Supplementary material is available at Brain online. Bassi MT 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/NXG.0000000000200032. 2023 Feb;182(2):825-836. doi: 10.1007/s00431-022-04744-w. Epub 2022 Dec 9. Blood vessels were congested; the leptomeninges contained subarachnoid haemorrhage (agonal) and were adherent to the brain surface. Calame DG, Houck K, Lotze T, Emrick L, Parnes M. Eur J Paediatr Neurol. , et al. , Capovilla G doi: 10.1212/WNL.0000000000200927. The atoms of nucleotide bound to the N-site are shown as spheres. , Chapman T Bethesda, MD 20894, Web Policies In silico evaluation predicted all mutations to be detrimental. Background ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. The https:// ensures that you are connecting to the RDP, CAPOS) However, recognition of attacks may have been hampered by severe hypotonia and frequent seizures in the other children. All had variants predicted to be disease causing (p.Ile293Met, p.Glu1000Lys, c.1017+5G>A, p.Leu809Arg, and 3 patients with p.Met813Lys). Surface gyri were difficult to assess due to adherent meninges with subarachnoid haemorrhage (agonal) and congested blood vessels (Fig. The remaining five mutations resulted in partially conserved NKA pump activity allowing long term COS-1 cell survival. 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. Our study provides additional examples of mutations affecting homologous residues in ATP1A2 and ATP1A3 (Supplementary Table 2). Na+ and K+ affinity of ATP1A2/A3 mutants. HHS Vulnerability Disclosure, Help Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. , Luebbert T Other deleterious variants found in patients with unclassified refractory epilepsy were in VRK2, 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. 29De Fusco M ATPase, Na+/K+ TRANSPORTING, ALPHA-2 3I). Web619606 - DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 99; DEE99 In 16 patients from 15 families with DEE99, Vetro et al. Genetic Testing for Malformations of Cortical Development: A Clinical Diagnostic Study. Callosal fibres did not cross the midline posteriorly, but instead formed Probst bundles (PB). In Patient 17, there is diffuse polymicrogyria with more severe perisylvian involvement. In our series, a short QT interval, an ECG abnormality that is potentially predisposing to life threatening arrhythmia, was present in one patient (Patient 13) and was the only abnormal finding observed among 19 patients whose ECGs were available for inspection. 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. Careers. Zhang X, Qiu S, Yang L, Li Y, Xu L, Xu N, Mi C, Li M. Mol Genet Genomic Med. Brain MRI in nine patients with polymicrogyria. , et al. 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. 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). (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). ATP1A3-related epileptic encephalopathy responding to 9). 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. (B) Turnover rate (min1) determined by relating the maximum NKA activity to the phosphorylation level. , Pisciotta L Different studies have suggested a direct link between the Na+,K+-ATPase and signal transduction pathways involving, among others, the Src family kinases, and PI3K, which has been implicated in a spectrum of brain malformations. , Corry B , et al. Epilepsy 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. ATP1A2 government site. 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. , Berkovic S , Richardson JP ATP1A2 and transmitted securely. 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 7). reaction cycle in Fig. Notably, a few of these mutations were associated with more than one phenotype. 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. In Group 1, two individuals without polymicrogyria carried the severe A2-G366A mutation, while the remaining three all had polymicrogyria with mutations affecting the transmembrane helices (A3-L292R, A3-K764del, and A3-D992dup) and causing severe impairment of NKA pump activity. Associated findings included microcephaly in 7/10 and thick corpus callosum in 4/10 patients (Supplementary Table 1 and Fig. In two further patients with ATP1A3 mutations, similar apnoeic episodes lacked any electrographic correlate and were classified as central apnoeas. 2F and G). The M3 mutant (A2-I293M; Supplementary Fig. Symbols with error bars represent mean SD. We identified 92 ATP1A2 and 136 ATP1A3 heterozygous mutations in the Human Gene Mutation Database (https://portal.biobase-international.com), and stratified them based on the reported phenotypes, adding to previously published data the 11 novel mutations (two in ATP1A2 and nine in ATP1A3) we reported in this series. Leptomeningeal glioneuronal heterotopia were widespread over the external surface of the hemispheres (Fig. We 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. = phosphorylation; PMG = polymicrogyria; SEV = severe; TO = turnover; WT = wild-type. See this image and copyright information in PMC. 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. 2021 Jun 22;144(5):1435-1450. doi: 10.1093/brain/awab052. 5B and Table1). 5A and Table1). , Mei D 53Sweadner KJ , et al. The same pathophysiological mechanism might cause the nonepileptic episodic respiratory disturbances in Patients 14 and 18. Midline section revealed that the corpus callosum was small but present, including the splenium (arrow Fig. A retrospective chart review of a cohort of seven patients was conducted. ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria. 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. , Einholm AP Each line represents the best fit of the Hill equation for inhibitory ligand binding.27 The apparent K+ affinities (K0.5 values) were as follows: A2-wt, 18843 M; A2-G366A, >100 mM; A3-wt, 28163 M; A3-L292R, 4570700 M; A3-G316V, >10 mM. 1). The glycine is important for the direction of this strand. , Xaidara A Note focal parenchymal calcifications (arrows). A number of factors argue against haploinsufficiency as the main pathogenetic mechanism, including absence of phenotypic manifestations in carrier parents, similarities of the neuropathological polymicrogyria phenotype with that observed with biallelic mutations (Patient 23)12 and the non-malformative phenotypes observed in individuals with large deletions involving ATP1A2/A3 (DECIPHER, https://decipher.sanger.ac.uk/; ClinVar, https://www.ncbi.nlm.nih.gov/clinvar/). , Ishii A , Tortora D , et al. WebATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria. 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. Early Treatment in Acute Severe Encephalopathy Caused by ATP1A2 Mutation of Familial Hemiplegic Migraine Type 2: Case Report and Literature Review. However, the turnover rate (rate of Pi liberation per active site in the presence of both Na+ and K+) was markedly reduced for A2-I293M (27% wild-type) and A2-R593Q (42% wild-type) (Fig. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments.
Aim
We aimed to describe the Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. Clipboard, Search History, and several other advanced features are temporarily unavailable. 2022 Jun 27;10(7):1518. doi: 10.3390/biomedicines10071518. ATP1A2 : 182340 : 1q25.3 : Developmental and epileptic encephalopathy 69 : AD: 3 : 618285 : CACNA1E : 601013 : 1q31.3 : Developmental and epileptic encephalopathy 57 reported a consanguineous Palestinian family in which 4 members had a severe developmental and epileptic encephalopathy consistent with a clinical Panel version: Imported from Epileptic encephalopathy panel version 0 Natalie Trump (NHS - Great Ormond Street Hospital) Red List (low evidence) ATP1A2 was added to Genetic Epilepsy Syndromes panel. Notably, a few of these mutations were associated with more than one phenotype (Fig. , et al. , Spontarelli K 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. 19De Vries B , et al. , Freilinger T In summary, in every patient whose mutations were tested at least one of the assays used showed severe impairment, as summarized in Table1. Early lethal hydrops fetalis, arthrogryposis, micro-cephaly, and polymicrogyria have been associated with , et al. The pie charts show the distribution of heterozygous mutations of ATP1A2 (left) and ATP1A3 (right) across their associated phenotypes. Neuropediatrics. For a detailed description see Supplementary Fig. Epub 2018 May 31. 44Platzer K Webmutations of ATP1A2/A3 associated with severe childhood epilepsies. 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. , Marconi R 2023 Jun;270(6):3266-3269. doi: 10.1007/s00415-023-11673-7. WebAcute encephalopathy in familial hemiplegic migraine with ATP1A2 mutation . An official website of the United States government. , Donahue MJ , Aldinger K Global developmental delay and intellectual disability was documented in 18/22 patients, including all who survived long enough to be assessed. Before , et al. 1). , Hevner R , Cabet S , Ohlenbusch A Among the five stably expressed mutants retaining transport activity (cell survival), only A2-I293M and A2-R593Q showed phosphorylation levels >50% wild-type, whereas levels of A2-R908Q, A3-P972del, and A3-D887Y were 26-35% wild-type (Fig. No obvious brain anatomical defects have been reported in ATP1A2/A3 mouse models.33,34 However, mouse models are not particularly suitable to unveil abnormal cortical folding and defective cortical lamination might have remained unnoticed as no specific studies seem to have investigated it. , Toustrup-Jensen MS eEF1A2 and epilepsy , Barakat TS ATP1A2- and ATP1A3-associated early profound ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA. The most obvious similarities were small size of the hemispheres with widespread polymicrogyria covered by extensive leptomeningeal glioneuronal heterotopia, confirmed histologically in both brains. Clinical Study Group. (D and E) Coronal slices of brain, (D) level of amygdala and (E) anterior hippocampus. The expression of both isoforms is primarily neuronal during embryonic development. 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). The cerebellum was moderately hypoplastic, with reduced foliation (Fig. DEVELOPMENTAL AND EPILEPTIC Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). National Library of Medicine Swoboda KJ Enter the email address you signed up with and we'll email you a reset link. 5). (C) Phosphorylation level of transiently expressed ATP1A2 and ATP1A3 wild-type and mutants determined as described for A. Early onset severe ATP1A2 epileptic encephalopathy: , et al. The Seizure-Associated Genes Across Species (SAGAS) database offers insights into epilepsy genes, pathways and treatments. 3E, arrows). A3-L888P inserts a proline redirecting the L7-8 loop, predicted to disrupt the interaction between the - and -subunits, which should prevent expression in the plasma membrane (Supplementary Fig. 7). A novel ATP1A2 variant associated with severe stepwise regression, hemiplegia, epilepsy and movement disorders in two unrelated patients. WebFamilial Hemiplegic Migraine With Asymmetric Encephalopathy Secondary to ATP1A2 Mutation: A Case Series The images were generated using Pymol. epileptic encephalopathy Alternating hemiplegia of childhood: a distinct clinical entity and ATP1A3-related disorders: A narrative review. Collectively, up to 5% of ATP1A2 (6/94) and 12% of ATP1A3 (18/145) mutations can be associated with developmental and epileptic encephalopathy. 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. The shaded area represents the perspective in E. E. Structural interactions at the C-terminal region involving Glu1000. DEVELOPMENTAL AND EPILEPTIC 2D and E). 6). Frontiers | Presenting Patterns of Genetically - Open Access 16Heinzen EL Since the first reports of ATP1A2 and ATP1A3 mutations in 20030428,29 more than 200 mutations (n=92 ATP1A2, n=136 ATP1A3) have been identified [Human Gene Mutation Database (HGMD) Professional 2018.3, https://portal.biobase-international.com, last accessed June 2020]. European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium. Brain. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. 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-5 (DEE5) is a neurologic disorder characterized by global Epub 2022 May 24. Email. In Patient 6, polymicrogyria is diffuse and more prominent posteriorly. Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations. Epub 2023 Feb 7. The gene encoding eEF1A2 has been found to be mutated in 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. Early onset 25Weigand KM , Yuan H Keywords: , Clausen MJ Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish. Transient expression (bottom row): A2-wt, 59580 M (nH = 2.5); A2-G366A, 3079192 M (nH = 1.3); A3-wt, 1120127 M (nH = 2.1); A3-L292R, 3013254 M (nH = 1.9); A3-G316V, 27247 M (nH = 1.3). 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. Typical onset is in adulthood or older childhood 8600 Rockville Pike 59Oegema R 2022 Jun 29;63(9):2403-12. doi: 10.1111/epi.17352. In the 10 remaining patients, brain MRI was normal or showed mild atrophic changes, and remained so in the two who were scanned twice (Patients 9 and 10). The primary sequence comparison is shown for human 2 isoform relative to the 3 human and porcine isoforms. Modeling revealed that mutations interfered with ATP1A2 ion binding and translocation sites. Epub 2014 Oct 13. , Messchaert M , et al. Molecular modeling was performed using PyMol program. 6). ATP1A2 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), We reviewed medical records, ECG, EEGs, and brain MRI scans. 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. FOIA 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. Federal government websites often end in .gov or .mil. (2010) 75:96772. 32Prontera P 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%). , et al. Epub 2019 Nov 25. government site. The ATP1A2 glycine 366 (A2-G366), which is mutated in Patients 3 and 4 (A2-G366A) with early lethal phenotypes, corresponds to the G358 residue in ATP1A3 mutated in a newborn with seizures and progressive brain atrophy who died prematurely (G358V).11 Different de novo substitutions of A2-G366 have been reported in one patient with refractory epilepsy (A2-G366V)10 and in another with a non-specific neurodevelopmental disorder (A2-G366C).55 A2-G366, or its equivalent in ATP1A3, is located in the P-domain at the junction between the P1-helix and the P1--strand leading directly to the phosphorylated active site aspartate of the DKTGT motif (Supplementary Fig. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six , Swoboda KJ In addition, phenotype-guided genetic testing, largely applied in the past, might have prevented novel malformation phenotypes from being found. : a novel ATP1A2 mutation, Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation, Novel and de novo mutations in pediatric refractory epilepsy, Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly, A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants, Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations, ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology, The genetic landscape of epilepsy of infancy with migrating focal seizures, De novo mutations in ATP1A3 cause alternating hemiplegia of childhood, Early-onset encephalopathy with paroxysmal movement disorders and epileptic seizures without hemiplegic attacks: about three children with novel ATP1A3 mutations, Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study, Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine, Clinical application of whole-exome sequencing across clinical indications, Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood-a study of 155 patients, Diagnostic targeted resequencing in 349 patients with drug-resistant pediatric epilepsies identifies causative mutations in 30 different genes, Clinical benefit of NMDA receptor antagonists in a patient with ATP1A2 gene mutation, A functional correlate of severity in alternating hemiplegia of childhood, Alternating hemiplegia of childhood mutations have a differential effect on Na+,K+-ATPase activity and ouabain binding, Factors in the disease severity of ATP1A3 mutations: impairment, misfolding, and allele competition, Distinct effects of Q925 mutation on intracellular and extracellular Na+ and K+ binding to the Na+, K+-ATPase, Mutations in the Na+/K+-ATPase 3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism, Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump 2 subunit associated with familial hemiplegic migraine type 2, The expanding clinical and genetic spectrum of ATP1A3-related disorders, Epilepsy as part of the phenotype associated with ATP1A2 mutations, Epilepsy in hemiplegic migraine: genetic mutations and clinical implications, Degeneration of the amygdala/piriform cortex and enhanced fear/anxiety behaviors in sodium pump 2 subunit (Atpla2)-deficient mice, Knockout of sodium pump 3 subunit gene (Atp1a3/) results in perinatal seizure and defective respiratory rhythm generation, Cardiac phenotype in ATP1A3-related syndromes: a multicentre cohort study, Research conference summary from the 2014 International Task Force on ATP1A3-related disorders, Progressive brain atrophy in alternating hemiplegia of childhood, White matter and cerebellar involvement in alternating hemiplegia of childhood, Magnetic resonance imaging volumetric analysis in patients with Alternating hemiplegia of childhood: a pilot study, Malformations of cortical development: clinical features and genetic causes, Sodium channel SCN3A (NaV1.3) regulation of human cerebral cortical folding and oral motor development, SCN3A-related neurodevelopmental disorder: a spectrum of epilepsy and brain malformation, De novo mutations in GRIN1 cause extensive bilateral polymicrogyria, GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects, Ion channel functions in early brain development, Neuronal migration disorder in Zellweger mice is secondary to glutamate receptor dysfunction, Recurrent coma and fever in familial hemiplegic migraine type 2. Cartoon representation of the structure of the sodium potassium ATPase. Seizures were either focal or generalized. FOIA 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. , et al. , et al. In addition, A2-G366A disturbed K+ binding, as the E2P phosphoenzyme intermediate of this mutant was completely insensitive to K+. 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). Also, the cerebellar deep nuclei were dysplastic, and the pyramidal tracts were severely hypoplastic (not shown). Online ahead of print. Histology confirmed diffuse polymicrogyria throughout the cortex except in the hippocampus, which displayed relatively normal lamination (Fig. Histology revealed that the macroscopically pachygyric cortex was thick, disorganized, and partially covered by rinds of leptomeningeal glioneuronal heterotopia (Fig. (A) Left brain, lateral view. WebGRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers. 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. The site is secure. 42Zaman T Both patients died within the first year of life without achieving developmental or motor skills. , Huppke P , et al. , et al. Accessibility [15] Please see section 3.2 for further details. Homology of -subunit isoforms. 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). The phosphorylation level (pmol/mg total plasma membrane protein) is shown in per cent of wild-type. reaction cycle in Fig. 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. In Patient 11 too, there is asymmetry with the right hemisphere being more severely affected and smaller. Neurology. Polymicrogyria, which we observed with consistent features in 10 patients (45%), is a novel phenotype for heterozygous ATP1A2 and ATP1A3 mutations. 36Rosewich H The predicted structural impacts of all mutations in our cohort are detailed in Supplementary Table 2 and illustrated in Supplementary Figs 410. ATP1A2- and ATP1A3-associated early profound Unauthorized use of these marks is strictly prohibited. , Tonelli A 8) leading to retention of immature protein in the endoplasmic reticulum and/or decreased stability. Prolonged seizure-related apnoeic episodes were a recurrent feature in five additional individuals, all exhibiting ATP1A3 mutations. 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. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). 12Chatron N In Patient 7, the cortical abnormality is asymmetrical, due to a smaller right hemisphere. 99, 802816. Scale bars = 1 cm in A, for AF; 1 mm in G, for G and H; 100 m in I, for I and J; 50 m in I, for K and L. The brain of Patient 11 appeared small for the age of four postnatal months (brain weight not available). The phosphorylated intermediate (E2P) is hydrolysed to the E2 state which equilibrates to the E1 state in the presence of intracellular ATP, delivering two K+ to the intracellular space. A prospective 15-year follow-up of a large family with a novel ATP1A2 mutation, The multiple faces of the ATP1A3-related dystonic movement disorder, Perfusion and pH MRI in familial hemiplegic migraine with prolonged aura, Clinical spectrum in three families with familial hemiplegic migraine type 2 including a novel mutation in the ATP1A2 gene, Developmental cell-specific regulation of Na+-K+-ATPase 1-, 2-, and 3-isoform gene expression, Na+,K+-ATPase as a docking station: protein-protein complexes of the Na+,K+-ATPase, Genotype-structure-phenotype relationships diverge in paralogs ATP1A1, ATP1A2, and ATP1A3, Impaired plasma membrane targeting or protein stability by certain ATP1A2 mutations identified in sporadic or familial hemiplegic migraine, Prevalence and architecture of de novo mutations in developmental disorders, ATP1A3 mosaicism in families with alternating hemiplegia of childhood, Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study, The spectrum of brain malformations and disruptions in twins, International consensus recommendations on the diagnostic work-up for malformations of cortical development, Comprehensive genomic analysis of patients with disorders of cerebral cortical development, The Author(s) (2021).John Deere 2600 Rate Controller,
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