atp1a2 epileptic encephalopathyatp1a2 epileptic encephalopathy

Pediatr Neurol. 5A and Table1). WebKeywords: epilepsy, migraine, CACNA1A, ATP1A2, SCN1A Journals; Why Publish With Us? , Corry B 3). This series links profound early lethal phenotypes with COS-1 lethal mutations, but also reveals a continuum of phenotypic severity, in which both severe and milder phenotypes can be associated with mutations partially sparing NKA pump function, while polymicrogyria is distributed across mutations of variable effect. Histology also demonstrated that the macroscopic appearance of pachygyria actually corresponded to disorganized layers with some features of classic four-layered polymicrogyria (Fig. Copyright 2020 Elsevier Inc. All rights reserved. Accessibility All 14 of the mutations we tested caused reduced NKA pump activity in the COS-1 cellular model. In slices, the corpus callosum was present but small at the genu and was truncated with lack of midline crossing at the level of the posterior body and splenium, thus forming Probst bundles (Fig. One individual with catastrophic infantile-onset epileptic encephalopathy who died at age 16 months had a novel heterozygous p.Gly358Val variant in ATP1A3. Some blood vessels had abnormally thick walls (intimal hyperplasia) as well as mineralizations (Fig. , Ohlenbusch A Search for other works by this author on: Department of Biomedicine, Aarhus University, Department of Pathology, University of California San Diego. , Aldinger K E-mail: Department of Epilepsy Genetics and Personalized Medicine Danish Epilepsy Centre, Department of Regional Health Services, University of Southern Denmark, Department of Neonatal Intensive Care Unit, Bolognini Hospital, ASST-Bergamo Est, Neurology (Child Neurology and Neuropathology), Department of Neuroscience, Biomedicine and Movement, University of Verona, Department of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon, Division of Neurology, Children's Hospital of Philadelphia, Centre for Clinical Genetics, Sydney Children's Hospital, School of Women's and Children's Health, University of New South Wales, Neonatal Intensive Care Unit, Pediatric Section, Department of Medical Sciences, Ferrara University, Department of Clinical Genetics, Leiden University Medical Center, Division of Pediatric Epileptology, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Department of Human Neuroscience, Unit of Child Neurology and Psychiatry, Sapienza University, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Genetic Medicine, Department of Pediatrics, University of California, San Francisco/Fresno, Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Child Neuropsychiatry Unit, IRCCS, Institute of Neurological Sciences, Bellaria Hospital, The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Department of Clinical Genetics, Erasmus MC University Medical Center, Manchester Centre for Genomic Medicine, University of Manchester, St Mary's Hospital, Medical Genetics Unit, Department of Mother and Child, Ferrara University Hospital, University of Melbourne, Austin Health and Royal Children's Hospital, Florey and Murdoch Institutes, Department of Pediatrics (Genetics), University of Minnesota. In the presence of ATP and intracellular Na+, the ATP-NKA pump in its E1 state forms a phosphorylated intermediate (E1P) that changes configuration from the E1P to E2P state, exposing Na+ to the extracellular space. WebATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. , et al. Early Treatment in Acute Severe Encephalopathy Caused by ATP1A2 Mutation of Familial Hemiplegic Migraine Type 2: Case Report and Literature Review. One child with a biallelic mutation of ATP1A2 (Patient 23) was described clinically in a prior report.13 Here we report brain autopsy findings and compare them to another child in this cohort. 37Sasaki M Hence, the NKA pump activity calculated by multiplying the phosphorylation level by the turnover rate was markedly reduced for all five mutants (1736% wild-type), thus accounting for the pathogenic effects of all five stably expressed mutations (Table1). , et al. Histology revealed that the macroscopically pachygyric cortex was thick, disorganized, and partially covered by rinds of leptomeningeal glioneuronal heterotopia (Fig. 2020 Jun;51(3):215-220. doi: 10.1055/s-0039-3400986. , Hitomi Y , Kirovski G Misfolding of the mutant -subunit and allele competition for the -subunit might also contribute to deleteriousness of ATP1A3 mutations and their phenotypic heterogeneity.26. , et al. , Silvestri L Online ahead of print. FOIA , McDaniel SS In silico evaluation predicted all mutations to be detrimental. 2022 Jun 29;63(9):2403-12. doi: 10.1111/epi.17352. WebCase report: Here, we described a patient who developed a severe early onset drug-resistant epileptic encephalopathy and months later, he presented episodes of hemiplegic attacks and monocular nystagmus. 5D). Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence. Histology also revealed abundant focal calcifications (or mineralization) involving cerebral grey and white matter, leptomeninges and blood vessels (Fig. Brain 144: 1435-1450, 2021. These images were generated from the pdb: 3WUG, [26] which is the structure of the porcine enzyme with the 3-isoform. , McTague A ATP1A2; Alternating Hemiplegia of Childhood; Encephalopathy; Familial Hemiplegic Migraine; Memantine; NMDA Receptor Antagonist. 24Li M Nine different aspect of the NKA pump function investigated by at least one of the different experimental approaches are showed. A distinctive, profound phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). 3L). , Marini C A retrospective chart review of a cohort of seven patients was conducted. Surface gyri were difficult to assess due to adherent meninges with subarachnoid haemorrhage (agonal) and congested blood vessels (Fig. Sources: Expert,Expert Review Red 4 Apr 2018, Gel status: 1 Created , Gawlinski P Accessibility 1). WebATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria Annalisa Vetro,1 Hang N. Nielsen,2 Rikke Holm,2 Robert F. Hevner,3 Elena Parrini,1 Zoe Powis,4 Rikke S. Mller,5,6 Cristina Bellan,7 Alessandro Simonati,8 Gaetan Lesca,9 Katherine L. Helbig,10 Elizabeth E. Palmer,11,12 Davide Mei,1 Elisa Ballardini,13 WebThese findings assign novel, 'profound' and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments. WebConstitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), (K) Cortical blood vessel with mineralized walls (arrows). Another individual with epilepsy, episodic prolonged apnea, postnatal microcephaly, ATP1A2-related disorders. developmental and epileptic encephalopathy, Oxford University Press is a department of the University of Oxford. 5 legend.3, Among the COS-1 cell lines transfected with the 14 mutations we tested, only three ATP1A2 and two ATP1A3 mutants retained the 510% wild-type NKA pump activity required for cell survival under ouabain selection.3 The remaining two ATP1A2 and seven ATP1A3 mutants could not support cell growth in stable transfections, indicating that they lacked NKA pump activity or were not expressed in the plasma membrane (Table1 and Supplementary Table 2). The -subunit is required for protein folding and targeting the -subunit to the plasma membrane, while both - and -subunits act as fine modulators of ion affinity in different tissues.2. (G) Frontal cortex, coronal section (midline right). , et al. 14Scheffer IE , et al. , Capovilla G 46Gressens P R35 GM131731/GM/NIGMS NIH HHS/United States. Unauthorized use of these marks is strictly prohibited. (B) K+ affinity determined from K+ inhibition of phosphorylation. Hemispheric white matter was also reduced. eCollection 2022 Oct. Vezyroglou A, Akilapa R, Barwick K, Koene S, Brownstein CA, Holder-Espinasse M, Fry AE, Nmeth AH, Tofaris GK, Hay E, Hughes I, Mansour S, Mordekar SR, Splitt M, Turnpenny PD, Demetriou D, Koopmann TT, Ruivenkamp CAL, Agrawal PB, Carr L, Clowes V, Ghali N, Holder SE, Radley J, Male A, Sisodiya SM, Kurian MA, Cross JH, Balasubramanian M. Neurology. The gene encoding eEF1A2 has been found to be mutated in Clinical Study Group. 2F and G, arrows), while other areas showed essentially normal cortical lamination. All 22 patients with ATP1A2/A3 heterozygous mutations had at least one brain MRI scan and six were scanned more than once at greater than 1-year intervals. Early lethal hydrops fetalis, arthrogryposis, micro-cephaly, and polymicrogyria have been associated with 5B and Table1). , et al. Response to open-label memantine therapy, used off-label due to its NMDA receptor antagonist effects, was assessed by the Global Rating Scale of Change (GRSC) and Clinical Global Impression Scale of Improvement (CGI-I) methodologies. 17Marzin P In one qualitative MRI study, brain and cerebellar atrophy were reported in up to 50% of patients with ATP1A3-AHC.37 Microcephaly with rapidly progressive brain atrophy was described in a single patient with ATP1A3-related DEE.11 Two quantitative MRI studies in small series confirmed reduced total brain volume, with prevalent white matter involvement38 and mild, possibly age related, cerebellar atrophy.39, Polymicrogyria is aetiologically heterogeneous and variable in topography.40 In this series, the malformation was either limited to the perisylvian cortex or more diffuse but perisylvian predominant. DYT = dystonia; DEE = developmental and epileptic encephalopathy (this term includes epileptic encephalopathies and developmental encephalopathies with epilepsy); PMG = polymicrogyria; RDP = rapid-onset dystonia-parkinsonism; RP = rare phenotypes [this subgroup includes CAPOS (cerebellar ataxia-areflexia-progressive optic atrophy), RECA (relapsing encephalopathy with cerebellar ataxia), ataxia and non-specified nervous system abnormalities]. Neuropathology of Patient 23, age 1 day (A2-R279Gfs4*, homozygous). 2F and G). Cartoon representation of the structure of the sodium potassium ATPase. , Luebbert T National Library of Medicine Federal government websites often end in .gov or .mil. The corpus callosum was thin (white arrow). D. Cartoon representation of the structure of the sodium potassium ATPase. 6A, B, Supplementary Figs 11 and 12, with full text presentation in the Supplementary material. The -subunit is colored in grey, the -subunit is colored in blue, and the FXYD subunit is colored in magenta. 53Sweadner KJ Patients 3 and 4 exhibited a remarkably severe phenotype among those with ATP1A2 mutations reported so far, manifesting neonatal onset super-refractory status epilepticus featuring prolonged apnoeic episodes. Combining our report with other studies, we estimate that 5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Europe PMC. Additional clinical findings in this cohort included Pierre-Robin sequence (micrognathia with cleft palate, Patient 11), optic nerve atrophy (Patient 10), and hypogenetic lung syndrome (Patient 14). Epub 2021 Jan 16. Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations. , Tonelli A (F and G) Histology of the brain slices demonstrated leptomeningeal glioneuronal heterotopia (black arrowheads) covering cortex that appeared externally pachygyric, but histologically showed features of four-layered polymicrogyria, also seen in other cortical areas (black arrows). Nesti C, Ticci C, Rubegni A, Doccini S, Scaturro G, Vetro A, Guerrini R, Santorelli FM, Procopio E. J Neurol. (L) Meningeal blood vessel with medial calcifications (arrows), and intimal hyperplasia possibly due to thrombosis and recanalization. , Yamakado M E-mail: ATP1A2 mutations in migraine: seeing through the facets of an ion pump onto the neurobiology of disease, Neurological disease mutations of 3 Na+,K+-ATPase: structural and functional perspectives and rescue of compromised function, Na, K-ATPase subunit heterogeneity as a mechanism for tissue-specific ion regulation, Immunofluorescent localization of three Na,K-ATPase isozymes in the rat central nervous system: both neurons and glia can express more than one Na,K-ATPase, The Na,K-ATPase 2 isoform is expressed in neurons, and its absence disrupts neuronal activity in newborn mice, A novel mutation in the ATP1A2 genes causes alternating hemiplegia of childhood, Alternating hemiplegia of childhood or familial hemiplegic migraine? Hemidystonia with polymicrogyria is part of ATP1A3-related disorders. The images were generated using Pymol. Detailed materials and methods for MRI investigations, brain neuropathology in Patients 11 and 23, genetic analysis, homology modelling and structural analysis, and functional characterization of ATP1A2 and ATP1A3 heterozygous mutations are reported in the Supplementary material. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. from the National Health and Medical Research Council of Australia (grants APP1091593, APP1104831). ATP1A2 : 182340 : 1q25.3 : Developmental and epileptic encephalopathy 69 : AD: 3 : 618285 : CACNA1E : 601013 : 1q31.3 : Developmental and epileptic encephalopathy 57 : AD: 3 : 617771 : KCNT2 : 610044 : 1q42.11 : Developmental and epileptic encephalopathy-12 (DEE12) is an autosomal recessive neurologic disorder Incomplete penetrance and variable expressivity have also been observed with SCN3A-associated polymicrogyria.41 Similarly, GRIN1 mutations even within the same functional domain can result in DEE with normal MRI or polymicrogyria.43. Stable expression (top row): A2-wt (wild-type), 53452 M (nH = 2.0); A2-I293M, 2790592 M (nH = 1.7); A2-R593Q, 38424 M (nH = 2.6); A2-R908Q, 60181 M (nH = 1.7); A3-wt, 916105 M (nH = 2.4); A3-D887Y, 126093 M (nH = 2.1); A3-P972del, 1331303 M (nH = 1.2). Severe variants are linked to profound neurodevelopmental disorders with infantile onset (<2 years of age) such as AHC and early infantile epileptic encephalopathy (EIEE), whereas mild variants associate with childhood or adult onset disorders with better developmental outcomes (e.g. Notably, a few of these mutations were associated with more than one phenotype. About. , Mei D The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). (F) The occipital lobes (coronal slices) exhibited polymicrogyria and moderate colpocephaly. , et al. , Stagnaro M Polymicrogyria can be associated with 1% of ATP1A2 and 5.5% of ATP1A3 mutations (yellow-dashed area). The Seizure-Associated Genes Across Species (SAGAS) database offers insights into epilepsy genes, pathways and treatments. ATP1A2; ATP1A3; Na+/K+-ATPase pump; developmental and epileptic encephalopathy; polymicrogyria. 2021 May;88:87-94. doi: 10.1016/j.seizure.2021.03.028. , Conti V Description. Eleven heterozygous mutations were novel (ATP1A2 n=2; ATP1A3 n=9; Supplementary Table 1). Careers. The C341F variant in the ATP1A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Unable to load your collection due to an error, Unable to load your delegates due to an error, Collaborators, ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. , Koenderink JB 2021 Mar;31:21-26. doi: 10.1016/j.ejpn.2021.01.004. (2021) identified 14 heterozygous mutations in the ATP1A2 gene (see, e.g., 182350.0019-182350.0021).The mutations occurred de novo in all except for a mother and son pair (patients 14 and 15). 1). Published by Oxford University Press on behalf of the Guarantors of Brain. Perisylvian involvement was accompanied in all by severe disruption of the sulcal pattern, with a vertically-oriented and extended Sylvian fissure. , Onaka T Typical onset is in adulthood or older The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and beyond. Epileptic encephalopathies are devastating neurological disorders characterized by early onset of multiple Barbance C, Depienne C, Tournier-Lasserve E. De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine. The 11 mutations not supporting cell growth in culture were associated with the most severe clinical phenotype, while the five mutations supporting cell growth were associated with more variable clinical phenotypes. Refractory status epilepticus had occurred in 10 patients, in five of whom as the presenting type of seizure in the neonatal period (Patients 3, 4, 7, 11 and 13). , Stam AH 4) had a strong conformational shift in favour of E1/E1P explaining the reduced turnover rate. Collectively, up to 5% of ATP1A2 (6/94) and 12% of ATP1A3 (18/145) mutations can be associated with developmental and epileptic encephalopathy. In nine mutants the NKA pump activity was too low for survival of the transfected COS-1 cells, substantiating the profound phenotypes featuring early death, DEE, progressive brain atrophy and polymicrogyria observed in most patients carrying these mutations (Table1). Phosphorylation was measured at the indicated concentrations of K+ on transiently expressed NKA enzyme. 7). 2018 Oct;40(9):768-774. doi: 10.1016/j.braindev.2018.05.008. , et al. Each line represents the best fit of a Hill equation. In two further patients with ATP1A3 mutations, similar apnoeic episodes lacked any electrographic correlate and were classified as central apnoeas. (A) Left brain, lateral view. WebOur observations describe a distinctive clinical profile of seven unrelated probands with early onset severe ATP1A2-related epileptic encephalopathy, provide insights into Na+ binding was also disturbed by one of the mutations in the P-domain (A2-G366A; Supplementary Fig. Hence, these mutations are predicted to interfere with the - interaction crucial to expression in the plasma membrane. Severe axial hypotonia was reported in 14 individuals including three with dyskinetic quadriparesis (Patients 2, 10 and 18). In individuals with epilepsy, sequence analysis of ATP1A2 can be performed first De novo CACNA1A pathogenic variants are a common cause of epileptic encephalopathy [Allen et al 2016], and epileptic encephalopathy may be the presenting phenotype in an individual who develops CACNA1A-FHM. Clinical and genetic data for 22 patients (11 males/11 females) with 19 heterozygous mutations in ATP1A2 (n=6, Patients 16) or ATP1A3 (n=16, Patients 722) are summarized in Table1 and Supplementary Table 1; data for Patient 23 who carries a biallelic ATP1A2 mutation and was not considered in the clinical study, is also included. We also thank Mrs Diana Bazan for her skilful technical assistance (Neuropathology). (C) Brainstem and right cerebellum, medial view. Am. The NKA activity per mg total plasma membrane protein, calculated by multiplying the turnover rate by the phosphorylation level, was 17% (A2-I293M), 36% (A2-R593Q), 22% (A2-R908Q), 30% (A3-P972del), and 33% (A3-D887Y), relative to wild-type, indicating that the function of these mutants was substantially impaired despite their ability to support cell growth. Keywords: WebFamilial Hemiplegic Migraine With Asymmetric Encephalopathy Secondary to ATP1A2 Mutation: A Case Series For permissions, please email: journals.permissions@oup.com. WebAcute encephalopathy in familial hemiplegic migraine with ATP1A2 mutation . Keywords: The phosphorylation level (pmol/mg total plasma membrane protein) is shown in per cent of wild-type. For A3-K764del and A3-D992dup, phosphorylation and expression were very low or undetectable, most likely caused by misfolding and/or disruption of Na+ binding, as these residues are involved in an intricate hydrogen bonding network that is essential for positioning of the transmembrane helices and C-terminus forming the fold for Na+ binding at site III (Supplementary Fig. Background: Patients (age 2.5-20 years) had symptom onset at an early age (6 days-1 year). , Dorison N WebThis is the homepage for eEF1A2 information hosted by Cathy Abbotts lab at the IGMM, University of Edinburgh. Bookshelf Epub 2022 May 24. Accumulation of phosphoenzyme is inhibited by K+, because K+ activates dephosphorylation of E2P and competes with Na+ for binding to E1 (cf. Annalisa Vetro and others, ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria, Brain, Volume 144, Issue 5, May 2021, Pages 14351450, https://doi.org/10.1093/brain/awab052. We tested 10 mutations from this group, including five (A2-C341F, A3-G316V, A3-S361P, A3-P775R, A3-L888P) that resulted in loss of NKA pump activity as indicated by lack of COS-1 cell survival. Straka B, Hermanovska B, Krskova L, Zamecnik J, Vlckova M, Balascakova M, Tesner P, Jezdik P, Tichy M, Kyncl M, Musilova A, Lassuthova P, Marusic P, Krsek P. Neurol Genet. There is some degree of vermian hypoplasia in Patients 7 and 17. Genet. The shaded area represents the perspective in E. E. Structural interactions at the C-terminal region involving Glu1000. 36Rosewich H 2) and were interpreted as pathogenic based on both in silico analysis using sequence data and the functional studies described below. Lacombe D, Van-Gils J, Lebrun M, Trimouille A, Michaud V, Cabet S, Chateil JF, Pedespan JM, Bar C, Lesca G. Brain Dev. Epub 2022 Jul 18. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2.