Natural History of ATP1A3-related Disease: a Deep Phenotyping-genotyping Project

Alternating hemiplegia of childhood (AHC) is a rare very disabling neurodevelopmental syndrome caused by mutations in the gene ATP1A3. AHC is characterized by paroxysmal events including attacks of hemiplegia (weakness), dystonia (painful stiffening), oculomotor abnormalities and epileptic seizures. As the condition progresses permanent neurological symptoms, including unsteadiness and learning problems, emerge. Mutations in ATP1A3 also cause other related syndromes: rapid-onset dystonia-parkinsonism (RDP), less severe and usually presenting in adulthood, as well as cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome, a severe syndrome of early childhood.

Currently therapeutic options are very limited aiming at symptomatic relief with limited success. As ATP1A3-related syndromes are very rare diseases, with an estimated prevalence of about 1/1000000, randomised clinical trials of available therapies are not possible due to lack of a large enough patient cohort. However, the revolution in genetic diagnostics has made the identification of these patients and the correlation between their phenotypes possible. At the same time further novel technologies in neuromonitoring and neuroimaging, as well as videography and sleep monitoring have become available that could help us further examine and understand the underlying mechanisms especially of the paroxysmal episodes that characterise all ATP1A3-related syndromes. The investigators believe that based on these scientific advances they will be able to recruit a UK-wide patient cohort to conduct an in depth study of the progression of this disease.

This is particularly relevant at the moment as rapid progress in genetic therapies and other novel therapeutics makes the availability of new treatment options in the near future a realistic prospect and, even though we will most probably still not be able to identify a large enough cohort for randomised clinical trials, our natural history study will act as a much needed benchmark to which the success of novel treatments can be evaluated.