atp1a2 epileptic encephalopathy

The cortical gyri were diffusely small with extensive folding, suggestive of polymicrogyria, except for the hippocampus, which appeared relatively normal bilaterally (Fig. , et al. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments.

Aim

We aimed to describe the The most striking difference between the two brains were the abundant mineralizations seen in the brain and blood vessels of Patient 23, which were not observed in Patient 11. , et al. 44Platzer K , Spontarelli K In two additional neonates, apnoeic episodes were attributed to central apnoeas (Patients 14 and 18). 7). official website and that any information you provide is encrypted 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. These circumstances of death were not consistent with a sudden cardiac event but it cannot be excluded that a compromised cardiac function might have contributed to these patients vulnerability. WebATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria. PMC , Messchaert M Common features were: drug resistance, recurrent status epilepticus, etc., severe developmental delay with episodes of acute severe encephalopathy often with headaches, dystonias, hemiplegias, seizures, and developmental regression. In addition, phenotype-guided genetic testing, largely applied in the past, might have prevented novel malformation phenotypes from being found. The glycine is important for the direction of this strand. In Patient 15 too, who is the mother of Patient 14, the cortical abnormality is perisylvian but unilateral only involving the right hemisphere. Early onset severe ATP1A2 epileptic encephalopathy: Clinical https://orcid.org. doi: 10.1093/brain/awab052 According to these studies, the transmembrane NKA pump would act as a scaffold, tethering signalling proteins together into distinct cellular compartments, thus contributing to the modulation of signal transduction within the cell.52, A clustering of AHC-associated ATP1A3 mutations in transmembrane domains 29 has been previously reported.3,30 Conversely, FHM-associated ATP1A2 mutations and RDP-associated ATP1A3 mutations are scattered throughout the protein.3,30. For A3-P972del, the cooperativity of Na+ binding at the three sites was severely reduced (Hill coefficient 1.2 versus 2.4 for the wild-type). Histopathology (haematoxylin and eosin, G-N). The disability was rated as severe to profound in 14, moderate in three, and mild in 1/18 patients. Most of the mutations found in our cohort result in severe functional defects based on both disruption of protein structure and biochemical analysis. Of the 19 mutations in our cohort, eight ATP1A3 mutations, but only two ATP1A2 mutations, affected the transmembrane helices M3 (A3-L292R, A2-I293M), M4 (A3-G316V, A2-C341F), M5 (A3-K764del, A3-P775R), M6 (A3-D801N), M7 (A3-F857del), M8 (A3-L924P), and M10 (A3-D992dup) (Fig. , Stam AH ATP1A2 doi: 10.1212/WNL.0b013e3181f25e8f. Epilepsy was reported in 21/22 individuals, with seizure onset during the neonatal period in 11 individuals and during infancy or childhood in the remaining 10. , Sweney MT ", For permissions, please email: journals.permissions@oup.com. Focal calcifications (arrows) were noted in deep white matter. ATP1A3-related epileptic encephalopathy responding to Pump-Opathies: Mutations in Na+K+-ATPase Genes Produce , Sweadner KJ Collectively, up to 5% of ATP1A2 (6/94) and 12% of ATP1A3 (18/145) mutations can be associated with developmental and epileptic encephalopathy. Associated findings included microcephaly in 7/10 and thick corpus callosum in 4/10 patients (Supplementary Table 1 and Fig. Hemispheric white matter was also reduced. Misfolding of the mutant -subunit and allele competition for the -subunit might also contribute to deleteriousness of ATP1A3 mutations and their phenotypic heterogeneity.26. The mutations occurred de novo in 20/22 patients and were inherited in two individuals from one family (Patients 14 and 15: A3-D887Y). Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations. 2F and G). Epilepsy as part of the phenotype associated with ATP1A2 CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms. , et al. ATP1A2 WebBackground: ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. 2G). 17Marzin P Unauthorized use of these marks is strictly prohibited. ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria. The IBAHC Consortium. 51Herrera VLM Disclaimer. Schematic representation of the main clinical features in our cohort with structural location and functional effect of the corresponding mutations in ATP1A2 (A2) and ATP1A3 (A3). In Patient 11, with a heterozygous ATP1A3 mutation (A3-K764del), and in Patient 23, with a homozygous ATP1A2 frameshift mutation (A2-R279G*4), we performed post-mortem neuropathological examination and compared findings (Figs2 and 3). William B Dobyns, Bente Vilsen and Renzo Guerrini authors contributed equally to this work. Hence, these mutations are predicted to interfere with the - interaction crucial to expression in the plasma membrane. Background ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Epileptic Encephalopathy For A2-C341F and A3-P775R, the inserted bulky side chains appear to disturb ion binding and helix packing in the membrane, especially when charged arginine is involved (Supplementary Figs 5 and 9). Web619606 - DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 99; DEE99 In 16 patients from 15 families with DEE99, Vetro et al. In the six subjects harbouring these mutations, the phenotypes were of variable severity. A retrospective chart review of a cohort of seven patients was conducted. Callosal fibres did not cross the midline posteriorly, but instead formed Probst bundles (PB). Early onset 12Chatron N , Hitomi Y Brain. Overall, these findings indicated a variable malformation of cortical development affecting central regions more severely that was also associated with malformations of brainstem and cerebellar nuclei. , Aldinger K Hemidystonia with polymicrogyria is part of ATP1A3-related disorders. doi: 10.1016/j.ajhg.2016.07.013. (B) Right hemisphere, medial view. , et al. 3B). , et al. novo mutations in pediatric refractory epilepsy , Yuan H , Ohlenbusch A ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria. 2021 May;88:87-94. doi: 10.1016/j.seizure.2021.03.028. These four mutations were all associated with polymicrogyria. epilepsy , et al. 3L). All rights reserved. 4) had a strong conformational shift in favour of E1/E1P explaining the reduced turnover rate. WebFor Peer Review ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria Journal: Brain Manuscript ID BRAIN-2020-01771.R2 Manuscript Type: Original , Hevner R The primary sequence comparison is shown for human 2, A. Analysis of the variant allele frequency (VAF) showed that 21/22 mutations were constitutional and one mosaic with VAF 26.2%. 2) and were interpreted as pathogenic based on both in silico analysis using sequence data and the functional studies described below. DEVELOPMENTAL AND EPILEPTIC The perspective is that shown in B after rotation along the y-axis by 90. or. Weband epileptic encephalopathies, epilepsy syndrome with stereotyp - paroxysmal movement disorders and epilepsy Hemiplegic migraine ATP1A2 SCN1A Episodic ataxia KCNA1 SCN8A SLC16A2 CHRNA4 KCNMA1 SLC2A1 TBC1D24 PKD PNKD PED Paroxysmal dyskinesias Channelopathies SCN8A CACNA1A KCNMA1 SCN1A Molecular modeling was performed using PyMol program. A similar, but less strong conformational shift was seen for the P-domain mutation near the ATP binding site (A2-R593Q; Supplementary Fig. ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy Nine different aspect of the NKA pump function investigated by at least one of the different experimental approaches are showed. The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary material. , Baes M Editorial Policies; Author Guidelines; Peer Review Guidelines; Open Outlook; Hot topics; Podcasts Lortie A, et al. The isoforms differ in affinity for Na+, K+ and ATP, and have different enzyme kinetics.4 The 2- and 3-isoforms, encoded by ATP1A2 and ATP1A3, are predominantly expressed in CNS. In this image, TM8 and TM9 are shown while TM1 and TM2 are not shown. 8). Unable to load your collection due to an error, Unable to load your delegates due to an error, Collaborators, Clipboard, Search History, and several other advanced features are temporarily unavailable. Its characteristics shared similarities with those observed with mutations in several developmental genes (the microcephaly gene WDR62, multiple tubulin genes, the PIK3CA-AKT pathway associated PIK3R2 gene), but recently also associated with the ion channel genes SCN3A41,42 and, in more severe forms, GRIN1 and GRIN2B.43,44, Mutations of SCN3A were initially associated with non-malformation epilepsy and DEE (MIM #617935; MIM #617938), and more recently with polymicrogyria.41,42 However, mutations associated with polymicrogyria proved to be gain-of-function resulting in increased non-inactivating persistent Na+ currents (I-NaP). ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA. from the National Health and Medical Research Council of Australia (grants APP1091593, APP1104831). In Patient 17, there is diffuse polymicrogyria with more severe perisylvian involvement. Please enable it to take advantage of the complete set of features! The polar interactions related to Glu1000 are shown. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Early Treatment in Acute Severe Encephalopathy Caused by Sign in | Create an account. All had variants predicted to be disease causing (p.Ile293Met, p.Glu1000Lys, c.1017+5G>A, p.Leu809Arg, and 3 patients with p.Met813Lys). 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). , et al. Early onset severe ATP1A2 epileptic encephalopathy: Clinical Phosphorylation by ATP (indicated by P). Please enable it to take advantage of the complete set of features! The -subunit, MeSH , Penniston JT , et al. 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? , Berkovic S , Sassoon D or reset password. 99, 802816. Close Log In. , Phillips JM National Library of Medicine WebAcute encephalopathy in familial hemiplegic migraine with ATP1A2 mutation . 24Li M Histology revealed that the macroscopically pachygyric cortex was thick, disorganized, and partially covered by rinds of leptomeningeal glioneuronal heterotopia (Fig. Epub 2021 Jan 16. Na+ and K+ affinity of ATP1A2/A3 mutants. , et al. , et al. DEVELOPMENTAL AND EPILEPTIC 28De Carvalho Aguiar P 47Pelzer N , et al. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). Group 1 included 11 patients harbouring nine different mutations, all resulting in lack of cell survival; we observed early mortality in 5/11 (45%), severe microcephaly in 6/11 (55%), polymicrogyria in 5/11 (45%) and severe or profound intellectual disability in 8/9 (89%) patients. , et al. 11Paciorkowski AR Unable to load your collection due to an error, Unable to load your delegates due to an error. Remember me on this computer. ATP1A2- and ATP1A3-associated early profound epileptic 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. The cerebellar folia showed no obvious defects. The porcine enzyme is highly homologous to the human enzyme and the 2-isoform is highly homologous to the 3-isoform, especially in TM1-10. The apparent Na+ affinities (K0.5 values) and Hill coefficients (nH) were as follows. The carbon atoms of residues Ile293, Leu809, Met813 and Glu1000 are spheres and colored light blue. Puljko B, Stojanovi M, Ilic K, Kalanj-Bognar S, Mlinac-Jerkovic K. Biomedicines. 2023 Jun;19(6):363-370. doi: 10.1038/s41582-023-00811-4. Thus, AHC was hypothesized and a novel mutation in ATP1A3 gene was found. , Curry CJ J. Hum. 35Balestrini S The known expression patterns of ATP1A2 and ATP1A3 support the microcephaly and polymicrogyria seen in our series (mouse: http://www.informatics.jax.org; human: http://www.hdbr.org/expression). Combining our report of 19 mutations (11 novel) with all prior reports, we estimate that 5% of mutations in ATP1A2 and 12% in ATP1A3 are associated with the severe and novel phenotypes that we describe in this series. 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. sharing sensitive information, make sure youre on a federal , et al. The M3 mutant (A2-I293M; Supplementary Fig. In developing mouse brain, Atp1a2 is highly expressed in neural progenitors and meninges, then persists after birth in glial cells.5,6,51,Atp1a3 is also expressed in neural progenitors but not in meninges and persists after birth in postnatal neurons.5,51 Thus, both genes could be implicated in direct injury to radial glia and migrating neurons. We obtained written informed consent from all participants or their legal guardians according to local requirements. Background: Would you like email updates of new search results? 7). The apparent Na+ affinity was reduced 35-fold (K0.5 increased) for A2-I293M, A2-G366A, and A3-L292R, and increased 4-fold for A3-G316V (K0.5 decreased). Marzin P, Mignot C, Dorison N, Dufour L, Ville D, Kaminska A, Panagiotakaki E, Dienpendaele AS, Penniello MJ, Nougues MC, Keren B, Depienne C, Nava C, Milh M, Villard L, Richelme C, Rivier C, Whalen S, Heron D, Lesca G, Doummar D. Brain Dev. , et al. ATP1A2 epileptic encephalopathy In the presence of extracellular K+, three Na+ are released and two K+ bound (Fig. Note focal parenchymal calcifications (arrows). 49Blicher JU Memantine, given to five, was tolerated in all (mean treatment: 2.3 years, range 6 weeks-4.8 years) with some improvements reported in all five. It is possible that previously reported patients may not have had adequate MRI imaging and thus subtle alterations of the cortical folding might have been overlooked in older studies. , Arystarkhova E , et al. E1 and E1P are Na+ selective conformations, whereas E2 and E2P are K+ selective conformations. and transmitted securely. Bassi MT , Gawlinski P 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 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 98; Polymicrogyria can be associated with 1% of ATP1A2 and 5.5% of ATP1A3 mutations (yellow-dashed area). , Jazayeri D WebATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria Ballardini, Elisa; Bigoni, Stefania; 2021 Abstract Constitutional 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), Our initial discovery cohort consisted of 2800 individuals referred to the Neuroscience and Neurogenetics Department of the Meyer Childrens Hospital to investigate the genetic causes of developmental and epileptic encephalopathies (DEEs, defined according to Scheffer et al.14). ATP1A2; Alternating Hemiplegia of Childhood; Encephalopathy; Familial Hemiplegic Migraine; Memantine; NMDA Receptor Antagonist. We thank Nina Juste and Randi Scheel, Aarhus University, for expert technical assistance. In two further patients with ATP1A3 mutations, similar apnoeic episodes lacked any electrographic correlate and were classified as central apnoeas. We tested 14 mutations from 17 patients and next separated our patient cohort into two groups based on COS-1 cell survival in ouabain selection pressure (Table1). , Huppke P The https:// ensures that you are connecting to the Constitutional heterozygous mutations of ATP1A2/A3 have been associated with several autosomal dominant neurological disorders with limited overlap. All 19 mutations affected highly conserved residues among both orthologs and paralogues of ATP1A2 and ATP1A3 (Supplementary Table 1 and Supplementary Fig. 8600 Rockville Pike Copyright 2020 Elsevier Inc. All rights reserved. We identified 19 heterozygous mutations of ATP1A2 (n=5) or ATP1A3 (n=14; Supplementary Table 1) including 15 missense substitutions, three in-frame deletions, and one insertion. Seizure types were classified following ILAE criteria14 whenever applicable and used more descriptive terms when seizure phenomenology could not be easily classified using classification terminology. Before Epilepsy in patients with familial hemiplegic migraine. They usually begin in infancy. Disclaimer. Aim We aimed to describe the manifestations of early onset severe ATP1A2-related epileptic encephalopathy and its underlying mutations in a cohort of seven patients. Patients (age 2.5-20 years) had symptom onset at an early age (6 days-1 year). Gracie L, Rostami-Hochaghan D, Taweel B, Mirza N; SAGAS Scientists' Collaborative. 2D and E). The latter was inherited across three generations from a reportedly healthy male to his daughter (Patient 15) and grandson (Patient 14). FOIA 5C), the phosphorylation levels of A2-G366A (61%), A3-L292R (61%), and A3-G316V (70%) indicated that they were expressed in the plasma membrane and retained the ability to bind Na+ and ATP, despite their inability to undergo the complete transport cycle. 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. 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. 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The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Hemiplegic Migraine With Asymmetric Encephalopathy , Haq IU , et al. Early lethal hydrops fetalis, arthrogryposis, micro-cephaly, and polymicrogyria have been associated with , et al. doi: 10.1002/mgg3.2146. 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. Our study provides additional examples of mutations affecting homologous residues in ATP1A2 and ATP1A3 (Supplementary Table 2). , Fawcett KA The two patients with alternating hemiplegia in this group (Patients 16 and 20) were the only ones to manifest this disorder in the entire series. Moya-Mendez ME, Mueller DM, Pratt M, Bonner M, Elliott C, Hunanyan A, Kucera G, Bock C, Prange L, Jasien J, Keough K, Shashi V, McDonald M, Mikati MA Epilepsy Behav 2021 Mar;116:107732. Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish. Neuropediatrics. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities.
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