scholarly journals De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Hirotomo Saitsu ◽  
Tenpei Akita ◽  
Jun Tohyama ◽  
Hadassa Goldberg-Stern ◽  
Yu Kobayashi ◽  
...  
Keyword(s):  
De Novo ◽  
Neuronal Firing ◽  
Infantile Epilepsy

scholarly journals The Genotype and Phenotype of Proline-Rich Transmembrane Protein 2 Associated Disorders in Chinese Children

2021 ◽  
Vol 9 ◽  
Author(s):  
Han-yu Luo ◽  
Ling-ling Xie ◽  
Si-qi Hong ◽  
Xiu-juan Li ◽  
Mei Li ◽  
...  
Keyword(s):  
De Novo ◽  
Transmembrane Protein ◽  
Chinese Children ◽  
Gene Deletions ◽  
Targeted Next Generation Sequencing ◽  
Mild Developmental Delay ◽  
Good Treatment Response ◽  
Infantile Epilepsy ◽  
Next Generation Sequencing Ngs

Objectives: To study the genetic and clinical characteristics of Chinese children with pathogenic proline-rich transmembrane protein 2 (PRRT2) gene-associated disorders.Methods: Targeted next generation sequencing (NGS) was used to identify pathogenic PRRT2 variations in Chinese children with epilepsy and/or kinesigenic dyskinesia. Patients with confirmed PRRT2-associated disorders were monitored and their clinical data were analyzed.Results: Forty-four patients with pathogenic PRRT2 variants were recruited. Thirty-five of them (79.5%) had heterozygous mutations, including 30 frameshifts, three missenses, one nonsense, and one splice site variant. The c.649dupC was the most common variant (56.8%). Eight patients (18.2%) showed whole gene deletions, and one patient (2.3%) had 16p11.2 microdeletion. Thirty-four cases (97.1%) were inherited and one case (2.9%) was de novo. Forty patients were diagnosed with benign familial infantile epilepsy (BFIE), two patients had paroxysmal kinesigenic dyskinesia (PKD) and two had infantile convulsions and choreoathetosis (ICCA). Patients with whole gene deletions had a later remission than patients with heterozygous mutations (13.9 vs. 7.1 months, P = 0.001). Forty-two patients were treated with antiseizure medications (ASMs). At last follow-up, 35 patients, including one who did not receive therapy, were asymptomatic, and one patient without ASMs died of status epilepticus at 12 months of age. One patient developed autism, and one patient showed mild developmental delay/intellectual disability.Conclusion: Our data suggested that patients with whole gene deletions could have more severe manifestations in PRRT2-associated disorders. Conventional ASMs, especially Oxcarbazepine, showed a good treatment response.

scholarly journals A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay

2017 ◽  
Vol 100 (2) ◽  
pp. 343-351 ◽  
Author(s):  
Kelly Schoch ◽  
Linyan Meng ◽  
Szabolcs Szelinger ◽  
David R. Bearden ◽  
Asbjorg Stray-Pedersen ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Infantile Epilepsy ◽  
De Novo Variant

PRRT2 Related Epilepsies: A Gene Review

2021 ◽  
Author(s):  
Carmela Rita Massimino ◽  
Laura Portale ◽  
Annamaria Sapuppo ◽  
Francesco Pizzo ◽  
Laura Sciuto ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
De Novo ◽  
Transmembrane Protein ◽  
Common Disease ◽  
Hemiplegic Migraine ◽  
Pathogenic Variants ◽  
Disease Spectrum ◽  
Paroxysmal Kinesigenic Dyskinesia ◽  
Paroxysmal Disorders ◽  
Infantile Epilepsy

Abstract PRRT2 encodes for proline-rich transmembrane protein 2 involved in synaptic vesicle fusion and presynaptic neurotransmitter release. Mutations in human PRRT2 have been related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with choreoathetosis, benign familial infantile epilepsies, and hemiplegic migraine. PRRT2 mutations cause neuronal hyperexcitability, which could be related to basal ganglia or cortical circuits dysfunction, leading to paroxysmal disorders. PRRT2 is expressed in the cerebral cortex, basal ganglia, and cerebellum. Approximately, 90% of pathogenic variants are inherited and 10% are de novo. Paroxysmal attacks in PKD are characterized by dystonia, choreoathetosis, and ballismus. In the benign familial infantile epilepsy (BFIE), seizures are usually focal with or without generalization, usually begin between 3 and 12 months of age and remit by 2 years of age. In 30% of cases of PRRT2-associated PKD, there is an association with BFIE, and this entity is referred to as PKD with infantile convulsions (PKD/IC). PRRT2 mutations are the cause of benign family childhood epilepsy and PKD/IC. On the other hand, PRRT2 mutations do not seem to correlate with other types of epilepsy. The increasing incidence of hemiplegic migraine in families with PRRT2-associated PKD or PKD/IC suggests a common disease pathway, and it is possible to assert that BFIE, paroxysmal kinesigenic dyskinesia, and PKD with IC belong to a continuous disease spectrum of PRRT2-associated diseases.

scholarly journals A New Case of de novo Variant c.892C>T (p.Arg298Trp) in NACC1: A First Case Report From China

2021 ◽  
Vol 9 ◽  
Author(s):  
Baiyu Lyu ◽  
Yan Dong ◽  
Juan Kang
Keyword(s):  
Intellectual Disability ◽  
Congenital Cataract ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Brain Mri ◽  
Case Presentation ◽  
Feeding Difficulties ◽  
Severe Intellectual Disability ◽  
First Case ◽  
Infantile Epilepsy

Background: The nucleus accumbens associated 1 (NACC1) gene is a transcription factor member of the BTB/POZ family. A de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 may define a syndrome characterized by intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties.Case Presentation: We report a new case with a neurodevelopmental disorder characterized by severe intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. Brain MRI reveals brain dysplasia. We observe a de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 gene in this case. Now, the child regularly goes to the hospital for rehabilitation training (once a month). Sodium Valproate (10 mg/kg/day) and Clobazam (10 mg/kg/day) are used in the treatment of epilepsy. A total of three articles were screened, and two papers were excluded. The search revealed one article related to a syndrome caused by a de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1; they screened the main clinical features of eight cases of a syndrome, which were summarized and analyzed.Conclusions: The NACC1 gene is a member of the BTB/POZ family of transcription factors. A de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 may define a syndrome characterized by intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. At present, there is no effective cure. In the future, we need more cases to determine the phenotype–genotype correlation of NACC1 variants. Many questions remain to be answered, and many challenges remain to be faced. Future transcriptional studies may further clarify this rare, recurrent variant, and could potentially lead to targeted therapies.

The Spectrum of KCNQ2- and KCNQ3-Related Epilepsy

2021 ◽  
Author(s):  
Anna Portale ◽  
Mattia Comella ◽  
Giulia Salomone ◽  
Alessandra Di Nora ◽  
Lidia Marino ◽  
...  
Keyword(s):  
De Novo ◽  
Epileptic Encephalopathy ◽  
Response To Treatment ◽  
Psychomotor Development ◽  
K Channel ◽  
Loss Of Function ◽  
M Current ◽  
Wide Range ◽  
Cortical Visual Impairment ◽  
Infantile Epilepsy

Abstract KCNQ genes encode for a family of six transmembrane domains, single pore-loop, and K+ channel α-subunits that have a wide range of physiological correlates. In the brain, KCNQ2 and KCNQ3 heteromultimers are thought to underlie the M-current which is essential in raising the threshold for firing an action potential; mutations in these genes may cause several types of infantile epilepsies. KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes that range from KCNQ2 benign familial neonatal epilepsy (BFNE), a seizure disorder that occur in children who typically have a normal psychomotor development and are inherited as an autosomal dominant trait, to KCNQ2 early-onset epileptic encephalopathy (EOEE) as the result of a de novo pathogenic variant. KCNQ3-related disorders are rarer and include BFNE, benign familial infantile epilepsy and KCNQ3-related epileptic encephalopathy with intellectual disability with or without seizures and/or cortical visual impairment. For both KCNQ2- and KCNQ3-related disorders, it is possible to use several drugs for different classes of mutations (i.e., gain of function vs. loss of function), and usually their effects vary in relation to the clinical presentation and the phenotype of the patient. However, KCNQ2-EOEE patients have a worse response to treatment than KCNQ2-BFNE patients and usually become drug resistant with multiple daily seizures.

scholarly journals Mutations of the Histone Linker H1-4: An Expanded Cohort and Functional Characterization of Frameshift Mutant H1.4 in Neurons

2020 ◽  
Author(s):  
Martine W Tremblay ◽  
Matthew V Green ◽  
Jill A Rosenfeld ◽  
Haley Streff ◽  
William Craigen ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
De Novo ◽  
Genetic Disorder ◽  
Functional Characterization ◽  
Autism Spectrum ◽  
Dendritic Morphology ◽  
Neuronal Firing ◽  
Neurological Dysfunction ◽  
Severe Intellectual Disability ◽  
Frameshift Mutant

Abstract Background: Rahman syndrome (RMNS) is a rare genetic disorder characterized by mild to severe intellectual disability, hypotonia, anxiety, autism spectrum disorder, vision problems, brittle bones, and dysmorphic facies. De novo heterozygous mutations in H1-4 (HIST1H1E) encoding the linker histone H1.4 are found in patients with RMNS; however, the underlying mechanisms causing the pronounced neurological manifestations are not understood. The majority of reported mutations in H1-4 are small insertions or deletions that create a shared frameshift, resulting in an H1.4 protein that is both truncated and possessing an abnormal C-terminal tail.Methods: Seven Rahman syndrome subjects with C-terminal frameshift mutations as well as three patients with heterozygous null mutations in H1-4 were described in detail. Lymphoblastoid cells from these patients were used to identify transcriptional abnormalities in RMNS. Wildtype or mutant frameshifted human H1.4 protein was exogenously expressed in primary rat hippocampal neurons, and neuronal structure and function were assessed using immunohistochemistry and multi-electrode array recordings. Results: Individuals with heterozygous null variants in the H1-4 gene lack several key RMNS phenotypes, supporting the hypothesis that RMNS is due to a gain-of-function of the frameshift mutant H1.4 protein. In cultured rat hippocampal neurons, H1.4 was localized to the nucleus, though the frameshift mutant H1.4 had a distinct subnuclear distribution and enlarged nuclei. Overexpression of frameshift mutant H1.4 had minimal effects on dendritic morphology; however, it significantly reduced neuronal firing rate relative to neurons overexpressing wildtype human H1.4. Limitations: Given the small number of RMNS cases worldwide, the true breadth of phenotypes remains unknown. Though our data do not show robust differential expression of any genes, larger cohorts for clinical and molecular studies will be needed to gain reliable data.Conclusions: These data are the first to characterize the consequence of frameshift mutant H1.4 in neurons. These data provide new insights into the breadth of phenotypes and causes of neurological dysfunction in RMNS and highlight the need for future studies on the function of histone H1.4 in neurons.

The Morphology of the Rat Kidney Following Folic Acid Administration

1970 ◽  
Vol 28 ◽  
pp. 200-201
Author(s):  
Aline Byrnes ◽  
Elsa E. Ramos ◽  
Minoru Suzuki ◽  
E.D. Mayfield
Keyword(s):  
Folic Acid ◽  
De Novo ◽  
Specific Activity ◽  
Rat Kidney ◽  
Present Report ◽  
Intracellular Localization ◽  
Male Rats ◽  
Renal Hypertrophy ◽  
Electron Microscopic ◽  
Biochemical Alterations

Renal hypertrophy was induced in 100 g male rats by the injection of 250 mg folic acid (FA) dissolved in 0.3 M NaHCO3/kg body weight (i.v.). Preliminary studies of the biochemical alterations in ribonucleic acid (RNA) metabolism of the renal tissue have been reported recently (1). They are: RNA content and concentration, orotic acid-c14 incorporation into RNA and acid soluble nucleotide pool, intracellular localization of the newly synthesized RNA, and the specific activity of enzymes of the de novo pyrimidine biosynthesis pathway. The present report describes the light and electron microscopic observations in these animals. For light microscopy, kidney slices were fixed in formalin, embedded, sectioned, and stained with H & E and PAS.

Measurement of spontaneous neuronal membrane activity by time lapse confocal microscopy

1995 ◽  
Vol 53 ◽  
pp. 972-973
Author(s):  
R H. Selinfreund ◽  
A. H. Cornell-Bell
Keyword(s):  
Membrane Potential ◽  
Confocal Microscopy ◽  
Patch Clamp ◽  
Electrical Activity ◽  
Time Lapse ◽  
Neuronal Firing ◽  
Neuronal Membrane ◽  
Pituitary Cells ◽  
Patch Clamp Recording ◽  
Spontaneous Electrical Activity

Cellular electrophysiological properties are normally monitored by standard patch clamp techniques . The combination of membrane potential dyes with time-lapse laser confocal microscopy provides a more direct, least destructive rapid method for monitoring changes in neuronal electrical activity. Using membrane potential dyes we found that spontaneous action potential firing can be detected using time-lapse confocal microscopy. Initially, patch clamp recording techniques were used to verify spontaneous electrical activity in GH4\C1 pituitary cells. It was found that serum depleted cells had reduced spontaneous electrical activity. Brief exposure to the serum derived growth factor, IGF-1, reconstituted electrical activity. We have examined the possibility of developing a rapid fluorescent assay to measure neuronal activity using membrane potential dyes. This neuronal regeneration assay has been adapted to run on a confocal microscope. Quantitative fluorescence is then used to measure a compounds ability to regenerate neuronal firing.The membrane potential dye di-8-ANEPPS was selected for these experiments. Di-8- ANEPPS is internalized slowly, has a high signal to noise ratio (40:1), has a linear fluorescent response to change in voltage.

Early ossicle growth in the regenerating disc of a brittle star

1994 ◽  
Vol 52 ◽  
pp. 364-365
Author(s):  
M. Shlepr ◽  
R. L. Turner
Keyword(s):  
Cell Membrane ◽  
Light Microscopy ◽  
De Novo ◽  
Current Model ◽  
Syncytium Formation ◽  
Brittle Star ◽  
Intracellular Location ◽  
Limited Volume ◽  
Tissue Calcification

Calcification in the echinoderms occurs within a limited-volume cavity enclosed by cytoplasmic extensions of the mineral depositing cells, the sclerocytes. The current model of this process maintains that the sheath formed from these cytoplasmic extensions is syncytial. Prior studies indicate that syncytium formation might be dependent on sclerocyte density and not required for calcification. This model further envisions that ossicles formed de novo nucleate and grow intracellularly until the ossicle effectively outgrows the vacuole. Continued ossicle growth occurs within the sheath but external to the cell membrane. The initial intracellular location has been confirmed only for elements of the echinoid tooth.The regenerating aboral disc integument of ophiophragmus filograneus was used to test the current echinoderm calcification model. This tissue is free of calcite fragments, thus avoiding questions of cellular engulfment, and ossicles are formed de novo. The tissue calcification pattern was followed by light microscopy in both living and fixed preparations.

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