<i>KCNC1</i>‐related disorders: new de novo variants expand the phenotypic spectrum

Park, Joo Hyun; Koko, Mahmoud; Hedrich, Ulrike B. S.; Hermann, Andreas; Cremer, Kirsten; Haberlandt, Edda; Grimmel, Mona; Alhaddad, Bader; Beck‐Woedl, Stefanie; Harrer, Merle; Kingelhoefer, Lisa; Tzschach, Andreas; Matthies, Lars C.; Strom, Tim M.; Ringelstein, E. B.; Sturm, Marc; Engels, Hartmut; Wolff, Markus; Lerche, Holger; Haack, Tobias B.

doi:10.1002/acn3.50799

Cited by 44 publications

(39 citation statements)

References 22 publications

(33 reference statements)

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“…The seizure onset age of two children with the mutation p.Ala421Val was 3 and 4 months respectively. Three sporadic children were also reported to harbor the mutation p.Ala421Val, and the seizure onset age of them were 5 months, 3 weeks and 5 months respectively [33]. However, the seizure onset age of two children with mutation p.Arg320His in our study were 11 years and 9 months of age and 10 years old respectively, and the seizure onset age of 22 children in reported study were 3 to 15 years [5,24].…”

Section: Discussioncontrasting

confidence: 54%

Clinical phenotype features and genetic etiologies of 38 children with progressive myoclonic epilepsy

Zhang

Yang

Niu

et al. 2020

Acta Epileptologica

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Background: Progressive myoclonic epilepsy (PME) is a group of neurodegenerative diseases with genetic heterogeneity and phenotypic similarities, and many cases remain unknown of the genetic causes. This study is aim to summarize the clinical features and study the genetic causes of PME patients. Methods: Sanger sequencing of the target gene, Next Generation Sequencing (NGS) panels of epilepsy, trio-based Whole Exome Sequencing (WES) and detection of cytosine-adenine-guanine (CAG) repeat number were used to investigate the genetic causes of PME patients. Results: Thirty-eight children with PME whose seizure onset age ranged from 3 months to 12 years were collected from February 2012 to November 2019 in three hospitals in Beijing, China. The seizure types included myoclonic seizures (n = 38), focal seizures (n = 19), generalized tonic-clonie seizure (GTCS) (n = 13), absence seizures (n = 4), atonic seizures (n = 3), epileptic spasms (n = 2) and tonic seizures (n = 1). Twenty-seven cases were sporadic and 11 had family members affected. Established PME-related genes were identified in 30 out of 38 (78.9%) patients who had either recessively inherited or de novo heterozygous mutations. Among these 30 cases, there were 12 cases (31.6%) of neuronal ceroid lipofuscinoses (the causing gene contains TPP1, PPT1, CLN5, CLN6 and MFSD8), two cases of sialidosis (the causing gene is NEU1), two cases of neuronopathic Gaucher disease (the causing gene is GBA), one case of spinal muscular atrophy-progressive myoclonic epilepsy (the causing gene is ASAH1), four cases of KCNC1 mutation-related PME, four cases of KCTD7 mutation-related PME, two cases of TBC1D24 mutation-related PME, one case of GOSR2 related PME, and two of dentatorubral-pallidoluysian atrophy (the causing gene is ATN1). In total, 13 PME genes were identified in our cohort. The etiology was not clear in eight patients. Conclusion: PME is a group of clinically and genetically heterogeneous diseases. Genetic diagnosis was clear in 78.9% of PME patients. Various of genetic testing methods could increase the rate of genetic diagnosis. Neuronal ceroid lipofuscinoses (NCL) is the most common etiology of PME in children. Nearly one third PME children were diagnosed with NCL. GOSR2 related PME was in our cohort in Asia for the first time.

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Section: Discussioncontrasting

confidence: 54%

Clinical phenotype features and genetic etiologies of 38 children with progressive myoclonic epilepsy

Zhang

Yang

Niu

et al. 2020

Acta Epileptologica

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“…For instance, ADAM metallopeptidase domain 21 (ADAM21) is associated with neurogenesis and axonal growth in postnatal development 132 . Potassium voltage-gated channel subfamily C member 1 (KCNC1) mediates the voltage-dependent potassium ion permeability of excitable membranes and variants prevent neuronal inhibition, which is associated with epilepsy, ataxia, intellectual disability, and developmental delay 133 . Myocyte enhancer factor 2C (MEF2C) is highly expressed in developing cortical excitatory neurons, variants linked to autism, intellectual disability, and schizophrenia 134 .…”

Section: Discussionmentioning

confidence: 99%

Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids

et al. 2020

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Maternal alcohol exposure during pregnancy can substantially impact the development of the fetus, causing a range of symptoms, known as fetal alcohol spectrum disorders (FASDs), such as cognitive dysfunction and psychiatric disorders, with the pathophysiology and mechanisms largely unknown. Recently developed human cerebral organoids from induced pluripotent stem cells are similar to fetal brains in the aspects of development and structure. These models allow more relevant in vitro systems to be developed for studying FASDs than animal models. Modeling binge drinking using human cerebral organoids, we sought to quantify the downstream toxic effects of alcohol (ethanol) on neural pathology phenotypes and signaling pathways within the organoids. The results revealed that alcohol exposure resulted in unhealthy organoids at cellular, subcellular, bioenergetic metabolism, and gene expression levels. Alcohol induced apoptosis on organoids. The apoptotic effects of alcohol on the organoids depended on the alcohol concentration and varied between cell types. Specifically, neurons were more vulnerable to alcohol-induced apoptosis than astrocytes. The alcohol-treated organoids exhibit ultrastructural changes such as disruption of mitochondria cristae, decreased intensity of mitochondrial matrix, and disorganized cytoskeleton. Alcohol exposure also resulted in mitochondrial dysfunction and metabolic stress in the organoids as evidenced by (1) decreased mitochondrial oxygen consumption rates being linked to basal respiration, ATP production, proton leak, maximal respiration and spare respiratory capacity, and (2) increase of non-mitochondrial respiration in alcohol-treated organoids compared with control groups. Furthermore, we found that alcohol treatment affected the expression of 199 genes out of 17,195 genes analyzed. Bioinformatic analyses showed the association of these dysregulated genes with 37 pathways related to clinically relevant pathologies such as psychiatric disorders, behavior, nervous system development and function, organismal injury and abnormalities, and cellular development. Notably, 187 of these genes are critically involved in neurodevelopment, and/or implicated in nervous system physiology and neurodegeneration. Furthermore, the identified genes are key regulators of multiple pathways linked in networks. This study extends for the first time animal models of binge drinking-related FASDs to a human model, allowing in-depth analyses of neurotoxicity at tissue, cellular, subcellular, metabolism, and gene levels. Hereby, we provide novel insights into alcohol-induced pathologic phenotypes, cell type-specific vulnerability, and affected signaling pathways and molecular networks, that can contribute to a better understanding of the developmental neurotoxic effects of binge drinking during pregnancy.

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“…2018; Park et al. 2019). Since these molecular analyses were performed using bulk cerebellar tissue and because Thap1 is universally expressed in the cerebellar circuit, including Purkinje cells, cerebellar nuclei cells and interneurons in the cerebellar cortex, the observed molecular changes could drive changes in the intrinsic excitability and firing patterns of all cerebellar neurons.…”

Section: Discussionmentioning

confidence: 99%

Abnormal cerebellar function and tremor in a mouse model for non‐manifesting partially penetrant dystonia type 6

Heijden

Kizek

Perez

et al. 2021

The Journal of Physiology

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Loss-of-function mutations in the Thap1 gene cause partially penetrant dystonia type 6 (DYT6). r Some non-manifesting DYT6 mutation carriers have tremor and abnormal cerebellothalamo-cortical signalling. r We show that Thap1 heterozygote mice have action tremor, a reduction in cerebellar neuron number, and abnormal electrophysiological signals in the remaining neurons. r These results underscore the importance of Thap1 levels for cerebellar function. r These results uncover how cerebellar abnormalities contribute to different dystonia-associated motor symptoms.

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KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

Cited by 44 publications

References 22 publications

Clinical phenotype features and genetic etiologies of 38 children with progressive myoclonic epilepsy

Clinical phenotype features and genetic etiologies of 38 children with progressive myoclonic epilepsy

Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids

Abnormal cerebellar function and tremor in a mouse model for non‐manifesting partially penetrant dystonia type 6

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