Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations
Alessandro Capuano,1 Giacomo Garone,1,2 Giuseppe Tiralongo,1 Federica Graziola1 1Movement Disorders Clinic, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy; 2University Hospital Pediatric Department, IRCCS Bambino Ges&u...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2020-03-01
|
| Series: | The Application of Clinical Genetics |
| Subjects: | |
| Online Access: | https://www.dovepress.com/alternating-hemiplegia-of-childhood-understanding-the-genotypendashphe-peer-reviewed-article-TACG |
| _version_ | 1818150508429312000 |
|---|---|
| author | Capuano A Garone G Tiralongo G Graziola F |
| author_facet | Capuano A Garone G Tiralongo G Graziola F |
| author_sort | Capuano A |
| collection | DOAJ |
| description | Alessandro Capuano,1 Giacomo Garone,1,2 Giuseppe Tiralongo,1 Federica Graziola1 1Movement Disorders Clinic, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy; 2University Hospital Pediatric Department, IRCCS Bambino Gesù Children’s Hospital, University of Rome Tor Vergata, Rome, ItalyCorrespondence: Alessandro CapuanoMovement Disorders Clinic, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children’s Hospital, Viale Di San Paolo, Rome 15 – 00153, ItalyTel +39 066 859 4092Email alessandro.capuano@opbg.netAbstract: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder affecting children with an onset before 18 months. Diagnostic clues include transient episodes of hemiplegia alternating in the laterality or quadriparesis, nystagmus and other paroxysmal attacks as tonic and dystonic spells. Epilepsy is also a common feature. In the past, a great effort has been done to understand the genetic basis of the disease leading to the discovery of mutations in the ATP1A3 gene encoding for the alpha3 subunit of Na+/K+ATPase, a protein already related to another disease named Rapid Onset Dystonia Parkinsonism (RDP). ATP1A3 mutations account for more than 70% of cases of AHC. In particular, three hotspot mutations account for about 60% of all cases, and these data have been confirmed in large population studies. Specifically, the p.Asp801Asn variant has been found to cause 30– 43% of all cases, p.Glu815Lys is responsible for 16– 35% of cases and p.Gly947Arg accounts for 8– 15%. These three mutations are associated with different clinical phenotype in terms of symptoms, severity and prognosis. In vitro and in vivo models reveal that a crucial role of Na+/K+ATPase pump activity emerges in maintaining a correct membrane potential, survival and homeostasis of neurons. Herein, we attempt to summarize all clinical, genetic and molecular aspects of AHC considering ATP1A3 as its primary disease-causing determinant.Keywords: ATP1A3, Na+/K+ATPase, AHC, genetics, animal models
|
| first_indexed | 2024-12-11T13:24:03Z |
| format | Article |
| id | doaj.art-5e0fe139d6d94516bb71c29d4ed582db |
| institution | Directory Open Access Journal |
| issn | 1178-704X |
| language | English |
| last_indexed | 2024-12-11T13:24:03Z |
| publishDate | 2020-03-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | The Application of Clinical Genetics |
| spelling | doaj.art-5e0fe139d6d94516bb71c29d4ed582db2022-12-22T01:05:39ZengDove Medical PressThe Application of Clinical Genetics1178-704X2020-03-01Volume 13718152811Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 VariationsCapuano AGarone GTiralongo GGraziola FAlessandro Capuano,1 Giacomo Garone,1,2 Giuseppe Tiralongo,1 Federica Graziola1 1Movement Disorders Clinic, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy; 2University Hospital Pediatric Department, IRCCS Bambino Gesù Children’s Hospital, University of Rome Tor Vergata, Rome, ItalyCorrespondence: Alessandro CapuanoMovement Disorders Clinic, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children’s Hospital, Viale Di San Paolo, Rome 15 – 00153, ItalyTel +39 066 859 4092Email alessandro.capuano@opbg.netAbstract: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder affecting children with an onset before 18 months. Diagnostic clues include transient episodes of hemiplegia alternating in the laterality or quadriparesis, nystagmus and other paroxysmal attacks as tonic and dystonic spells. Epilepsy is also a common feature. In the past, a great effort has been done to understand the genetic basis of the disease leading to the discovery of mutations in the ATP1A3 gene encoding for the alpha3 subunit of Na+/K+ATPase, a protein already related to another disease named Rapid Onset Dystonia Parkinsonism (RDP). ATP1A3 mutations account for more than 70% of cases of AHC. In particular, three hotspot mutations account for about 60% of all cases, and these data have been confirmed in large population studies. Specifically, the p.Asp801Asn variant has been found to cause 30– 43% of all cases, p.Glu815Lys is responsible for 16– 35% of cases and p.Gly947Arg accounts for 8– 15%. These three mutations are associated with different clinical phenotype in terms of symptoms, severity and prognosis. In vitro and in vivo models reveal that a crucial role of Na+/K+ATPase pump activity emerges in maintaining a correct membrane potential, survival and homeostasis of neurons. Herein, we attempt to summarize all clinical, genetic and molecular aspects of AHC considering ATP1A3 as its primary disease-causing determinant.Keywords: ATP1A3, Na+/K+ATPase, AHC, genetics, animal models https://www.dovepress.com/alternating-hemiplegia-of-childhood-understanding-the-genotypendashphe-peer-reviewed-article-TACGatp1a3na+/k+atpaseahcgeneticsanimal models |
| spellingShingle | Capuano A Garone G Tiralongo G Graziola F Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations The Application of Clinical Genetics atp1a3 na+/k+atpase ahc genetics animal models |
| title | Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations |
| title_full | Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations |
| title_fullStr | Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations |
| title_full_unstemmed | Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations |
| title_short | Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations |
| title_sort | alternating hemiplegia of childhood understanding the genotype ndash phenotype relationship of atp1a3 variations |
| topic | atp1a3 na+/k+atpase ahc genetics animal models |
| url | https://www.dovepress.com/alternating-hemiplegia-of-childhood-understanding-the-genotypendashphe-peer-reviewed-article-TACG |
| work_keys_str_mv | AT capuanoa alternatinghemiplegiaofchildhoodunderstandingthegenotypendashphenotyperelationshipofatp1a3variations AT garoneg alternatinghemiplegiaofchildhoodunderstandingthegenotypendashphenotyperelationshipofatp1a3variations AT tiralongog alternatinghemiplegiaofchildhoodunderstandingthegenotypendashphenotyperelationshipofatp1a3variations AT graziolaf alternatinghemiplegiaofchildhoodunderstandingthegenotypendashphenotyperelationshipofatp1a3variations |