scholarly journals Early-onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in NF1 and MAGEL2

2017 ◽  
Vol 3 (1) ◽  
pp. 81-85 ◽  
Author(s):  
Satoshi Akamine ◽  
Noriaki Sagata ◽  
Yasunari Sakai ◽  
Takahiro A. Kato ◽  
Takeshi Nakahara ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy

scholarly journals The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Maria A. Gandini ◽  
Ivana A. Souza ◽  
Laurent Ferron ◽  
A. Micheil Innes ◽  
Gerald W. Zamponi
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Structural Damage ◽  
De Novo ◽  
Splice Variants ◽  
Cerebellar Atrophy ◽  
Familial Hemiplegic Migraine ◽  
Significant Loss ◽  
Loss Of Function ◽  
Hemiplegic Migraine

AbstractCACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

scholarly journals A Novel Heterozygous Missense Variant in YWHAG Gene Cause Early-Onset Epilepsy in a Chinese Family

2020 ◽  
Author(s):  
Zhi Yi ◽  
Zhenfeng Song ◽  
Jiao Xue ◽  
Chengqing Yang ◽  
Fei Li ◽  
...  
Keyword(s):  
Early Onset ◽  
Seizure Control ◽  
De Novo ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Chinese Family ◽  
Gene Variants ◽  
Case Presentation ◽  
Epileptic Encephalopathies ◽  
Refractory Seizures

Abstract Background: Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of severe disorders which are characterized by early-onset, refractory seizures and developmental slowing or regression. Genetic variations are significant causes for them. De novo variants in an increasing number of candidate genes have been found to be causal. YWHAG gene variants have been reported to cause developmental and epileptic encephalopathy 56 (DEE56). Case presentation: Here, we report a novel heterozygous missense variant c.170G>A (p.R57H) in YWHAG gene cause early-onset epilepsy in a Chinese family. Both the proband and his mother exhibit early onset seizures, intellectual disability, developmental delay. While the proband achieve seizure control with sodium valproate, his mother's seizures were not well controlled. Conclusions: Our report further confirming the haploinsufficiency of YWHAG results in developmental and epileptic encephalopathies.

A case of early onset epileptic encephalopathy with de novo mutation in SLC35A2: Clinical features and treatment for epilepsy

2017 ◽  
Vol 39 (3) ◽  
pp. 256-260 ◽  
Author(s):  
Tomokazu Kimizu ◽  
Yukitoshi Takahashi ◽  
Taikan Oboshi ◽  
Asako Horino ◽  
Takayoshi Koike ◽  
...  
Keyword(s):  
Clinical Features ◽  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
De Novo Mutation

scholarly journals De novo hotspot variants in CYFIP2 cause early‐onset epileptic encephalopathy

2018 ◽  
Vol 83 (4) ◽  
pp. 794-806 ◽  
Author(s):  
Mitsuko Nakashima ◽  
Mitsuhiro Kato ◽  
Kazushi Aoto ◽  
Masaaki Shiina ◽  
Hazrat Belal ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy

scholarly journals KCNQ2 mutations: genotype-phenotype association beyond epilepsy

2015 ◽  
Vol 42 (S1) ◽  
pp. S8-S8
Author(s):  
SE Buerki ◽  
GA Horwath ◽  
MI Van Allen ◽  
A Datta ◽  
C Boelman ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Autonomic Dysfunction ◽  
De Novo ◽  
Focal Epilepsy ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
High Signal ◽  
Brain Volume Loss ◽  
Hyperkinetic Movement Disorder

Background: KCNQ2 abnormalities were described in infants with benign familial neonatal seizures (BFNS) and epileptic encephalopathy (EE). Associated features possibly include abnormal neuroimaging findings such as hypomyelination and/or T2 high signal of basal ganglia. Methods: This report describes 4 infants carrying different heterozygous KCNQ2 variants and 2 infants with 20q13.33 deletions encompassing KCNQ2 gene. Results: The different KCNQ2 mutations led to EE in 3 patients and included a novel de novo missense variant, p.Arg201Cys/c.601C>T, in an infant with severe EE and global developmental delay, hyperkinetic movement disorder, autonomic dysfunction with chronic hypoventilation, apnea, low GABA levels in CSF, and hypomyelination. She died at age 3 years of respiratory failure. One patient with BFNS and normal MRI has a previously reported c.508delG frame shift mutation in KCNQ2. Of the two de novo 22q13.33 deletions (1.2Mb versus 254.1 Kb) the larger caused a more severe phenotype, including focal epilepsy from infancy until 4 years, moderate developmental delay and diffuse brain volume loss. Conclusions: Along with varied epilepsy phenotypes and neuroimaging findings KCNQ abnormalities were associated with severe autonomic dysfunction and reduced CSF GABA levels. This might have further treatment implications, besides that the altered potassium channel function itself presents a therapeutic target.

scholarly journals X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009608
Author(s):  
Jia-Hui Sun ◽  
Jiang Chen ◽  
Fernando Eduardo Ayala Valenzuela ◽  
Carolyn Brown ◽  
Diane Masser-Frye ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Prolonged Exposure ◽  
De Novo ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Decay Kinetics ◽  
Gain Of Function ◽  
Ca1 Neurons ◽  
Pathogenic Variants

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

scholarly journals De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

2020 ◽  
Author(s):  
Chiara Klöckner ◽  
◽  
Heinrich Sticht ◽  
Pia Zacher ◽  
Bernt Popp ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy
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