Unauthorized use of these marks is strictly prohibited. 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-81 (DEE81) is an autosomal recessive neurodevelopmental Pathogenic variants in ATP1A2 were first recognized in familial hemiplegic migraine type 2 (FHM2; autosomal dominant inheritance) [1] and were then reported to cause alternating hemiplegia of childhood (AHC; autosomal dominant Cartoon representation of the structure of the sodium potassium ATPase. 99, 802816. ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. Collectively, up to 5% of ATP1A2 (6/94) and 12% of ATP1A3 (18/145) mutations can be associated with developmental and epileptic encephalopathy. ", , Gawlinski P , Kanavakis E Our observations describe a distinctive clinical profile of seven unrelated probands with early onset severe ATP1A2-related epileptic encephalopathy, provide insights into structure-function relationships of ATP1A2 mutations, and support further studies of NMDAR antagonist therapy in ATP1A2-encephalopathy. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. The primary function of ATP driven NKA pumps is to rapidly exchange three intracellular Na+ ions for two extracellular K+ ions. DEVELOPMENTAL AND EPILEPTIC This patients mutation, the A3-D801N, a highly recurrent AH mutation, was also present in one patient with AH and short QT reported by Balestrini et al.35 The six patients with ATP1A3 mutations who died prematurely in our series had normal ECGs. 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). 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%). , Phillips JM The site is secure. Brain. Log in with Facebook Log in with Google. Further, all the phenotypes in both groups were relatively severe, which fits with our finding of severe functional defects in various experimental paradigms for all mutations (Table1). doi: 10.1002/mgg3.2146. 8600 Rockville Pike Pump-Opathies: Mutations in Na+K+-ATPase Genes (D and E) Coronal slices through (D) anterior and (E) middle regions of the hemispheres showed thick cortex corresponding to externally apparent pachygyria (asterisks), and thin but intact genu of the corpus callosum (D, white arrow). Molecular modeling was performed using PyMol program. Declaration of Competing Interest Mohamad Mikati MD and Arsen Hunanyan PhD have a pending patent application for gene therapy of ATPase-related diseases. , et al. reaction cycle in Fig. epilepsy 14Scheffer IE Homology of -subunit isoforms. Sources: Expert,Expert Review Red 4 Apr 2018, Gel status: 1 Created Would you like email updates of new search results? Histology also demonstrated that the macroscopic appearance of pachygyria actually corresponded to disorganized layers with some features of classic four-layered polymicrogyria (Fig. In our cohort we observed an enrichment of ATP1A3 mutations in transmembrane domains M3-M10 clustered around the ion binding sites (8/14; Supplementary Fig. Epub 2023 May 18. The remaining five mutations resulted in partially conserved NKA pump activity allowing long term COS-1 cell survival. We submitted all novel mutations to DECIPHER. Park K 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). 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). 35Balestrini S 57Mirzaa GM ATP1A2 epileptic encephalopathy iris.unife.it , Blom DE 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). List of variants in gene ATP1A2 studied for epilepsy - ClinVar Miner 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). The D923N mutation is recurrent in RDP but has also been observed in one family with four affected individuals with alternating hemiplegia.48 These authors postulated that these clinical syndromes represent the different expressions of the same disorder and that the specific ATP1A3 mutation is not the only determinant of clinical expression, implying that genetic, epigenetic, and environmental factors may all influence clinical expression of ATP1A3 related disease. Hence, we analysed these mutants by transient transfection into COS-1 cells using siRNA to knock down the endogenous NKA pump, as described previously.27. A retrospective chart review of a cohort of seven patients was conducted. , et al. The -subunit (PDB ID 3WGV, chain B, teal colour) consists of a transmembrane helix m and an extracellular domain that interacts with the -subunit loop connecting M7 and M8 (L7-8 loop). Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence. 1). Affiliations. Careers. Panagiotakaki E and transmitted securely. (J) Leptomeninges with focal calcifications (arrows). For a detailed description see Supplementary Fig. Phosphorylation by ATP (indicated by P). Early onset severe ATP1A2 epileptic encephalopathy: Clinical , et al. WebDevelopmental and epileptic encephalopathy, 1; Episodic ataxia type 2; Spinocerebellar ataxia type 6; Dyskinesia; Intellectual disability; Developmental and epileptic Typical onset is in adulthood or older childho , Haq IU 3B). Hemispheric white matter was also reduced. The phenotypes observed in our cohort were predominately severe, with short survival (death at 03 years) observed in 7/22 (32%), severe congenital or postnatal microcephaly in 10/22 (45%), polymicrogyria in 10/22 (45%), and severe or profound early developmental delay or intellectual disability in 14/18 (78%) individuals. Moseley AE 3L). Methods: Frontiers | From Genotype to Phenotype - Open Access , et al. , et al. , Ohlenbusch A 19De Vries B McGrail KM 53Sweadner KJ The Weizmann Institute of Science GeneCards and MalaCards databases. Gracie L, Rostami-Hochaghan D, Taweel B, Mirza N; SAGAS Scientists' Collaborative. One child from a large family segregating FHM (A2-R348P) was reported to have lissencephaly with microcephaly and retinal dysplasia, likely an unrelated phenotype.47 One of the mutations found in our series has been reported in 40% of individuals with AHC (Patient 13: A3-D801N) with no brain malformation reported.18 Different phenotypes associated to the same mutation are not new to ATP1A3. 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. A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. In these patients, structure of the brainstem was intact, suggesting a disturbance of respiratory system regulation. Most had multiple seizure types, with multifocal (n=9) and focal seizures (n=7) being most frequent. 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. 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. In Patient 15 too, who is the mother of Patient 14, the cortical abnormality is perisylvian but unilateral only involving the right hemisphere. ATP1A2; Alternating Hemiplegia of Childhood; Encephalopathy; Familial Hemiplegic Migraine; Memantine; NMDA Receptor Antagonist. Full details are provided in the Supplementary material. In two additional neonates, apnoeic episodes were attributed to central apnoeas (Patients 14 and 18). Unable to load your collection due to an error, Unable to load your delegates due to an error. , et al. 5). Surface gyri were difficult to assess due to adherent meninges with subarachnoid haemorrhage (agonal) and congested blood vessels (Fig. official website and that any information you provide is encrypted Typical onset is in adulthood or older ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA. (K) Cortical blood vessel with mineralized walls (arrows). In the adult brain, 3 maintains its neuronal expression while 2 is primarily expressed in glial cells.5,6 Multiple isoforms of and regulatory subunits also exist, with different tissue distribution and functional effects. 54Tavraz NN 2022 Sep 27;8(5):e200032. We obtained written informed consent from all participants or their legal guardians according to local requirements. (D and E) Coronal slices of brain, (D) level of amygdala and (E) anterior hippocampus. Homology of -subunit isoforms. Epilepsy occurs in about 50% of patients with AHC and 1530% of those with FHM.16,18,31,32 In our cohort, which was assembled based on clinical features of developmental encephalopathy, epilepsy occurred in 21 of 22 patients (95%), with neonatal or early infantile onset in most and episodes of status epilepticus in 10 (45%). Note focal parenchymal calcifications (arrows). , et al. The phenotype consists of hemiplegia and seizures starting by 2.5 Leptomeningeal glioneuronal heterotopia were widespread over the external surface of the hemispheres (Fig. Histopathology (haematoxylin and eosin, G-N). ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria. Before 32Prontera P , et al. In Patients 13, 14, 16 and 17, polymicrogyria is almost exclusively bilateral perisylvian, sparing the remaining cortex. Based on the impaired NKA pump activity observed in the COS-1 cells, where only the mutant NKA is expressed, we classify the mutations in our cohort as loss-of-function, including those mutants for which the impaired pump activity is due to reduced plasma membrane targeting, as previously indicated for A2-R908Q.54, Dominant negative effects, which have previously been suggested for A3-D801N (Patient 3), A3-E815K and A3-G947R24 may also be contributing to the severe phenotype in our series. The effects of mutations on the E1-E2 and E1P-E2P conformational changes (cf. Swoboda KJ , Stam AH doi: 10.1016/j.ajhg.2016.07.013. 41Smith RS , Tortora D Interestingly, ketogenic diet (KD) was started and both The primary sequence comparison is shown for human 2, A. 11Paciorkowski AR Brain. Early onset severe ATP1A2 epileptic encephalopathy: , Huppke P Histology also revealed abundant focal calcifications (or mineralization) involving cerebral grey and white matter, leptomeninges and blood vessels (Fig. (2010) 75:96772. Results: The four known human isoforms of the -subunit (14) encoded by four paralogous genes (ATP1A14) share 8491% of the amino acid sequence and have developmental and tissue expression specificity. Callosal fibres did not cross the midline posteriorly, but instead formed Probst bundles (PB). We reviewed medical records, ECG, EEGs, and brain MRI scans. (B) K+ affinity determined from K+ inhibition of phosphorylation. , Mei D , Jansen LA , Corry B Some areas exhibited more definitive features of polymicrogyria (Fig. 8). Epileptic Encephalopathy (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). Our study provides additional examples of mutations affecting homologous residues in ATP1A2 and ATP1A3 (Supplementary Table 2). , Clayton S , Stagnaro M , et al. All patients have polymicrogyria with abnormal cortical infoldings and packed microgyri, combined with abnormal sulcation. , et al. The images were generated using Pymol. R35 GM131731/GM/NIGMS NIH HHS/United States. encephalopathy , Chapman T Phosphorylation and expression were very low or undetectable for A2-C341F, A3-S361P, A3-P775R, and A3-L888P. The https:// ensures that you are connecting to the , Penniston JT The study was approved by the Pediatric Ethics Committee of the Tuscany Region (grant 602531). Seizures were either focal or generalized. Severe axial hypotonia was reported in 14 individuals including three with dyskinetic quadriparesis (Patients 2, 10 and 18). We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations effects on the NKA-pump function, and studied genotype-phenotype correlations. 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. 6). Epub 2023 Mar 20. , Mikati MA 4 and Supplementary Fig. ATP1A2 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. 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). Roubergue A 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. 2AC). , Hitomi Y 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 Both patients died within the first year of life without achieving developmental or motor skills. , Tonelli A WebAcute encephalopathy in familial hemiplegic migraine with ATP1A2 mutation . ATP1A2 In addition, phenotype-guided genetic testing, largely applied in the past, might have prevented novel malformation phenotypes from being found. There are some differences in individual patients. , Ishii A In silico evaluation predicted all mutations to be detrimental. The pie charts show the distribution of heterozygous mutations of ATP1A2 (left) and ATP1A3 (right) across their associated phenotypes. A comparison of the two groups suggests a trend towards more severe phenotype in Group 1, but the differences were not statistically significant due to small numbers (Fisher's exact test). 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. The cortical gyri were diffusely small with extensive folding, suggestive of polymicrogyria, except for the hippocampus, which appeared relatively normal bilaterally (Fig. doi: 10.1212/WNL.0000000000200927. WebEpileptic encephalopathies are an epileptic condition characterized by early-onset seizures. HHS Vulnerability Disclosure, Help Eleven heterozygous mutations were novel (ATP1A2 n=2; ATP1A3 n=9; Supplementary Table 1). Ghusayni R 25Weigand KM developmental and epileptic encephalopathy, Oxford University Press is a department of the University of Oxford. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. These include familial hemiplegic migraine (FHM; ATP1A2, MIM#602481); rapid-onset dystonia-parkinsonism (RDP; ATP1A3, MIM#128235); alternating hemiplegia of childhood (AHC; ATP1A3, MIM #614820 and a single family with an ATP1A2 mutation)7,8 cerebellar ataxia-areflexia-progressive optic atrophy (CAPOS; ATP1A3, MIM#601338); and relapsing encephalopathy with cerebellar ataxia (RECA; ATP1A3).9 Epilepsy and intellectual disability may co-occur with AHC and FHM, and severe epilepsies have been described in rare patients with ATP1A2 or ATP1A3 mutations.10,11 Early lethal hydrops fetalis, intrauterine growth restriction, arthrogryposis, microcephaly, polymicrogyria, and lack of respiratory drive have been associated with homozygous truncating mutations in ATP1A2.12,13. The Genetic Relationship between Paroxysmal Movement colpocephaly: Fig. We also thank Mrs Diana Bazan for her skilful technical assistance (Neuropathology). , et al. 20Retterer K , Yamakado M Cartoon representation of the position of Ile293, Leu809, Met813 and Glu1000. , Freilinger T The ATP1A2 spectrum should include early onset severe epileptic encephalopathy. The A2-R908Q mutation was associated with early onset epileptic encephalopathy in one patient in our series and with familial hemiplegic migraine in multiple unrelated individuals in the literature,19,49,50 demonstrating that phenotypic heterogeneity is not limited to ATP1A3 mutations. 2F and G, arrowheads); the pachygyric appearance was conferred in part by the rind of leptomeningeal heterotopia. 55McRae JF , Thiele H , Garcia-Roves RA ATP1A2 2G). Clipboard, Search History, and several other advanced features are temporarily unavailable. doi: 10.1212/WNL.0b013e3181f25e8f. , Silvestri L These 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. Epilepsy 10). The atoms of nucleotide bound to the N-site are shown as spheres. 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. The p.Gly900Arg mutation was present in a family with epilepsy and FHM, and the p.Cys702Tyr mutation 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. We explore the detrimental effects of causative mutations on NKA pump function using several different experimental paradigms and show that the most severe phenotypes are caused by mutations that are lethal in mammalian cell culture (COS-1 cells). In Patient 8: A3-G316V, the low pump activity was associated with low K+ affinity, compatible with insertion of a bulky valine close to the ion binding sites (Supplementary Fig. The expression of both isoforms is primarily neuronal during embryonic development. 9). Hence, these mutations are predicted to interfere with the - interaction crucial to expression in the plasma membrane. 2022 Aug 5;101(31):e29413. WebATP1A2 : 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-35 (DEE35) is an autosomal recessive neurodegenerative disorder Mechanisms underlying phenotypic variation in neurogenetic disorders. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. Encephalopathy A distinctive, profound phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). We also observed incomplete penetrance and variable expressivity within a single family in which the proband (Patient 14: A3-D887Y) had early onset DEE and bilateral polymicrogyria, his mother (Patient 15) had migraine, mild intellectual disability and unilateral polymicrogyria, and the maternal grandfather had no reported symptoms and a normal brain MRI despite carrying a germline mutation. ATP1A2 , et al. 2F and G). , Conti V Epub 2021 Mar 31. The glycine is important for the direction of this strand. Overall, four children died within the first 2 months of life (Patients 4, 7, 17 and 19), too early to detect progressive worsening, which was instead apparent in the remaining four who died at a later age. All 19 mutations affected highly conserved residues among both orthologs and paralogues of ATP1A2 and ATP1A3 (Supplementary Table 1 and Supplementary Fig. 30Rosewich H WebEEF1A2 encodes protein elongation factor 1-alpha 2, which is involved in Guanosine triphosphate (GTP)-dependent binding of aminoacyl-transfer RNA (tRNA) to the A-site 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. A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. Unable to load your collection due to an error, Unable to load your delegates due to an error, Collaborators, These four mutations were all associated with polymicrogyria. 2022 Nov 11;13(1):6841. doi: 10.1038/s41467-022-34354-x. The perspective is that of the shaded area in A but TM8 and TM9 are not shown. , et al. Pavone P, Pappalardo XG, Ruggieri M, Falsaperla R, Parano E. Medicine (Baltimore). The Italian IBAHC Consortium. , Cova T Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations. Global developmental delay and intellectual disability was documented in 18/22 patients, including all who survived long enough to be assessed. Polymicrogyria can be associated with 1% of ATP1A2 and 5.5% of ATP1A3 mutations (yellow-dashed area). Two mutations (A2-G366A and A3-S361P) were recurrent, occurring in two individuals each. 4) had a strong conformational shift in favour of E1/E1P explaining the reduced turnover rate. Brain MRI in nine patients with polymicrogyria. Early lethal hydrops fetalis, arthrogryposis, micro-cephaly, and polymicrogyria have been associated with , Barakat TS An official website of the United States government. , Schtz H Most of the mutations found in our cohort result in severe functional defects based on both disruption of protein structure and biochemical analysis.