six other DA cases revealed NALCN mutations in ten additional families with “atypical” forms of DA. All fourteen mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that mutant NALCN nearly abolished the expression of wildtype NALCN, suggesting that mutations that cause CLIFAHDD syndrome have a dominant negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families with an autosomal recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition with varied though overlapping phenotypic features perhaps depending on the type of mutation and affected protein domain(s).

Flexible Stoichiometry: Implications for KCNQ2- and KCNQ3-Associated Neurodevelopmental Disorders

2021 ◽  
pp. 1-10
Author(s):  
Kristen Springer ◽  
Nissi Varghese ◽  
Anastasios V. Tzingounis
Keyword(s):  
Age Of Onset ◽  
Cell Types ◽  
Brain Regions ◽  
Epileptic Activity ◽  
Epileptic Encephalopathy ◽  
Current View ◽  
Great Effort ◽  
Neonatal Seizures ◽  
Developmentally Regulated ◽  
Disease States

KCNQ2 and KCNQ3 pathogenic channel variants have been associated with a spectrum of developmentally regulated diseases that vary in age of onset, severity, and whether it is transient (i.e., benign familial neonatal seizures) or long-lasting (i.e., developmental and epileptic encephalopathy). KCNQ2 and KCNQ3 channels have also emerged as a target for novel antiepileptic drugs as their activation could reduce epileptic activity. Consequently, a great effort has taken place over the last 2 decades to understand the mechanisms that control the assembly, gating, and modulation of KCNQ2 and KCNQ3 channels. The current view that KCNQ2 and KCNQ3 channels assemble as heteromeric channels (KCNQ2/3) forms the basis of our understanding of KCNQ2 and KCNQ3 channelopathies and drug design. Here, we review the evidence that supports the formation of KCNQ2/3 heteromers in neurons. We also highlight functional and transcriptomic studies that suggest channel composition might not be necessarily fixed in the nervous system, but rather is dynamic and flexible, allowing some neurons to express KCNQ2 and KCNQ3 homomers. We propose that to fully understand KCNQ2 and KCNQ3 channelopathies, we need to adopt a more flexible view of KCNQ2 and KCNQ3 channel stoichiometry, which might differ across development, brain regions, cell types, and disease states.

scholarly journals The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura B. Jones ◽  
Colin H. Peters ◽  
Richard E. Rosch ◽  
Maxine Owers ◽  
Elaine Hughes ◽  
...  
Keyword(s):  
De Novo ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Channel Function ◽  
Biophysical Analysis ◽  
Gain And Loss ◽  
Patients With Epilepsy

Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel NaV1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the NaV1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of NaV1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.

scholarly journals Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome

2018 ◽  
Author(s):  
Juan Arranz ◽  
Elisa Balducci ◽  
Krisztina Arató ◽  
Gentzane Sánchez-Elexpuru ◽  
Sònia Najas ◽  
...  
Keyword(s):  
Biochemical Characterization ◽  
Catalytic Domain ◽  
De Novo ◽  
Epileptic Activity ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Mutant Mice ◽  
Chromosome 21 ◽  
Missense Mutations ◽  
Human Pathology

ABSTRACTAutism spectrum disorders are early onset neurodevelopmental disorders characterized by deficits in social communication and restricted repetitive behaviors, yet they are quite heterogeneous in terms of their genetic basis and phenotypic manifestations. Recently, de novo pathogenic mutations in DYRK1A, a chromosome 21 gene associated to neuropathological traits of Down syndrome, have been identified in patients presenting a recognizable syndrome included in the autism spectrum. These mutations produce DYRK1A kinases with partial or complete absence of the catalytic domain, or they represent missense mutations located within this domain. Here, we undertook an extensive biochemical characterization of the DYRK1A missense mutations reported to date and show that most of them, but not all, result in enzymatically dead DYRK1A proteins. We also show that haploinsufficient Dyrk1a+/- mutant mice mirror the neurological traits associated with the human pathology, such as defective social interactions, stereotypic behaviors and epileptic activity. These mutant mice present altered proportions of excitatory and inhibitory neocortical neurons and synapses. Moreover, we provide evidence that alterations in the production of cortical excitatory neurons are contributing to these defects. Indeed, by the end of the neurogenic period, the expression of developmental regulated genes involved in neuron differentiation and/or activity is altered. Therefore, our data indicate that altered neocortical neurogenesis could critically affect the formation of cortical circuits, thereby contributing to the neuropathological changes in DYRK1A haploinsufficiency syndrome.

scholarly journals Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate

2019 ◽  
Author(s):  
Alba Sanchis-Juan ◽  
Marcia A Hasenahuer ◽  
James A Baker ◽  
Amy McTague ◽  
Katy Barwick ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Neuronal Excitability ◽  
Transmembrane Domain ◽  
De Novo ◽  
Structural Information ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Missense Mutations ◽  
Pathogenic Variants ◽  
Activation Gate

AbstractCys-loop receptors are vital for controlling neuronal excitability in the brain and their dysfunction results in numerous neurological disorders. Recently, six de novo missense variants in GABRA2 gene, a member of this family, have been associated with early infantile epileptic encephalopathy (EIEE) and intellectual disability with seizures. Here, using whole-genome sequencing we identified a de novo missense variant in GABRA2 gene in a patient with EIEE and developmental delay. We perform protein structural analysis of the seven variants and show that all the mutations are in the transmembrane domain, either close to the desensitization gate, the activation gate or in inter-subunit interfaces. Further investigations demonstrated that the majority of pathogenic variants reported are at equivalent positions in other Cys-loop receptors, emphasizing the importance of these residues for the adequate function of the receptor. Also, a comparison of the distribution of the mutations in all the Cys-loop receptors showed that pathogenic variants are more common in the transmembrane helices, more specifically in the M2 helix, highlighting the importance of this segment. Our study expands the clinical spectrum of individuals with pathogenic missense mutations in GABRA2, defines the regions where pathogenic mutations are in the protein structure, and highlights the value of considering sequence, evolutionary, and structural information from other Cys-loop receptors as a strategy for variant interpretation of novel missense mutations in GABRA2.

scholarly journals Mild head trauma: Acute encephalopathy trigger in children with RHOBTB2 de novo mutation

Neurología ◽  
2021 ◽  
Author(s):  
A. Jové Blanco ◽  
J. Lorente Romero ◽  
E. Barredo Valderrama ◽  
P. Castro de Castro
Keyword(s):  
Head Trauma ◽  
De Novo ◽  
De Novo Mutation ◽  
Acute Encephalopathy

scholarly journals SYT1-associated neurodevelopmental disorder: a case series

Brain ◽  
2018 ◽  
Vol 141 (9) ◽  
pp. 2576-2591 ◽  
Author(s):  
Kate Baker ◽  
Sarah L Gordon ◽  
Holly Melland ◽  
Fabian Bumbak ◽  
Daniel J Scott ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Case Series ◽  
Missense Mutations ◽  
Severe Intellectual Disability ◽  
Specific Manner ◽  
Synaptotagmin 1 ◽  
Presynaptic Vesicle ◽  
Key Features

Baker, Gordon et al. present the first international case series describing the neurodevelopmental disorder associated with Synaptotagmin 1 (SYT1) de novo missense mutations. Key features include movement abnormalities, severe intellectual disability, and hallmark EEG alterations. Expression of patients’ SYT1 mutations in mouse neurons disturbs presynaptic vesicle dynamics in a mutation-specific manner.

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