Respiratory disturbances have been described in ATP1A3-AHC.30 Biallelic ATP1A2 mutations have also been associated with respiratory failure due to absence of spontaneous respiratory effort12,13 resembling knockout Atp1a2 or Atp1a3 mice, whose defective respiratory rhythm generation was attributed to failed Cl clearance through the K-Cl transporter (KCC2) in brainstem postsynaptic neurons.33,34 The KCC2 transporter relies on the K+ gradient created by the NKA to pump Cl out of the cells. Holm R 17Marzin P Patient 21 carried the A3-F857del in 26.2% of WES reads. , et al. Nielsen HN 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. 5A and Table1). Prolonged seizure-related apnoeic episodes were a recurrent feature in five additional individuals, all exhibiting ATP1A3 mutations. The binding of three Na+ to the E1 form activates phosphorylation from ATP. The numbering is that of the human 2 isoform. Brain. WebWe investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. Alerted by this association, we identified another 13 patients with similar features through international collaborations and by interrogating the DECIPHER database (http://decipher.sanger.ac.uk) (Patients 1, 2, 4, 5, 7, 8, 10, 13, 1719, 21 and 22). Patients with ATP1A3-related disease are at increased risk of exhibiting dynamic ECG abnormalities, a finding substantiated by the multiple cardiac rhythm abnormalities observed the in murine Atp1a3 model.35 However, while sudden seizure-related cardiac death has been induced in murine Atp1a3-related disease, premature mortality remained limited to 2% in the international AHC-ATP1A3 registry cohort over a 20 years period,36 mainly as a consequence of accidental events or respiratory complications of status epilepticus. Survival was often short; eight children died due to complications of status epilepticus (Patients 3, 4, 7, 10, 11, 17, 19), or intercurrent respiratory infections (Patient 18); seven of these children died between 10 days and 30 months of life (Patients 3, 4, 7, 11 and 1719) and one at 14 years (Patient 10). A novel heterozygous ATP1A2 pathogenic variant in a Chinese child with MELAS-like alternating hemiplegia. 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. , Wang S WebBackground: Alternating Hemiplegia of Childhood (AHC) is a rare neurological disease caused by mutations in ATP1A3 gene codifying for alpha3 subunit of Na + -K + ATPase 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), , Fawcett KA , et al. ATP1A3-related epileptic encephalopathy responding to Damien Sanlaville, Rani Sachdev, Ian Andrews, Francesco Mari, Anna Cavalli, Carmen Barba, Beatrice De Maria, Giampaolo Garani, Johannes R. Lemke, Mario Mastrangelo, Emily Tam, Elizabeth Donner, Helen Branson, Fabiola P. Monteiro, Fernando Kok, Katherine B. Howell, Stephanie Leech, Heather Mefford, Alison Muir. from the National Health and Medical Research Council of Australia (grants APP1091593, APP1104831). 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. , McTague A DEVELOPMENTAL AND EPILEPTIC 28De Carvalho Aguiar P epilepsy , Leroux P Brain MRI in nine patients with polymicrogyria. , Peeters K 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). 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 37Sasaki M (B) K+ affinity determined from K+ inhibition of phosphorylation. The NKA -subunit consists of three major cytoplasmic domains A (actuator), N (nucleotide-binding), and P (phosphorylation) linked to a membrane domain composed of ten transmembrane helices (M1-M10) with their intervening loops on both membrane sides. European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium. ATP1A2 Phosphorylation by ATP (indicated by P). The apparent Na+ affinities (K0.5 values) and Hill coefficients (nH) were as follows. The glycine is important for the direction of this strand. , Richardson JP The main finding, observed in 10 patients (45%), was polymicrogyria (nine ATP1A3 mutations: Patients 7, 11, 1316, 17, 19 and 20; one ATP1A2 mutation: Patient 6), which was perisylvian predominant, bilateral in nine patients and unilateral in one (Patient 15), inconstantly involving other areas (Fig. (AC) Macroscopic views of the brain from (A) posterior, (B) right, and (C) left sides demonstrated overall small cerebral hemispheres, with externally apparent pachygyria (asterisks) involving pericentral cortex bilaterally. Many of the mutations replace or insert bulky and/or charged residues such as aromatic amino acids, proline or arginine with smaller or less charged residues, while a few simply delete or duplicate a residue. reaction cycle in Fig. , et al. Analysis of the variant allele frequency (VAF) showed that 21/22 mutations were constitutional and one mosaic with VAF 26.2%. , Yuan H , Hevner R , et al. The M3 mutant (A2-I293M; Supplementary Fig. Disclaimer. , et al. These abnormalities are better visible in column A (enlarged Sylvian space), column B (infolding) and column C (cortical thickening and verticalized Sylvian fissure). 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. The phosphorylation level (pmol/mg total plasma membrane protein) is shown in per cent of wild-type. 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. Eleven heterozygous mutations were novel (ATP1A2 n=2; ATP1A3 n=9; Supplementary Table 1). There are some differences in individual patients. 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. 11Paciorkowski AR Cartoon representation of the position of Ile293, Leu809, Met813 and Glu1000. The remaining five mutations caused reduced (1736%) activity that was sufficient for cell growth, attributed to either reduced expression level in the plasma membrane (A2-R908Q, A3-P972del, and A3-D887Y), or an E1P shift of the E1P-E2P conformational equilibrium (A2-I293M, A2-R593Q). Leptomeningeal glioneuronal heterotopia were widespread over the external surface of the hemispheres (Fig. Sources: Expert,Expert Review Red 4 Apr 2018, Gel status: 1 Created The cortical gyri were diffusely small with extensive folding, suggestive of polymicrogyria, except for the hippocampus, which appeared relatively normal bilaterally (Fig. 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), 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. Amino acid residues targeted by the mutations in the cohort are shown in blue (ATP1A2 mutations) and red (ATP1A3 mutations) in the structure of the ATP1A1 -subunit in E1 form (PDB ID 3WGV, chain A, grey colour) with 3Na+ (golden spheres labelled I, II, and III according to common nomenclature) and ADP with phosphate analogue AlF4 and the phosphorylated aspartate in green. 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). , Vuillaumier-Barrot S , et al. (K) Cortical blood vessel with mineralized walls (arrows). All 14 of the mutations we tested caused reduced NKA pump activity in the COS-1 cellular model. Focal calcifications (arrows) were noted in deep white matter. 2F and G). , et al. Introduction. , Yamakado M , et al. In Patient 17, there is diffuse polymicrogyria with more severe perisylvian involvement. 60Wiszniewski W Multiple antiseizure medications were used both in the acute treatment of status epilepticus/prolonged seizures and as chronic treatments, with no evidence of any drug being more effective than any other or causing seizure worsening. Early-onset encephalopathy with paroxysmal movement disorders and epileptic seizures without hemiplegic attacks: About three children with novel ATP1A3 mutations. 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. The expression of both isoforms is primarily neuronal during embryonic development. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Histology also demonstrated that the macroscopic appearance of pachygyria actually corresponded to disorganized layers with some features of classic four-layered polymicrogyria (Fig. Collectively, up to 5% of ATP1A2 (6/94) and 12% of ATP1A3 (18/145) mutations can be associated with developmental and epileptic encephalopathy. The site is secure. 5C). For example, seven children (five from Group 1, one from Group 2, and a further patient with the untested A3-G893W) died at 03 years with profound encephalopathies classified as DEE. In sum, the expression patterns of ATP1A2/A3 in developing brain combined with observations in two brains from our series support a mainly neural (radial glia, progenitors, migrating neurons) pathogenesis that may be compounded by meningeal and vascular abnormalities. WebFamilial hemiplegic migraine type 2 (FHM2) is an autosomal dominant inheritance disorder caused by ATP1A2mutation, and the clinical spectrum is heterogeneous even with acute 59Oegema R The very low or undetectable phosphorylation (expression) levels in the remaining six mutants (A2-C341F, A3-S361P, A3-K764del, A3-P775R, A3-L888P, and A3-P992dup), prevented further study of their phosphorylation properties (Fig. A3-D801N has previously been shown to impair Na+ and K+ transport as D801 is known to directly bind Na+ and K+ at both sites I and II.3,24,25 A3-L924P is predicted to break the M8 helix, thereby indirectly disturbing the interaction of the juxtaposed D923 with Na+ at site III.26 The mutations A3-L292R, A2-I293M, A3-G316V, A2-C341F, A3-K764del, A3-P775R, A3-L924P, and A3-D992dup found in transmembrane helices and A3-P972del in the L8-9 loop connecting the transmembrane helices M8 and M9 are predicted to affect the ion binding sites indirectly. The cerebellar folia showed no obvious defects. For permissions, please email: journals.permissions@oup.com. In this image, TM8 and TM9 are shown while TM1 and TM2 are not shown. , Aldinger K These patients died either as a consequence of an intercurrent respiratory infection or during status epilepticus after progressive worsening of their conditions. These images were generated from the pdb: 3WUG, [26] which is the structure of the porcine enzyme with the 3-isoform. 15Burgess R 2020 Jun;51(3):215-220. doi: 10.1055/s-0039-3400986. Molecular modeling was performed using PyMol program. 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. Affiliations. 6). Pavone P, Pappalardo XG, Ruggieri M, Falsaperla R, Parano E. Medicine (Baltimore). 2023 Feb;182(2):825-836. doi: 10.1007/s00431-022-04744-w. Epub 2022 Dec 9. Puljko B, Stojanovi M, Ilic K, Kalanj-Bognar S, Mlinac-Jerkovic K. Biomedicines. 51Herrera VLM 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), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). The Na+/K+-ATPase (NKA) ion pump is a ubiquitous transmembrane enzyme responsible for active exchange of Na+ and K+ ions across the plasma membranes of higher eukaryotic cells.1 In neural tissue, this process is pivotal for maintaining the resting membrane potential, excitability, and secondary active transport that involves Na+/H+ and Na+/Ca2+ exchange, K+/Cl cotransport, and Na+-dependent neurotransmitter uptake.2 The NKA pump transports three Na+ ions out of the cell and two K+ ions into the cell for each ATP hydrolysed, undergoing large conformational changes between two principal conformations (E1 and E2) and their phosphorylated intermediates (E1P and E2P).13 It is composed of a large catalytic -subunit and smaller - and -subunits. A3-F857del is likely to affect the interaction between M7 and the transmembrane helix of the -subunit. The atoms of nucleotide bound to the N-site are shown as spheres. 46Gressens P ATP1A2 epileptic encephalopathy 6A, B, Supplementary Figs 11 and 12, with full text presentation in the Supplementary material. Also, the white matter was atrophic and the corpus callosum small, suggesting that cortical axons were deficient. , Zelnik N However, recognition of attacks may have been hampered by severe hypotonia and frequent seizures in the other children. Brain 144: 1435-1450, 2021. , Messchaert M We aimed to describe the manifestations of early onset severe ATP1A2-related epileptic encephalopathy and its underlying mutations in a cohort of seven patients. 22Parrini E doi: 10.1212/NXG.0000000000200032. Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. WebFor Peer Review ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria Journal: Brain Manuscript ID BRAIN-2020-01771.R2 Manuscript Type: Original Careers. 3B). encephalopathy Epub 2023 Feb 7. The primary sequence comparison is shown for human 2, A. The perspective is that shown in B after rotation along the y-axis by 90. A novel ATP1A2 variant associated with severe stepwise regression, hemiplegia, epilepsy and movement disorders in two unrelated patients. Frontiers | From Genotype to Phenotype - Open Access The -subunit is colored in grey, the -subunit is colored in blue, and the FXYD subunit is colored in magenta. The phenotype consists of hemiplegia and seizures starting by 2.5 Phosphorylation was determined under stoichiometric conditions, thus reflecting the expression level (active site concentration). Here we describe 22 individuals with heterozygous ATP1A2 or ATP1A3 mutations associated with developmental encephalopathies manifesting most often as early-onset DEE, and associated with frequent early lethality (in 32%) and polymicrogyria (in 45%). 8600 Rockville Pike ATP1A2-and ATP1A3-associated early profound epileptic Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. , et al. 5B and Table1). We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. The .gov means its official. Sign in | Create an account. The -subunit, MeSH , Clausen MJ This work was generated within the European Reference Networks EpiCARE and ITHACA. ATP1A2- and ATP1A3-associated early profound Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). , Roze E We reviewed medical records, ECG, EEGs, and brain MRI scans. From top to bottom: Representative brain MRI findings in Patients 6, 7, 11, 1317 and 20 with an indication of the mutations and age at which imaging was performed. 38Severino M Most of the mutations found in our cohort result in severe functional defects based on both disruption of protein structure and biochemical analysis. , Timms AE Correspondence (neuropathology) may also be addressed to: Robert F. Hevner Department of Pathology, University of California San Diego San Diego, CA USA. 19De Vries B , Stam AH The most obvious similarities were small size of the hemispheres with widespread polymicrogyria covered by extensive leptomeningeal glioneuronal heterotopia, confirmed histologically in both brains. 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. , Swoboda KJ Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence. The cortex was diffusely polymicrogyric, had an attached external rind of leptomeningeal glioneuronal heterotopia, and contained focal calcifications (arrows). 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 The molecular diagnostic yield of polymicrogyria is low, with multiple genes accounting for a small number of diagnoses each, and a relevant number of patients resulting from non-genetic, mainly vascular or infective, prenatal causes.40,57,58 The proportion of patients with polymicrogyria related to ATP1A2/A3 remains unknown since available next generation studies on malformations of cortical development have been either performed with gene panels which included neither of the two genes59 or carrying out WES in small series in which no pathogenic variants in either gene emerged.57,60 This study widens the clinical spectrum of ATP1A2/A3-opathies to include profound epilepsy phenotypes, with and without associated polymicrogyria.
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