Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.
Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genot...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4440742?pdf=render |
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| author | Louis Viollet Gustavo Glusman Kelley J Murphy Tara M Newcomb Sandra P Reyna Matthew Sweney Benjamin Nelson Frederick Andermann Eva Andermann Gyula Acsadi Richard L Barbano Candida Brown Mary E Brunkow Harry T Chugani Sarah R Cheyette Abigail Collins Suzanne D DeBrosse David Galas Jennifer Friedman Lee Hood Chad Huff Lynn B Jorde Mary D King Bernie LaSalle Richard J Leventer Aga J Lewelt Mylynda B Massart Mario R Mérida Louis J Ptáček Jared C Roach Robert S Rust Francis Renault Terry D Sanger Marcio A Sotero de Menezes Rachel Tennyson Peter Uldall Yue Zhang Mary Zupanc Winnie Xin Kenneth Silver Kathryn J Swoboda |
| author_facet | Louis Viollet Gustavo Glusman Kelley J Murphy Tara M Newcomb Sandra P Reyna Matthew Sweney Benjamin Nelson Frederick Andermann Eva Andermann Gyula Acsadi Richard L Barbano Candida Brown Mary E Brunkow Harry T Chugani Sarah R Cheyette Abigail Collins Suzanne D DeBrosse David Galas Jennifer Friedman Lee Hood Chad Huff Lynn B Jorde Mary D King Bernie LaSalle Richard J Leventer Aga J Lewelt Mylynda B Massart Mario R Mérida Louis J Ptáček Jared C Roach Robert S Rust Francis Renault Terry D Sanger Marcio A Sotero de Menezes Rachel Tennyson Peter Uldall Yue Zhang Mary Zupanc Winnie Xin Kenneth Silver Kathryn J Swoboda |
| author_sort | Louis Viollet |
| collection | DOAJ |
| description | Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies. |
| first_indexed | 2024-12-11T02:03:32Z |
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| id | doaj.art-e7147684d4fa49fb9e01318e1d1efef6 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T02:03:32Z |
| publishDate | 2015-01-01 |
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| spelling | doaj.art-e7147684d4fa49fb9e01318e1d1efef62022-12-22T01:24:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01105e012704510.1371/journal.pone.0127045Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.Louis ViolletGustavo GlusmanKelley J MurphyTara M NewcombSandra P ReynaMatthew SweneyBenjamin NelsonFrederick AndermannEva AndermannGyula AcsadiRichard L BarbanoCandida BrownMary E BrunkowHarry T ChuganiSarah R CheyetteAbigail CollinsSuzanne D DeBrosseDavid GalasJennifer FriedmanLee HoodChad HuffLynn B JordeMary D KingBernie LaSalleRichard J LeventerAga J LeweltMylynda B MassartMario R MéridaLouis J PtáčekJared C RoachRobert S RustFrancis RenaultTerry D SangerMarcio A Sotero de MenezesRachel TennysonPeter UldallYue ZhangMary ZupancWinnie XinKenneth SilverKathryn J SwobodaMutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.http://europepmc.org/articles/PMC4440742?pdf=render |
| spellingShingle | Louis Viollet Gustavo Glusman Kelley J Murphy Tara M Newcomb Sandra P Reyna Matthew Sweney Benjamin Nelson Frederick Andermann Eva Andermann Gyula Acsadi Richard L Barbano Candida Brown Mary E Brunkow Harry T Chugani Sarah R Cheyette Abigail Collins Suzanne D DeBrosse David Galas Jennifer Friedman Lee Hood Chad Huff Lynn B Jorde Mary D King Bernie LaSalle Richard J Leventer Aga J Lewelt Mylynda B Massart Mario R Mérida Louis J Ptáček Jared C Roach Robert S Rust Francis Renault Terry D Sanger Marcio A Sotero de Menezes Rachel Tennyson Peter Uldall Yue Zhang Mary Zupanc Winnie Xin Kenneth Silver Kathryn J Swoboda Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry. PLoS ONE |
| title | Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry. |
| title_full | Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry. |
| title_fullStr | Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry. |
| title_full_unstemmed | Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry. |
| title_short | Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry. |
| title_sort | alternating hemiplegia of childhood retrospective genetic study and genotype phenotype correlations in 187 subjects from the us ahcf registry |
| url | http://europepmc.org/articles/PMC4440742?pdf=render |
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