Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Viollet Louis, Glusman Gustavo, Murphy Kelley J, Newcomb Tara M, Reyna Sandra P, Sweney Matthew, Nelson Benjamin, Andermann Frederick, Andermann Eva, Acsadi Gyula, Barbano Richard L, Brown Candida, Brunkow Mary E, Chugani Harry T, Cheyette Sarah R, Collins Abigail, DeBrosse Suzanne D, Galas David, Friedman Jennifer, Hood Lee, Huff Chad, Jorde Lynn B, King Mary D, LaSalle Bernie, Leventer Richard J, Lewelt Aga J, Massart Mylynda B, Mérida Mario R, Ptáček Louis J, Roach Jared C, Rust Robert S, Renault Francis, Sanger Terry D, Sotero de Menezes Marcio A, Tennyson Rachel, Uldall Peter, Zhang Yue, Zupanc Mary, Xin Winnie, Silver Kenneth, Swoboda Kathryn J
Аннотация
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.