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

Abstract

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.

Progressive Brain Atrophy in Alternating Hemiplegia of Childhood

“…The precise cause of these clinical variabilities in AHC is not yet known except for partial correlations between the genotype and phenotype as reported by several groups. [14][15][16][17] We found progressive localized brain atrophy in some patients, particularly where severe deterioration was evident. 18,19 We investigated Japanese patients with AHC to assess if they had structural brain abnormalities and to determine the critical brain structural differences between a group with irreversible severe deterioration and one without severe deterioration.…”

“…However, the relationship between the clinical course and changes in brain MRI findings has not yet been established in patients with AHC. The precise cause of these clinical variabilities in AHC is not yet known except for partial correlations between the genotype and phenotype as reported by several groups …”

Neuronal Modeling of Alternating Hemiplegia of Childhood Reveals Transcriptional Compensation and Replicates a Trigger-Induced Phenotype

“…While these syndromes share symptomatic profiles including triggered episodes, a strong genotype-to-phenotype correlation exists within this spectrum. In fact, 60% of patients worldwide diagnosed clinically as AHC have one of three unique ATP1A3 missense mutations, leading to amino acid changes D801N, E815K, or G947R (Heinzen et al, 2012;Viollet et al, 2015). Only symptomatic treatment options exist for patients diagnosed with AHC, including benzodiazepines and other antiepileptic drugs.…”

Paroxysmal Asymmetric Dystonic Arm Posturing—A Less Recognized but Characteristic Manifestation of ATP1A3‐related disease

“…Subsequently, a series of publications have suggested that ATP1A3 mutations are associated with a wide clinical spectrum, and that they are one of the “commoner rare diseases” . A diagnosis of ATP1A3 ‐related disease has specific management implications, including avoidance of triggers and pharmacological prophylaxis of attacks .…”

“…2,3 Subsequently, a series of publications have suggested that ATP1A3 mutations are associated with a wide clinical spectrum, and that they are one of the "commoner rare diseases". [4][5][6] A diagnosis of ATP1A3-related disease has specific management implications, including avoidance of triggers and pharmacological prophylaxis of attacks. 7 Routine blood tests and brain MRI are typically normal; hence, recognition of the disorder on clinical grounds is of utmost importance.…”