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 Not all SCN1A epileptic encephalopathies are Dravet syndrome

Neurology ◽  
2017 ◽  
Vol 89 (10) ◽  
pp. 1035-1042 ◽  
Author(s):  
Lynette G. Sadleir ◽  
Emily I. Mountier ◽  
Deepak Gill ◽  
Suzanne Davis ◽  
Charuta Joshi ◽  
...  
Keyword(s):  
Movement Disorder ◽  
Missense Mutation ◽  
De Novo ◽  
Age At Onset ◽  
Case Series ◽  
Febrile Seizures ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Developmental Impairment ◽  
Hyperkinetic Movement Disorder

Objective:To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder.Methods:A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation.Results:We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable.Conclusions:Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.

A De Novo Dominant Negative Mutation in DNM1L Causes Sudden Onset Status Epilepticus with Subsequent Epileptic Encephalopathy

2019 ◽  
Vol 50 (03) ◽  
pp. 197-201
Author(s):  
S. Schmid ◽  
M. Wagner ◽  
C. Goetz ◽  
C. Makowski ◽  
P. Freisinger ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Missense Mutation ◽  
De Novo ◽  
Mitochondrial Fission ◽  
Refractory Status Epilepticus ◽  
Sudden Onset ◽  
Epileptic Encephalopathy ◽  
Neurologic Outcome ◽  
Dominant Negative Mutation ◽  
Refractory Status

AbstractMitochondrial dynamics such as fission and fusion play a vital role in normal brain development and neuronal activity. DNM1L encodes a dynamin-related protein 1 (Drp1), which is a GTPase essential for proper mitochondrial fission. The clinical phenotype of DNM1L mutations depends on the degree of mitochondrial fission deficiency, ranging from severe encephalopathy and death shortly after birth to initially normal development and then sudden onset of refractory status epilepticus with very poor neurologic outcome. We describe a case of a previously healthy 3-year-old boy with a mild delay in speech development until the acute onset of a refractory status epilepticus with subsequent epileptic encephalopathy and very poor neurologic outcome. The de novo missense mutation in DNM1L (c.1207C > T, p.R403C), which we identified in this case, seems to determine a unique clinical course, strikingly similar to four previously described patients in literature with the identical de novo heterozygous missense mutation in DNM1L.

Recurrent GNAO1 Mutations Associated With Developmental Delay and a Movement Disorder

2016 ◽  
Vol 31 (14) ◽  
pp. 1598-1601 ◽  
Author(s):  
Leonie A. Menke ◽  
Marc Engelen ◽  
Mariel Alders ◽  
Vincent J. J. Odekerken ◽  
Frank Baas ◽  
...  
Keyword(s):  
Movement Disorder ◽  
Missense Mutation ◽  
Developmental Delay ◽  
Recurrence Risk ◽  
Epileptic Encephalopathy ◽  
Missense Mutations ◽  
Phenotype Correlation ◽  
Affected Child ◽  
Sibling Pairs ◽  
Hyperkinetic Movement Disorder

In 2 unrelated patients with axial hypotonia, developmental delay and a hyperkinetic movement disorder, a missense mutation was found in codon 209 of the GNAO1 gene. From the still scarce literature on GNAO1 mutations, a clear genotype-phenotype correlation emerged. From the 26 patients reported thus far, 12 patients had epileptic encephalopathy, and 14 had a developmental delay and a hyperkinetic movement disorder. All but 1 of the latter patients had missense mutations in GNAO1 codon 209 or 246, which thus appear to be mutation hotspots. At least 2 sibling pairs showed that the recurrence risk after 1 affected child with a GNAO1 mutation might be relatively high (5-15%), due to apparent gonadal mosaicism in the parents.

Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome

Neurology ◽  
2006 ◽  
Vol 66 (7) ◽  
pp. 1044-1048 ◽  
Author(s):  
G. Uyanik ◽  
N. Elcioglu ◽  
J. Penzien ◽  
C. Gross ◽  
Y. Yilmaz ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Autosomal Recessive ◽  
Sensory Neuropathy ◽  
Variable Degree ◽  
Missense Mutations ◽  
Novel Mutations ◽  
The Third ◽  
Truncating Mutation ◽  
Cerebral Mri ◽  
Different Types

Background: Andermann syndrome (OMIM 218000) is an autosomal recessive motor-sensory neuropathy associated with developmental and neurodegenerative defects. The cerebral MRI reveals a variable degree of agenesis of the corpus callosum. Recently, truncating mutations of the KCC3 gene (also known as SLC12A6) have been associated with Andermann syndrome.Methods: The authors assessed clinically and genetically three isolated cases from Germany and Turkey with symptoms consistent with Andermann syndrome.Results: The authors detected four novel mutations within the KCC3 gene in their patients: two different truncating mutations in the first patient, a homozygous truncating mutation in the second, and a homozygous missense mutation in the third patient. In contrast to the classic phenotype of the Andermann syndrome linked to truncating KCC3 mutations the phenotype and the course of the disease linked to the missense mutation appeared to be different (i.e., showing additional features like diffuse and widespread white matter abnormalities).Conclusions: Not only truncating but also missense mutations of the KCC3 gene are associated with Andermann syndrome. Different types of KCC3 mutations may determine different clinical phenotypes.

De novo truncating mutation in SCN1A as a cause of febrile seizures plus (FS+)

2020 ◽  
Vol 22 (3) ◽  
pp. 323-326
Author(s):  
Alex Jaimes ◽  
Rosa Guerrero-López ◽  
Beatriz González-Giráldez ◽  
Jose M. Serratosa
Keyword(s):  
De Novo ◽  
Febrile Seizures ◽  
Truncating Mutation ◽  
Febrile Seizures Plus

scholarly journals Truncating mutation in TANC2 in a Chinese boy associated with Lennox-Gastaut syndrome: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yang Tian ◽  
Zhen Shi ◽  
Chi Hou ◽  
Wenjuan Li ◽  
Xiuying Wang ◽  
...  
Keyword(s):  
Antiepileptic Drugs ◽  
Nonsense Mutation ◽  
Synapse Formation ◽  
De Novo ◽  
Association Studies ◽  
Gene Mutations ◽  
Epileptic Encephalopathy ◽  
Scaffolding Protein ◽  
Genome Wide Association Studies ◽  
Truncating Mutation

Abstract Background Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy that can be caused by brain malformations or genetic mutations. Recently, genome-wide association studies have led to the identification of novel mutations associated with LGS. The TANC2 gene, encodes a synaptic scaffolding protein that interacts with other proteins at the postsynaptic density to regulate dendritic spines and excitatory synapse formation. The TANC2 gene mutations were reported in neurodevelopmental disorders and epilepsy but not in LGS ever. Case presentation Here we describe the case of a boy with LGS who presented with multiple seizure patterns, such as myoclonic, atonic, atypical absence, generalized tonic-clonic, focal seizures, and notable cognitive and motor regression. The seizures were refractory to many antiepileptic drugs. He got seizure-free with ketogenic diet combined with antiepileptic drugs. A de novo nonsense mutation c.4321C > T(p.Gln1441Ter) in TANC2 gene was identified by the whole-exome sequencing and confirmed by Sanger sequencing. Conclusion We described the first Chinese case with LGS associated to a de novo nonsense mutation c.4321C > T(p.Gln1441Ter) in TANC2 gene, which would expand the clinical spectrum related to TANC2 mutations and contribute to better understanding of genotype-phenotype relationship to guide precision medicine.

scholarly journals Case Report: Novel mutations in TBC1D24 are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 553 ◽  
Author(s):  
Erika Banuelos ◽  
Keri Ramsey ◽  
Newell Belnap ◽  
Malavika Krishnan ◽  
Chris D. Balak ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Dominant ◽  
Epileptic Encephalopathy ◽  
Myoclonic Epilepsy ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Single Family ◽  
Whole Exome ◽  
Neurological Phenotype ◽  
Syndromic Hearing Loss

Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband’s mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy

scholarly journals A Novel De Novo TUBB3 Variant Causing Developmental Delay, Epilepsy and Mild Ophthalmological Symptoms in a Chinese Child.

2021 ◽  
Author(s):  
Jiao Xue ◽  
Zhenfeng Song ◽  
Shuyin Ma ◽  
Zhi Yi ◽  
Chengqing Yang ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Febrile Seizures ◽  
Extraocular Muscles ◽  
Global Developmental Delay ◽  
Missense Mutations ◽  
Brain Malformations ◽  
Heterozygous Variant ◽  
Type 3 ◽  
Congenital Fibrosis

Abstract Heterozygous missense mutations in TUBB3 have been implicated in various neurological disorders encompassing either isolated congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or complex cortical dysplasia with other brain malformations 1 (CDCBM1). The description of seizures in patients with TUBB3 mutations is rare. Here, we reported a patient who had febrile seizures before and focal seizure this time, which was diagnosed as epilepsy in combination with an abnormal EEG. MRI showed hypoplastic corpus callosum. Mutation analysis showed a novel de novo heterozygous variant of TUBB3 gene (NM_006086), c.763G>A (p.V255I). He had global developmental delay, photophobia and elliptic pupil, but lacking extraocular muscles involvement and malformations of cortical development, which might be a less severe phenotype of TUBB3 mutations. This was the first report of elliptic pupil in patients with TUBB3 mutations and expanded the spectrum of TUBB3 phenotypes. It indicated that the phenotypic range of TUBB3 mutations might be more continuous than discrete, with a severity ranging from mild to severe. Further studies are needed to elucidate the complete spectrum of TUBB3-related phenotypes.

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