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Article: Drosophila melanogaster

Fischer, Florian P / Karge, Robin A / Weber, Yvonne G / Koch, Henner / Wolking, Stefan / Voigt, Aaron

2023 Volume 16, Page(s) 1116000

Abstract: Epilepsy is one of the most prevalent neurological disorders, affecting more than 45 million people worldwide. Recent advances in genetic techniques, such as next-generation sequencing, have driven genetic discovery and increased our understanding of the ...

Abstract	Epilepsy is one of the most prevalent neurological disorders, affecting more than 45 million people worldwide. Recent advances in genetic techniques, such as next-generation sequencing, have driven genetic discovery and increased our understanding of the molecular and cellular mechanisms behind many epilepsy syndromes. These insights prompt the development of personalized therapies tailored to the genetic characteristics of an individual patient. However, the surging number of novel genetic variants renders the interpretation of pathogenetic consequences and of potential therapeutic implications ever more challenging. Model organisms can help explore these aspects
Language	English
Publishing date	2023-02-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2023.1116000
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Article ; Online: Video-EEG-monitoring to guide antiseizure medication withdrawal.

Dhaenens-Meyer, Laurien K L / Schriewer, Elisabeth / Weber, Yvonne G / Wolking, Stefan

Neurological research and practice

2023 Volume 5, Issue 1, Page(s) 20

Abstract: Background: Discontinuing anti-seizure medication (ASM) should be considered in persons with epilepsy with long-term seizure freedom. Clinicians should also pursue ASM withdrawal in persons with one-time seizures without increased recurrence risk and ... ...

Abstract	Background: Discontinuing anti-seizure medication (ASM) should be considered in persons with epilepsy with long-term seizure freedom. Clinicians should also pursue ASM withdrawal in persons with one-time seizures without increased recurrence risk and those with suspected non-epileptic events. However, ASM withdrawal is associated with the risk of recurring seizures. Monitored ASM withdrawal in an epilepsy monitoring unit (EMU) could help better evaluate the risk of seizure recurrence. Here, we investigate the practice of EMU-guided ASM withdrawal, assess its indications, and aim to determine positive and negative predictors for successful withdrawal. Methods: We screened the medical records of all patients admitted to our EMU between November 1, 2019, and October 31, 2021, and included patients of at least 18 years admitted with the aim of permanent ASM withdrawal. We defined four groups of withdrawal indications: (1) long-term seizure freedom; (2) suspected non-epileptic events; (3) history of epileptic seizures but not fulfilling diagnostic criteria of epilepsy; and (4) seizure-freedom after epilepsy surgery. Successful withdrawal was defined according to the following criteria: no recoding of (sub)clinical seizure activity during VEM (groups 1, 2, and 3), patients did not meet the International League Against Epilepsy (ILAE) definition of epilepsy (groups 2 and 3) [14], and patients were discharged without ongoing ASM treatment (all groups). We also evaluated the prediction model by Lamberink et al. (LPM) for the risk of seizure recurrence in groups 1 and 3. Results: 55/651 (8.6%) patients fulfilled the inclusion criteria. Withdrawal indications were distributed as follows; group 1: 2/55 (3.6%); group 2: 44/55 (80%); group 3: 9/55 (16,4%); group 4: 0/55. Overall, ASM withdrawal was successful in 90.9%. The sensitivity of the LPM for a 2-year 50% relapse risk threshold was 75%, the specificity 33.3%; for a 5-year relapse risk respectively 12.5% and 33.3%, suggesting that the model is not suitable for risk assessment in patients with one-time seizures or acute-symptomatic seizures, who constituted most of the evaluated patients. Conclusions: Our study suggests that EMU-guided ASM withdrawal could be a helpful tool to support clinical decision-making and improve patient safety. Prospective, randomized trials should further evaluate this method in the future.
Language	English
Publishing date	2023-05-18
Publishing country	England
Document type	Journal Article
ISSN	2524-3489
ISSN (online)	2524-3489
DOI	10.1186/s42466-023-00248-6
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Article ; Online: The glucose transporter type 1 (Glut1) syndromes.

Koch, Henner / Weber, Yvonne G

Epilepsy & behavior : E&B

2018 Volume 91, Page(s) 90–93

Abstract: The glucose transporter type 1 (Glut1) is the most important energy carrier of the brain across the blood-brain barrier. In the early nineties, the first genetic defect of Glut1 was described and known as the Glut1 deficiency syndrome (Glut1-DS). It is ... ...

Abstract	The glucose transporter type 1 (Glut1) is the most important energy carrier of the brain across the blood-brain barrier. In the early nineties, the first genetic defect of Glut1 was described and known as the Glut1 deficiency syndrome (Glut1-DS). It is characterized by early infantile seizures, developmental delay, microcephaly, and ataxia. Recently, milder variants have also been described. The clinical picture of Glut1 defects and the understanding of the pathophysiology of this disease have significantly grown. A special form of transient movement disorders, the paroxysmal exertion-induced dyskinesia (PED), absence epilepsies particularly with an early onset absence epilepsy (EOAE) and childhood absence epilepsy (CAE), myoclonic astatic epilepsy (MAE), episodic choreoathetosis and spasticity (CSE), and focal epilepsy can be based on a Glut1 defect. Despite the rarity of these diseases, the Glut1 syndromes are of high clinical interest since a very effective therapy, the ketogenic diet, can improve or reverse symptoms especially if it is started as early as possible. The present article summarizes the clinical features of Glut1 syndromes and discusses the underlying genetic mutations, including the available data on functional tests as well as the genotype-phenotype correlations. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond".
MeSH term(s)	Carbohydrate Metabolism, Inborn Errors/diagnosis ; Carbohydrate Metabolism, Inborn Errors/diet therapy ; Carbohydrate Metabolism, Inborn Errors/genetics ; Diet, Ketogenic/methods ; Dystonic Disorders/diagnosis ; Dystonic Disorders/diet therapy ; Dystonic Disorders/genetics ; Epilepsies, Myoclonic/diagnosis ; Epilepsies, Myoclonic/diet therapy ; Epilepsies, Myoclonic/genetics ; Epilepsies, Partial/diagnosis ; Epilepsies, Partial/diet therapy ; Epilepsies, Partial/genetics ; Epilepsy/diagnosis ; Epilepsy/diet therapy ; Epilepsy/genetics ; Epilepsy, Absence/diagnosis ; Epilepsy, Absence/diet therapy ; Epilepsy, Absence/genetics ; Glucose Transporter Type 1/genetics ; Humans ; Monosaccharide Transport Proteins/deficiency ; Monosaccharide Transport Proteins/genetics ; Movement Disorders/diagnosis ; Movement Disorders/diet therapy ; Movement Disorders/genetics ; Mutation/genetics
Chemical Substances	Glucose Transporter Type 1 ; Monosaccharide Transport Proteins ; SLC2A1 protein, human
Language	English
Publishing date	2018-07-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2010587-3
ISSN	1525-5069 ; 1525-5050
ISSN (online)	1525-5069
ISSN	1525-5050
DOI	10.1016/j.yebeh.2018.06.010
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Article ; Online: Drosophila melanogaster as a versatile model organism to study genetic epilepsies

Florian P. Fischer / Robin A. Karge / Yvonne G. Weber / Henner Koch / Stefan Wolking / Aaron Voigt

Frontiers in Molecular Neuroscience, Vol

An overview

2023 Volume 16

Abstract	Epilepsy is one of the most prevalent neurological disorders, affecting more than 45 million people worldwide. Recent advances in genetic techniques, such as next-generation sequencing, have driven genetic discovery and increased our understanding of the molecular and cellular mechanisms behind many epilepsy syndromes. These insights prompt the development of personalized therapies tailored to the genetic characteristics of an individual patient. However, the surging number of novel genetic variants renders the interpretation of pathogenetic consequences and of potential therapeutic implications ever more challenging. Model organisms can help explore these aspects in vivo. In the last decades, rodent models have significantly contributed to our understanding of genetic epilepsies but their establishment is laborious, expensive, and time-consuming. Additional model organisms to investigate disease variants on a large scale would be desirable. The fruit fly Drosophila melanogaster has been used as a model organism in epilepsy research since the discovery of “bang-sensitive” mutants more than half a century ago. These flies respond to mechanical stimulation, such as a brief vortex, with stereotypic seizures and paralysis. Furthermore, the identification of seizure-suppressor mutations allows to pinpoint novel therapeutic targets. Gene editing techniques, such as CRISPR/Cas9, are a convenient way to generate flies carrying disease-associated variants. These flies can be screened for phenotypic and behavioral abnormalities, shifting of seizure thresholds, and response to anti-seizure medications and other substances. Moreover, modification of neuronal activity and seizure induction can be achieved using optogenetic tools. In combination with calcium and fluorescent imaging, functional alterations caused by mutations in epilepsy genes can be traced. Here, we review Drosophila as a versatile model organism to study genetic epilepsies, especially as 81% of human epilepsy genes have an orthologous gene in Drosophila. ...
Keywords	Drosophila melanogaster ; epilepsy ; genetics ; precision medicine ; techniques ; translational research ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571
Subject code	616
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: Pyridoxine or pyridoxal-5-phosphate treatment for seizures in glycosylphosphatidylinositol deficiency: A cohort study.

Bayat, Allan / Aledo-Serrano, Angel / Gil-Nagel, Antonio / Korff, Christian M / Thomas, Ashley / Boßelmann, Christian / Weber, Yvonne / Gardella, Elena / Lund, Allan M / de Sain-van der Velden, Monique G M / Møller, Rikke S

Developmental medicine and child neurology

2022 Volume 64, Issue 6, Page(s) 789–798

Abstract: Aim: To investigate the short-term efficacy and safety of high-dose pyridoxine and pyridoxal 5-phosphate (P5P) in the treatment of inherited glycosylphosphatidylinositol (GPI) deficiency-associated epilepsy.: Method: Participants with genetically ... ...

Abstract	Aim: To investigate the short-term efficacy and safety of high-dose pyridoxine and pyridoxal 5-phosphate (P5P) in the treatment of inherited glycosylphosphatidylinositol (GPI) deficiency-associated epilepsy. Method: Participants with genetically confirmed GPI deficiency were treated with oral pyridoxine or P5P as compassionate use in an agreed-upon clinical regimen. Pyridoxine (20-30 mg/kg/day) was used for 3 months. Baseline evaluation included 4 weeks of prospective seizure data and one video electroencephalogram (EEG). Seizure frequency was captured daily. The EEG was repeated after reaching maximum dosage of pyridoxine. Pyridoxine was switched to P5P (20-30 mg/kg/day) if seizure burden was unchanged after 3 months' treatment. Another EEG was done after 3 months of P5P treatment. Primary outcome measures were reduction of seizure frequency and EEG improvements. Results: Seven participants (one female, six males; age range 5-23 year; mean age 11 years 10 months, SD 5 year 2 months) were included. The genetic causes of inherited GPI deficiency were phosphatidylinositol N-acetylglucosaminyltransferase subunit A/T/V deficiency. All had drug-resistant epilepsy and neurodevelopmental impairment. We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom. No remarkable changes in electrophysiological findings were observed in 6 out of 7 participants treated with pyridoxine or P5P when comparing the baseline and follow-up EEGs. Interpretation: We observed no long-lasting electrophysiological improvements during treatment but pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. What this paper adds: Inherited glycosylphosphatidylinositol (GPI) deficiency often causes early-onset and drug-resistant epilepsy. Vitamin B
MeSH term(s)	Cohort Studies ; Drug Resistant Epilepsy/drug therapy ; Epilepsy/complications ; Epilepsy/drug therapy ; Epilepsy/genetics ; Female ; Glycosylphosphatidylinositols/deficiency ; Glycosylphosphatidylinositols/therapeutic use ; Humans ; Infant ; Male ; Phosphates/therapeutic use ; Prospective Studies ; Pyridoxal Phosphate/therapeutic use ; Pyridoxine/therapeutic use ; Seizures/drug therapy ; Seizures/etiology
Chemical Substances	Glycosylphosphatidylinositols ; Phosphates ; Pyridoxal Phosphate (5V5IOJ8338) ; Pyridoxine (KV2JZ1BI6Z)
Language	English
Publishing date	2022-01-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80369-8
ISSN	1469-8749 ; 0012-1622
ISSN (online)	1469-8749
ISSN	0012-1622
DOI	10.1111/dmcn.15142
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Article: Pregnancy outcomes in female multiple sclerosis patients exposed to intramuscular interferon beta-1a or peginterferon beta-1a reported in a German Patient Support Programme - results from the non-interventional post-authorization safety study PRIMA.

Klehmet, Juliane / Begus-Nahrmann, Yvonne / Taipale, Kirsi / Niemczyk, Gabriele / Rehberg-Weber, Karin

Therapeutic advances in neurological disorders

2023 Volume 16, Page(s) 17562864231214041

Abstract: Background: Based on data from two large cohort studies, a label update became applicable for the class of interferon beta therapies in 9/2019, allowing interferons during pregnancy and breastfeeding.: Objective: To assess pregnancy outcomes of women ...

Abstract	Background: Based on data from two large cohort studies, a label update became applicable for the class of interferon beta therapies in 9/2019, allowing interferons during pregnancy and breastfeeding. Objective: To assess pregnancy outcomes of women with multiple sclerosis (MS) exposed to peginterferon beta-1a or intramuscular interferon beta-1a therapy (IFN). Design: Non-interventional post-authorization safety study. Methods: PRIMA was conducted from April to October 2021 in Germany. Retrospective pregnancy data were retrieved from adult female patients diagnosed with relapsing-remitting MS or clinically isolated syndrome, exposed to IFN before or during pregnancy and registered in the patient support programme (PSP) of the marketing authorization holder's MS Service Centre. The primary endpoint was the outcome of pregnancy. Prospective postpartum data were collected from mothers reporting live births. Results: In total, 426 women reporting 542 pregnancies between December 2001 and July 2020 (14 pregnancies after the label update) were enrolled. Among patients with confirmed exposure during pregnancy ( Conclusion: Overall, the prevalence of spontaneous abortions and congenital anomalies of females exposed to IFN exposure before or during pregnancy was within the range reported for the general population. Most mothers paused IFN during pregnancy and breastfeeding. Relapse activity during pregnancy and lactation was observed to be low. These real-world data from a PSP corroborate European and Scandinavian registry data. Trial registration: NCT04655222, EUPAS38347.
Language	English
Publishing date	2023-12-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2442245-9
ISSN	1756-2864 ; 1756-2856
ISSN (online)	1756-2864
ISSN	1756-2856
DOI	10.1177/17562864231214041
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Article ; Online: Impact of interferon beta exposure on birth outcome and child development - Results from the post-authorisation safety study PRIMA.

Klehmet, Juliane / Begus-Nahrmann, Yvonne / Taipale, Kirsi / Niemczyk, Gabriele / Rehberg-Weber, Karin

Multiple sclerosis and related disorders

2023 Volume 77, Page(s) 104844

Abstract: Background: Interferon beta therapies are well-established disease-modifying treatments for patients with relapsing multiple sclerosis (MS). Based on clinical evidence from two large cohort studies, both, the EMA and FDA updated the labels of the ... ...

Abstract	Background: Interferon beta therapies are well-established disease-modifying treatments for patients with relapsing multiple sclerosis (MS). Based on clinical evidence from two large cohort studies, both, the EMA and FDA updated the labels of the interferon beta class in terms of pregnancy and breastfeeding in 2019 and 2020, respectively. To complement pregnancy label updates with patient-reported real-world data, this study examined German pregnancy and outcome reports including available data on child development from women with MS treated with peginterferon beta-1a or intramuscular (IM) interferon beta-1a. Methods: The post-authorisation safety study PRIMA included adult women diagnosed with relapsing-remitting MS or clinically isolated syndrome, who were treated with peginterferon beta-1a or IM interferon beta-1a before or during pregnancy and registered in the marketing authorisation holder's MS Service center patient support program. In the prospective part of the study, conducted from April to October 2021, data on developmental milestones of the newborns were collected via telephone interview from mothers reporting live births. Results: In total, 426 women were enrolled, reporting 542 pregnancies that resulted in 466 live births. A total of 162 women completed the questionnaire for 192 live births (53.1% male). Newborns had Apgar scores indicative of healthy infants. Weight, length and head circumference at birth and physical growth curves up to 48 months lay within the expected range of the German general population. Most newborn screenings and examinations during check-ups were inconspicuous over the study period of 48 months. Out of 158 breastfed infants, 112 (70.9%) were breastfed exclusively until month 5. Conclusion: Study results confirmed former reports indicating that exposure to interferon beta therapies during pregnancy or lactation had no adverse effects on intrauterine growth and child development over the study period, which covered the first 4 years of life. These real-world data obtained within the scope of a patient support program for peginterferon beta-1a or IM interferon beta-1a corroborate German and Scandinavian registry data and support the label update of all interferon beta therapies. Registration: NCT04655222, EUPAS38347.
MeSH term(s)	Adult ; Female ; Humans ; Infant, Newborn ; Male ; Pregnancy ; Child Development ; Interferon beta-1a/therapeutic use ; Interferon-beta/therapeutic use ; Multiple Sclerosis/drug therapy ; Multiple Sclerosis, Relapsing-Remitting/drug therapy ; Multiple Sclerosis, Relapsing-Remitting/chemically induced ; Prospective Studies ; Infant ; Child, Preschool
Chemical Substances	Interferon beta-1a (XRO4566Q4R) ; Interferon-beta (77238-31-4)
Language	English
Publishing date	2023-06-24
Publishing country	Netherlands
Document type	Clinical Study ; Journal Article
ZDB-ID	2645330-7
ISSN	2211-0356 ; 2211-0348
ISSN (online)	2211-0356
ISSN	2211-0348
DOI	10.1016/j.msard.2023.104844
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Article: Good to Know: Baseline Data on Feed Intake, Fecal Pellet Output and Intestinal Transit Time in Guinea Pig as a Frequently Used Model in Gastrointestinal Research.

Elfers, Kristin / Armbrecht, Yvonne / Mazzuoli-Weber, Gemma

Animals : an open access journal from MDPI

2021 Volume 11, Issue 6

Abstract: Guinea pigs are a traditional and frequently used species in gastrointestinal research. Comprehensive knowledge of basic parameters connected with their intestinal function, such as feed intake, fecal pellet output and gastrointestinal transit time, is ... ...

Abstract	Guinea pigs are a traditional and frequently used species in gastrointestinal research. Comprehensive knowledge of basic parameters connected with their intestinal function, such as feed intake, fecal pellet output and gastrointestinal transit time, is important for evaluating results from basic gastrointestinal research that may be applied to practical problems in human and veterinary medicine, for example, when establishing diagnostic tools. Our study revealed that over a 24-h period, single-housed guinea pigs showed a continual but day-accentuated feeding activity, consuming 57% of the total feed during the light period, with pronounced peaks of feed intake during the beginning and end of the light period. This was mirrored by fecal pellet output during the light period and almost no defecation during the dark period, while potential coprophagy not measured in this study needs to be considered. A highly comparable feeding activity was recorded in pair-housed guinea pigs, with 60% of overall feed intake within the light period, indicating that such differences in housing conditions did not influence guinea pigs' feeding behavior. Intestinal transit time was successfully recorded by oral administration of carmine red and counted 5 h on average. Hence, this study provides important information on the basic functional parameters of guinea pigs' gastrointestinal tract physiology.
Language	English
Publishing date	2021-05-28
Publishing country	Switzerland
Document type	Journal Article
ISSN	2076-2615
ISSN	2076-2615
DOI	10.3390/ani11061593
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Article ; Online: The role of genetic testing in epilepsy diagnosis and management.

Weber, Yvonne G / Biskup, Saskia / Helbig, Katherine L / Von Spiczak, Sarah / Lerche, Holger

Expert review of molecular diagnostics

2017 Volume 17, Issue 8, Page(s) 739–750

Abstract: Introduction: Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. More than 500 epilepsy-associated genes have been described in the literature. Most of these genes play an important role in neuronal excitability, ... ...

Abstract	Introduction: Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. More than 500 epilepsy-associated genes have been described in the literature. Most of these genes play an important role in neuronal excitability, cortical development or synaptic transmission. A growing number of genetic variations have implications on diagnosis and prognostic or therapeutic advice in terms of a personalized medicine. Area covered: The review presents the different forms of genetic epilepsies with respect to their underlying genetic and functional pathophysiology and aims to give advice for recommended genetic testing. Moreover, it discusses ethical and legal guidelines, costs and technical limitations which should be considered. Expert commentary: Genetic testing is an important component in the diagnosis and treatment of many forms of epilepsy.
Language	English
Publishing date	2017-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2112530-2
ISSN	1744-8352 ; 1473-7159
ISSN (online)	1744-8352
ISSN	1473-7159
DOI	10.1080/14737159.2017.1335598
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Article ; Online: Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies.

EBioMedicine

2022 Volume 84, Page(s) 104244

Abstract: Background: De novo missense variants in KCNQ5, encoding the voltage-gated K: Methods: 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-clamp recordings, biotinylation and phospholipid overlay assays were performed ... ...

Abstract	Background: De novo missense variants in KCNQ5, encoding the voltage-gated K Methods: 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with homology modelling. Findings: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures; two variants were also associated with mild to moderate ID. All missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) K Interpretation: Our study identified deleterious KCNQ5 variants in GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional deficits. LOF of K Funding: DFG/FNR Research Unit FOR-2715 (Germany/Luxemburg), BMBF rare disease network Treat-ION (Germany), foundation 'no epilep' (Germany).
MeSH term(s)	Animals ; Epilepsy/genetics ; Epilepsy, Generalized/diagnosis ; Epilepsy, Generalized/genetics ; Humans ; Intellectual Disability/genetics ; Mammals ; Mutation ; Phospholipids
Chemical Substances	Phospholipids
Language	English
Publishing date	2022-09-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2022.104244
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