Correction: Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry

Viollet, Louis; Glusman, Gustavo; Murphy, Kelley J.; Newcomb, Tara; Reyna, Sandra P.; Sweney, Matthew; Nelson, Brent G.; Andermann, Frédérick; Andermann, Eva; Acsádi, Gyula; Barbano, Richard L.; Brown, Candida; Brunkow, Mary E.; Chugani, Harry T.; Cheyette, Sarah R.; Collins, Abigail; DeBrosse, Suzanne D.; Galas, David J.; Friedman, Jennifer; Hood, Lee; Huff, Chad; Jorde, Lynn B.; King, Mary D.; LaSalle, Bernie; Leventer, Richard J.; Lewelt, Aga J.; Massart, Mylynda; Merida, Mario; Ptáček, Louis J.; Roach, Jared C.; Rust, Robert S.; Renault, Francis; Sanger, Terry D.; Menezes, Marcio A Sotero de; Tennyson, Rachel B.; Uldall, Peter; Zhang, Yue; Zupanc, Mary L.; Xin, Winnie; Silver, Kenneth; Swoboda, Kathryn J.

doi:10.1371/journal.pone.0137370

Cited by 12 publications

(7 citation statements)

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“…Classical RDP patients typically develop stress-induced permanent dystonia and Parkinsonism in late adolescence or early adulthood. Other 59 different ATP1A3 de novo missense mutations are associated with AHC (Heinzen et al, 2014 ; Rosewich et al, 2014 ; Sasaki et al, 2014 ; Ulate-Campos et al, 2014 ; Yang et al, 2014 ; Panagiotakaki et al, 2015 ; Viollet et al, 2015 ). AHC is characterized by onset of hemiplegic/quadriplegic episodes within 18 months of birth.…”

Section: Atp1a3 -Related Diseasesmentioning

confidence: 99%

Insights into the Pathology of the α3 Na+/K+-ATPase Ion Pump in Neurological Disorders; Lessons from Animal Models

Holm

Lykke‐Hartmann

2016

Front. Physiol.

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The transmembrane Na+-/K+ ATPase is located at the plasma membrane of all mammalian cells. The Na+-/K+ ATPase utilizes energy from ATP hydrolysis to extrude three Na+ cations and import two K+ cations into the cell. The minimum constellation for an active Na+-/K+ ATPase is one alpha (α) and one beta (β) subunit. Mammals express four α isoforms (α1−4), encoded by the ATP1A1-4 genes, respectively. The α1 isoform is ubiquitously expressed in the adult central nervous system (CNS) whereas α2 primarily is expressed in astrocytes and α3 in neurons. Na+ and K+ are the principal ions involved in action potential propagation during neuronal depolarization. The α1 and α3 Na+-/K+ ATPases are therefore prime candidates for restoring neuronal membrane potential after depolarization and for maintaining neuronal excitability. The α3 isoform has approximately four-fold lower Na+ affinity compared to α1 and is specifically required for rapid restoration of large transient increases in [Na+]i. Conditions associated with α3 deficiency are therefore likely aggravated by suprathreshold neuronal activity. The α3 isoform been suggested to support re-uptake of neurotransmitters. These processes are required for normal brain activity, and in fact autosomal dominant de novo mutations in ATP1A3 encoding the α3 isoform has been found to cause the three neurological diseases Rapid Onset Dystonia Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC), and Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). All three diseases cause acute onset of neurological symptoms, but the predominant neurological manifestations differ with particularly early onset of hemiplegic/dystonic episodes and mental decline in AHC, ataxic encephalopathy and impairment of vision and hearing in CAPOS syndrome and late onset of dystonia/parkinsonism in RDP. Several mouse models have been generated to study the in vivo consequences of Atp1a3 modulation. The different mice show varying degrees of hyperactivity, gait problems, and learning disability as well as stress-induced seizures. With the advent of several Atp1a3-gene or chemically modified animal models that closely phenocopy many aspects of the human disorders, we will be able to reach a much better understanding of the etiology of RDP, AHC, and CAPOS syndrome.

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Section: Atp1a3 -Related Diseasesmentioning

confidence: 99%

Insights into the Pathology of the α3 Na+/K+-ATPase Ion Pump in Neurological Disorders; Lessons from Animal Models

Holm

Lykke‐Hartmann

2016

Front. Physiol.

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“…4 Frequency and severity spectrum of three most common mutations in decreasing order have been graded as E815K > D801N > G947R in various published series. 4,[21][22][23] Two novel pathogenic missense variations in our series, D814N and G960R, belong to the same cluster as E815K and G947R, respectively. Cases 3 and 4 with D814N mutation in our series (belonging to the same most severe mutational cluster as E815K) were more severe compared with case 1 with G960R who is ambulatory, and case 2 with D801N variant had intermediate severity being able to walk with support.…”

Section: Discussionmentioning

confidence: 65%

“…3,20 Most common genetic mutations in ATP1A3 gene in large cohorts include D801N, E815K, and G947R. 21 With addition of newer mutations, Rosewich et al introduced the notion of mutational clusters. 22 Panagiotakaki et al outlined such five mutational clusters in their cohort.…”

Section: Discussionmentioning

confidence: 99%

Alternating Hemiplegia of Childhood: A Series of Genetically Confirmed Four Cases from Southern India with Review of Published Literature

2020

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Alternating hemiplegia of childhood (AHC) is a rare autosomal dominant neurodevelopmental disorder with mutation on ATP1A3 gene. Delay in diagnosis and inappropriate diagnosis are common. We describe four genetically confirmed AHC patients to provide an improved understanding of the disorder. First symptom in two patients was seizures and in other two patients was abnormal eye deviation. All had onset of plegic attacks within the first 18 months of their life. Tone abnormalities and movement disorders were present in all patients. Electroencephalogram was abnormal in two patients and all had normal magnetic resonance imaging of the brain. Response to treatment of plegic attacks was poor and also epilepsy was drug resistant. All cases had significant development delay and disability as of last follow-up. Although there is no effective treatment so far, early diagnosis is required to avoid unnecessary treatment.

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“…ATP1A3-related diseases characteristics were determined by combining information from previous studies and the results of the present study. Given the phenotypic variations of ATP1A3related diseases, the following two points should be noted: (1) The symptoms did not occur in all patients, but they were very common; thus, they were considered important features of the clinical phenotypic spectrum. (2) Although some clinical manifestations were not marked as disease features, they may occured in a few patients with this gene mutation, and they were not included in the disease characteristics because they are not very common.…”

Section: Clinical Phenotypic Profile Associated With Atp a Mutationsmentioning

confidence: 99%

“…ATP1A3 contains 23 exons and 22 introns, and encodes a protein of 1013 amino acids, consisting of the α3 subunit of Na + /K + -ATPase, which is located on chromosome 19q13.2 and is expressed primarily in brain neuronal cells (1). Na + /K + -ATPase is a membrane-binding transporter with ATP hydrolase activity, which is mainly expressed in neuronal cells.…”

Section: Introductionmentioning

confidence: 99%

Molecular and clinical characteristics of ATP1A3-related diseases

Wang

et al. 2022

Front. Neurol.

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ObjectiveWith detailed studies of ATP1A3-related diseases, the phenotypic spectrum of ATP1A3 has greatly expanded. This study aimed to potentially identify the mechanisms by which ATP1A3 caused neurological dysfunction by analyzing the clinical features and phenotypes of ATP1A3-related diseases, and exploring the distribution patterns of mutations in the subregions of the ATP1A3 protein, thus providing new and effective therapeutic approaches.MethodsDatabases of PubMed, Online Mendelian Inheritance in Man, and Human Gene Mutation Database, Wanfang Data, and Embase were searched for case reports of ATP1A3-related diseases. Following case screening, we collected clinical information and genetic testing results of patients, and analyzed the disease characteristics on the clinical phenotype spectrum associated with mutations, genetic characteristics of mutations, and effects of drug therapy.ResultsWe collected 902 clinical cases related to ATP1A3 gene. From the results of previous studies, we further clarified the clinical characteristics of ATP1A3-related diseases, such as alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism; cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome, and relapsing encephalopathy with cerebellar ataxia, frequency of mutations in different phenotypes and their distribution in gene and protein structures, and differences in mutations in different clinical phenotypes. Regarding the efficacy of drug treatment, 80 of the 124 patients with AHC were treated with flunarizine, with an effectiveness rate of ~64.5%.ConclusionsNervous system dysfunction due to mutations of ATP1A3 gene was characterized by a group of genotypic–phenotypic interrelated disease pedigrees with multiple clinical manifestations. The presented results might help guide the diagnosis and treatment of ATP1A3-related diseases and provided new ideas for further exploring the mechanisms of nervous system diseases due to ATP1A3 mutations.

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Correction: Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry

Cited by 12 publications

References 1 publication

Insights into the Pathology of the α3 Na+/K+-ATPase Ion Pump in Neurological Disorders; Lessons from Animal Models

Insights into the Pathology of the α3 Na+/K+-ATPase Ion Pump in Neurological Disorders; Lessons from Animal Models

Alternating Hemiplegia of Childhood: A Series of Genetically Confirmed Four Cases from Southern India with Review of Published Literature

Molecular and clinical characteristics of ATP1A3-related diseases

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