Epilepsy and EEG Phenotype of SLC13A5 Citrate Transporter Disorder.
Child neurology open
2020; 7: 2329048X20931361
Case Studies in Neuroscience: A Novel Amino Acid Duplication in the N-terminus of the Brain Sodium Channel NaV1.1 Underlying Dravet Syndrome.
Journal of neurophysiology
Mutations in the SLC13A5 gene, a sodium citrate cotransporter, cause a rare autosomal recessive epilepsy (EIEE25) that begins during the neonatal period and is associated with motor and cognitive impairment. Patient's seizure burden, semiology, and electroencephalography (EEG) findings have not been well characterized. Data on 23 patients, 3 months to 29 years of age are reported. Seizures began during the neonatal period in 22 patients. Although seizures are quite severe in many patients later in life, seizure freedom was attainable in a minority of patients. Multiple patients' chronic seizure management included a few common medications, phenobarbital and valproic acid in particular. Patients EEGs had a relatively well-preserved background for age, even in the face of frequent seizures, little slowing and multiple normal EEGs and do not support an epileptic encephalopathy. Other causes for the motor and cognitive delay beyond epilepsy warrant further study.
View details for DOI 10.1177/2329048X20931361
View details for PubMedID 32551328
View details for PubMedCentralID PMC7281881
Seizures in Preterm Infants
JOURNAL OF CLINICAL NEUROPHYSIOLOGY
2016; 33 (5): 382–93
Dravet syndrome is a severe form of childhood epilepsy characterized by frequent temperature-sensitive seizures and delays in cognitive development. In the majority (80%) of cases, Dravet Syndrome is caused by mutations in the SCN1A gene, encoding the voltage-gated sodium channel NaV1.1, which is abundant in the central nervous system. Dravet syndrome can be caused by either gain-of-function mutation or loss-of-function in NaV1.1, making it necessary to characterize each novel mutation. Here we use a combination of patch-clamp recordings and immunocytochemistry to characterize the first known N-terminal amino acid duplication mutation found in a patient with Dravet Syndrome, M72dup. M72dup does not significantly alter rate of fast inactivation recovery, or rate of fast inactivation onset at any measured membrane potential. M72dup significantly shifts the midpoint of the conductance voltage relationship to more hyperpolarized potentials. Most interestingly, M72dup significantly reduces peak current of NaV1.1 and reduces membrane expression. This suggests that M72dup acts as a loss-of-function mutation primarily by impacting the ability of the channel to localize to the plasma membrane.
View details for DOI 10.1152/jn.00491.2019
View details for PubMedID 31533007
Plasma taurine levels are not affected by vigabatrin in pediatric patients.
2016; 57 (8): e168-72
Infants born prematurely are highly vulnerable to brain injury and susceptible to seizures in the first weeks of life. Many neonatal seizures occur without reliable clinical signs and are detectable only on electroencephalogram (EEG); understanding EEG findings in these neonates is crucial for providing appropriate care. This can be challenging, as EEG background activity and patterns vary considerably with gestational age. Some physiologic preterm EEG patterns, such as rhythmic temporal theta activity or delta brushes, may be sharply contoured and appear similar to epileptic EEG patterns later in life. Moreover, ictal patterns in preterms are of lower voltage and frequency than in full-term neonates. This article reviews current data on incidence of seizures in preterms and their typical ictal EEG patterns. It also identifies the pitfalls of EEG analysis in a neonatal intensive care unit environment and gives examples of typically observed artifacts. It then discusses the impact of seizures on long-term outcome of preterms, independent of other variables such as gestational age and brain injury. Finally, it suggests future directions for research in preterm seizures.
View details for DOI 10.1097/WNP.0000000000000310
View details for Web of Science ID 000385663200004
View details for PubMedID 27749458
A Distinctive Layering Pattern of Mouse Dentate Granule Cells is Generated by Developmental and Adult Neurogenesis
JOURNAL OF COMPARATIVE NEUROLOGY
2010; 518 (22): 4479–90
Vigabatrin is a highly effective antiseizure medication, but its use is limited due to concerns about retinal toxicity. One proposed mechanism for this toxicity is vigabatrin-mediated reduction of taurine. Herein we assess plasma taurine levels in a retrospective cohort of children with epilepsy, including a subset receiving vigabatrin. All children who underwent a plasma amino acid analysis as part of their clinical evaluation between 2006 and 2015 at Stanford Children's Health were included in the analysis. There were no significant differences in plasma taurine levels between children taking vigabatrin (n = 16), children taking other anti-seizure medications, and children not taking any anti-seizure medication (n = 556) (analysis of variance [ANOVA] p = 0.841). There were, however, age-dependent decreases in plasma taurine levels. Multiple linear regression revealed no significant association between vigabatrin use and plasma taurine level (p = 0.87) when controlling for age. These results suggest that children taking vigabatrin maintain normal plasma taurine levels, although they leave unanswered whether taurine supplementation is necessary or sufficient to prevent vigabatrin-associated visual field loss. They also indicate that age should be taken into consideration when evaluating taurine levels in young children.
View details for DOI 10.1111/epi.13447
View details for PubMedID 27344989
Epigenetic modulation of seizure-induced neurogenesis and cognitive decline
JOURNAL OF NEUROSCIENCE
2007; 27 (22): 5967–75
New neurons are continuously added throughout life to the dentate gyrus of the mammalian hippocampus. During embryonic and early postnatal development, the dentate gyrus is formed in an outside-in layering pattern that may extend through adulthood. In this work, we sought to quantify systematically the relative position of dentate granule cells generated at different ages. We used 5'-bromo-2'-deoxyuridine (BrdU) and retroviral methodologies to birth date cells born in the embryonic, early postnatal, and adult hippocampus and assessed their final position in the adult mouse granule cell layer. We also quantified both developmental and adult-born cohorts of neural progenitor cells that contribute to the pool of adult progenitor cells. Our data confirm that the outside-in layering of the dentate gyrus continues through adulthood and that early-born cells constitute most of the adult dentate gyrus. We also found that substantial numbers of the dividing cells in the adult dentate gyrus were derived from early-dividing cells and retained BrdU, suggesting that a subpopulation of hippocampal progenitors divides infrequently from early development onward.
View details for DOI 10.1002/cne.22489
View details for Web of Science ID 000283478500001
View details for PubMedID 20886617
View details for PubMedCentralID PMC2997649
Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels
2004; 41 (3): 351–65
The conceptual understanding of hippocampal function has been challenged recently by the finding that new granule cells are born throughout life in the mammalian dentate gyrus (DG). The number of newborn neurons is dynamically regulated by a variety of factors. Kainic acid-induced seizures, a rodent model of human temporal lobe epilepsy, strongly induce the proliferation of DG neurogenic progenitor cells and are also associated with long-term cognitive impairment. We show here that the antiepileptic drug valproic acid (VPA) potently blocked seizure-induced neurogenesis, an effect that appeared to be mainly mediated by inhibiting histone deacetylases (HDAC) and normalizing HDAC-dependent gene expression within the epileptic dentate area. Strikingly, the inhibition of aberrant neurogenesis protected the animals from seizure-induced cognitive impairment in a hippocampus-dependent learning task. We propose that seizure-generated granule cells have the potential to interfere with hippocampal function and contribute to cognitive impairment caused by epileptic activity within the hippocampal circuitry. Furthermore, our data indicate that the effectiveness of VPA as an antiepileptic drug may be partially explained by the HDAC-dependent inhibition of aberrant neurogenesis induced by seizure activity within the adult hippocampus.
View details for DOI 10.1523/JNEUROSCI.0110-07.2007
View details for Web of Science ID 000247048700016
View details for PubMedID 17537967
View details for PubMedCentralID PMC6672253
Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2002; 99 (6): 3974–79
Nitric oxide (NO) and zinc (Zn2+) are implicated in the pathogenesis of cerebral ischemia and neurodegenerative diseases. However, their relationship and the molecular mechanism of their neurotoxic effects remain unclear. Here we show that addition of exogenous NO or NMDA (to increase endogenous NO) leads to peroxynitrite (ONOO-) formation and consequent Zn2+ release from intracellular stores in cerebrocortical neurons. Free Zn2+ in turn induces respiratory block, mitochondrial permeability transition (mPT), cytochrome c release, generation of reactive oxygen species (ROS), and p38 MAP kinase activation. This pathway leads to caspase-independent K+ efflux with cell volume loss and apoptotic-like death. Moreover, Zn2+ chelators, ROS scavengers, Bcl-xL, dominant-interfering p38, or K+ channel blockers all attenuate NO-induced K+ efflux, cell volume loss, and neuronal apoptosis. Thus, these data establish a new form of crosstalk between NO and Zn2+ apoptotic signal transduction pathways that may contribute to neurodegeneration.
View details for DOI 10.1016/S0896-6273(04)00015-7
View details for Web of Science ID 000221457900007
View details for PubMedID 14766175
Myocyte enhancer factor-2 (MEF2) transcription factors are activated by p38 mitogen-activated protein kinase during neuronal and myogenic differentiation. Recent work has shown that stimulation of this pathway is antiapoptotic during development but proapoptotic in mature neurons exposed to excitotoxic or other stress. We now report that excitotoxic (N-methyl-D-aspartate) insults to mature cerebrocortical neurons activate caspase-3, -7, in turn cleaving MEF2A, C, and D isoforms. MEF2 cleavage fragments containing a truncated transactivation domain but preserved DNA-binding domain block MEF2 transcriptional activity via dominant interference. Transfection of constitutively active MEF2 (MEF2C-CA) rescues MEF2 transcriptional activity after N-methyl-D-aspartate insult and prevents neuronal apoptosis. Conversely, dominant-interfering MEF2 abrogates neuroprotection by MEF2C-CA. These results define a pathway to excitotoxic neuronal stress/apoptosis via caspase-catalyzed cleavage of MEF2. Additionally, we show that similar MEF2 cleavage fragments are generated in vivo during focal stroke damage. Hence, this pathway appears to have pathophysiological relevance in vivo.
View details for DOI 10.1073/pnas.022036399
View details for Web of Science ID 000174511000109
View details for PubMedID 11904443
View details for PubMedCentralID PMC122633