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Alternating hemiplegia of childhood: Retrospective genetic study and genotype-phenotype correlations in 187 subjects from the US AHCF registry

Viollet, L and Glusman, G and Murphy, KJ and Newcomb, TM and Reyna, SP and Sweney, M and Nelson, B and Andermann, F and Andermann, E and Acsadi, G and Barbano, RL and Brown, C and Brunkow, ME and Chugani, HT and Cheyette, SR and Collins, A and DeBrosse, SD and Galas, D and Friedman, J and Hood, L and Huff, C and Jorde, LB and King, MD and LaSalle, B and Leventer, RJ and Lewelt, AJ and Massart, MB and Mérida, MR and Ptáček, LJ and Roach, JC and Rust, RS and Renault, F and Sanger, TD and De Menezes, MAS and Tennyson, R and Uldall, P and Zhang, Y and Zupanc, M and Xin, W and Silver, K and Swoboda, KJ (2015) Alternating hemiplegia of childhood: Retrospective genetic study and genotype-phenotype correlations in 187 subjects from the US AHCF registry. PLoS ONE, 10 (5).

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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 clustered in exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K (26%) and 11 had G937R (8%) mutations. 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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Viollet, L
Glusman, G
Murphy, KJ
Newcomb, TM
Reyna, SP
Sweney, M
Nelson, B
Andermann, F
Andermann, E
Acsadi, G
Barbano, RL
Brown, C
Brunkow, ME
Chugani, HT
Cheyette, SR
Collins, A
DeBrosse, SD
Galas, D
Friedman, J
Hood, L
Huff, C
Jorde, LB
King, MD
LaSalle, B
Leventer, RJ
Lewelt, AJ
Massart, MBmbm66@pitt.eduMBM66
Mérida, MR
Ptáček, LJ
Roach, JC
Rust, RS
Renault, F
Sanger, TD
De Menezes, MAS
Tennyson, R
Uldall, P
Zhang, Y
Zupanc, M
Xin, W
Silver, K
Swoboda, KJ
ContributionContributors NameEmailPitt UsernameORCID
Date: 21 May 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 5
DOI or Unique Handle: 10.1371/journal.pone.0127045
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Family Medicine
Refereed: Yes
Date Deposited: 23 Aug 2016 14:18
Last Modified: 02 Apr 2021 22:55


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