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 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.

Fig 1. Schematic representation of ATP1A3 mutations.

Mutations identified in our cohort are indicated above the gene; all the mutations previously published are indicated in black; novel mutations are indicated in light blue; mutations identified in multiplex cases are underlined; mutations reported in DYT12 are indicated in green; the mutation reported in CAPOS syndrome is indicated in red. The mutation associated with a phenotype combining features of both AHC and RDP is in orange. The 2 most common mutations are in bold. Asterisks mean that 2 different nucleotide changes have been identified for these protein variants.

Fig 2. Ages at onset of AHC in each group of patients defined by their genotype.

The horizontal lines in the boxes indicate the 25th percentile (bottom), the median (middle) and the 75 percentile (top) values. Crosses indicate the mean values. Numbers of patients analyzed in each group are indicated above the boxes.

Fig 3. Ages at unsupported sitting acquisition in each group of patients defined by their genotype.

Cumulative probability of acquiring unsupported sitting by patients presenting the E815K mutation, compared to patientsmutation (3b). Patients with the E815K mutation are likely to gain unsupported sitting at a later age than patients in each of the other groups (respectively P = 0.0002 and P = 0.0020).

Fig 4. Ages at unaided walking acquisition in each group of patients defined by their genotype.

Cumulative probability of acquiring unaided walking by patients presenting the E815K mutation, compared to patients with all other ATP1A3 mutations (4a) and to patients with the D801N mutation (4b). Patients with the E815K mutation are likely to gain unaided walking at a later age than patients in each of the other groups (respectively P = 0.0264 and P = 0.0835).