Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study

BACKGROUND Alternating hemiplegia of childhood (AHC) is a rare neurological disorder characterised by early-onset episodes of hemiplegia, dystonia, various paroxysmal symptoms, and developmental impairment. Almost all cases of AHC are sporadic but AHC concordance in monozygotic twins and dominant transmission in a family with a milder phenotype have been reported. Thus, we aimed to identify de-novo mutations associated with this disease. METHODS We recruited patients with clinically characterised AHC from paediatric neurology departments in Germany and with the aid of a parental support group between Sept, 2004, and May 18, 2012. We used whole-exome sequencing of three proband-parent trios to identify a disease-associated gene and then tested whether mutations in the gene were also present in the remaining patients and their healthy parents. We analysed genotypes and characterised their associations with the phenotypic spectrum of the disease. FINDINGS We studied 15 female and nine male patients with AHC who were aged 8-35 years. ATP1A3 emerged as the disease-associated gene in AHC. Whole-exome sequencing showed three heterozygous de-novo missense mutations. Sequencing of the 21 remaining affected individuals identified disease-associated mutations in ATP1A3 in all patients, including six de-novo missense mutations and one de-novo splice-site mutation. Because ATP1A3 is also the gene associated with rapid-onset dystonia-parkinsonism (DYT12, OMIM 128235) we compared the genotypes and phenotypes of patients with AHC in our cohort with those of patients with rapid-onset dystonia-parkinsonism reported in the scientific literature. We noted overlapping clinical features, such as abrupt onset of dystonic episodes often triggered by emotional stress, a rostrocaudal (face to arm to leg) gradient of involvement, and signs of brainstem dysfunction, as well as clearly differentiating clinical characteristics, such as episodic hemiplegia and quadriplegia. INTERPRETATION Mutation analysis of the ATP1A3 gene in patients who met clinical criteria for AHC allows for definite genetic diagnosis and sound genetic counselling. AHC and rapid-onset dystonia-parkinsonism are allelic diseases related to mutations in ATP1A3 and form a phenotypical continuum of a dystonic movement disorder. FUNDING Eva Luise and Horst Köhler Foundation for Humans with Rare Diseases.