, et al. , et al. 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. Overview of the structural location of ATP1A2 and ATP1A3 disease mutations in the cohort. Please enable it to take advantage of the complete set of features! 2022 Jun 29;63(9):2403-12. doi: 10.1111/epi.17352. Both patients died within the first year of life without achieving developmental or motor skills. WebDevelopmental and epileptic encephalopathy, 1; Episodic ataxia type 2; Spinocerebellar ataxia type 6; Dyskinesia; Intellectual disability; Developmental and epileptic The perspective is that shown in B after rotation along the y-axis by 90. 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). In COS-1 cells, these mutations led to reduced expression in the plasma membrane by interference with the - interaction (Supplementary Fig. 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. , Mignot C
Notably, a few of these mutations were associated with more than one phenotype. sharing sensitive information, make sure youre on a federal 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. 2022 Jun 27;10(7):1518. doi: 10.3390/biomedicines10071518. , Fitzgerald TW
Attacks of alternating hemiplegia were observed in only two children (Patients 16 and 20), both having polymicrogyria. , et al. Nat Rev Neurol. Europe PMC is an archive of life sciences journal literature. , Juusola J
2023 Jun;270(6):3266-3269. doi: 10.1007/s00415-023-11673-7. 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. In silico evaluation predicted all mutations to be detrimental. 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. 3A and B). 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. FOIA 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]. , Sweney MT
A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). , Ohlenbusch A
, Barakat TS
50Roth C
, Yuan H
Aim: , et al. Full details are provided in the Supplementary material. ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria. , et al. Epub 2019 Nov 25. All rights reserved. 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. Brain. 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. Huang D, Song X, Ma J, Li X, Guo Y, Li M, Luo H, Fang Z, Yang C, Xie L, Jiang L. Eur J Pediatr. 19De Vries B
Gracie L, Rostami-Hochaghan D, Taweel B, Mirza N; SAGAS Scientists' Collaborative. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments.
Aim
We aimed to describe the The sodium ions are spheres and colored purple. Changes in the sodium flux in glia and neurons may reverse Na+/Ca2+ exchangers triggering calcium waves.41,42, In GRIN1-associated polymicrogyria, gain-of-function mutations causing hyperactivation of NMDA receptors increase intracellular Ca2+, which was predicted to induce polymicrogyria either by causing increased cell death during foetal brain development (excitotoxicity) or by activating signalling pathways such as PI3K-AKT.43 A similar mechanism would be at play with GRIN2B mutations.45 Altered NMDA receptor-mediated calcium mobilization disturbs neuronal migration in a mouse model of Zellweger syndrome, a rare metabolic disorder featuring a polymicrogyria-like cortical malformation.46 The altered functioning of the NKA pump provides further evidence that changes in ion homeostasis during embryogenesis may disrupt cortical development.45. William B Dobyns, Bente Vilsen and Renzo Guerrini authors contributed equally to this work. The surface gyri were abnormal, mostly small and irregular, but with apparent pachygyria of pericentral cortex bilaterally, and bilateral widening of the central sulcus (Fig. Patients 3 and 4 exhibited a remarkably severe phenotype among those with ATP1A2 mutations reported so far, manifesting neonatal onset super-refractory status epilepticus featuring prolonged apnoeic episodes. 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. , et al. Hence, these mutations are predicted to interfere with the - interaction crucial to expression in the plasma membrane. Supplementary material is available at Brain online. The basal ganglia and thalami appeared relatively spared, with almost normal size. This work was supported by grants to B.V. from the Lundbeck Foundation (grant R223-2016-595) and the Danish Medical Research Council (grant 7016-00193B), grants to R.G. 5A and Table1). 3DF). (B) Right hemisphere, medial view. MeSH , Chapman T
Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments. 1). This site needs JavaScript to work properly. Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations. The less severe phenotypes associated with A2-I293M and A2-R593Q may be related to their near normal expression level, which suggests a relatively stable protein, combined with retention of NKA pump activity, albeit with reduced maximal turnover rate. The remaining 15 subjects survived infancy although one later died at 14 years. , et al. , et al. The atoms of nucleotide bound to the N-site are shown as spheres. Conclusions: 33Ikeda K
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. 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 reaction cycle in Fig. There are some differences in individual patients. In Patients 13, 14, 16 and 17, polymicrogyria is almost exclusively bilateral perisylvian, sparing the remaining cortex. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. from the European Union Seventh Framework Programme FP7/2013 under the project DESIRE (grant 602531), the Italian Ministry of Health and Tuscany Region (grant RF-2013-02355240), the Tuscany Region Call for Health 2018 (grant DECODE EE) and grants to I.E.S. Severe congenital or postnatal (usually by age 2 years) microcephaly was observed in 10/22 patients. 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. , Kenny CJ
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. doi: 10.1002/mgg3.2146. Background ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. (1) Learning pr. Other deleterious variants found in patients with unclassified refractory epilepsy were in VRK2, 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. from the National Health and Medical Research Council of Australia (grants APP1091593, APP1104831). 617105 - developmental and epileptic encephalopathy 41; dee41 - epileptic encephalopathy, early infantile, 41; eiee41 Vetro A, Nielsen HN, Holm R, Hevner RF, Parrini E, Powis Z, et al. , et al. , Freilinger T
, Luebbert T
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. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. 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. , Timms AE
ATP1A2/A3-collaborators. 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). , et al. 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/). HHS Vulnerability Disclosure, Help , Fawcett KA
In Patient 15 too, who is the mother of Patient 14, the cortical abnormality is perisylvian but unilateral only involving the right hemisphere. (L) Meningeal blood vessel with medial calcifications (arrows), and intimal hyperplasia possibly due to thrombosis and recanalization. , Yamakado M
, Sassoon D
44Platzer K
The C341F variant in the ATP1A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. 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. 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). , et al. 3C). 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 Another individual with epilepsy, episodic prolonged apnea, postnatal microcephaly, ATP1A2-related disorders. Copyright 2020 Elsevier Inc. All rights reserved. The polar interactions related to Glu1000 are shown. 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). doi: 10.1093/brain/awab052 60Wiszniewski W
These findings assign novel, 'profound' and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the Note focal parenchymal calcifications (arrows). In slices, the corpus callosum was present but small at the genu and was truncated with lack of midline crossing at the level of the posterior body and splenium, thus forming Probst bundles (Fig. The site is secure. The apparent Na+ affinities (K0.5 values) and Hill coefficients (nH) were as follows. Unable to load your collection due to an error, Unable to load your delegates due to an error, Collaborators, 24Li M
Of the eight mutations previously reported, three were associated with FHM (Patient 6: A2-R908Q) or AHC (Patient 10: A3-D609Y; Patient 13: A3-D801N).1619 The mosaic mutations found in our series (Patient 21: A3-F857del) was reported as a constitutional mutation with no clinical details in one individual.20 Four additional mutations found in Patients 1, 3, 16 and 22 reported here had been mentioned in previous series within which these patients had been included.15,2123 No additional potentially pathogenic mutations were identified in the 20 patients with available whole-exome/whole genome sequencing (WES/WGS) data and in the two examined by targeted gene panel (Patients 2 and 5). Epilepsia. 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. 8), also reduced the phosphorylation level, either partially (A3-D887Y and A2-R908Q) or completely (A3-L888P), most likely due to reduced expression. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 2015 Jan;52(1):56-64. doi: 10.1016/j.pediatrneurol.2014.09.015. 2023 Feb;182(2):825-836. doi: 10.1007/s00431-022-04744-w. Epub 2022 Dec 9. The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and beyond. For A3-S361P, the lack of phosphorylation most likely results from redirection of the -strand leading to the phosphorylated aspartate by insertion of a proline five residues before the aspartate (Supplementary Fig. 2G). 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 Sources: Expert,Expert Review Red 4 Apr 2018, Gel status: 1 Created Severe variants are linked to profound neurodevelopmental disorders with infantile onset (<2 years of age) such as AHC and early infantile epileptic encephalopathy (EIEE), whereas mild variants associate with childhood or adult onset disorders with better developmental outcomes (e.g. 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. The cytoplasmic and extracellular sides are indicated by c and e, respectively. This site needs JavaScript to work properly. None of the mutations were present in either gnomAD or our internal dataset. (G) Frontal cortex, coronal section (midline right). 7). The cerebellum was moderately hypoplastic. WebATP1A2- 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. 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. Homology of -subunit isoforms. 3L). Nine different aspect of the NKA pump function investigated by at least one of the different experimental approaches are showed. , 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). A recurrent feature, present in all patients, is an abnormal Sylvian fissure with thickened cortex, pronounced infolding and vertically oriented axis.