Project start date: 01-Feb-2019 Project end date: 01-Feb-2022

Natural History in ATP1A3-related disease: a deep phenotyping - genotyping

Case Definitions:

Read/Download full APT1A3 protocol in Protocol Documents to the right of this page

To participate, please download the questionnaire in the Data Collection Document to the right of this page

Please return completed questionnaire per post below or email to

Dr Katerina Vezyroglou
UCL GOS Institute of Child Health
4th floor PUW30
Guilford Street


In recent years medical science has focused on the results of randomized clinical trials (RCTs) for advancing treatment standards. Observational studies, retrospective analysis or even phase II studies are afforded little weight in medical decision-making. This is clearly justified in common conditions, where large cohort studies are possible, but poses a problem in rare diseases where the sample size needed to conduct statistical analysis in a RCT is unrealistic. With rapid genetic discovery that makes promising novel treatments a realistic prospect, it is paramount that alternative strategies are developed to facilitate drug development in rare diseases. Natural history studies generate greater knowledge about the progress of these diseases, allowing the effects of novel treatments and their effects on disease progression, longevity and quality of life to be evaluated. Relying on observational studies does not automatically result in a compromise in the quality of the data; there are examples where a well-designed observational study has been able to provide information an underpowered RCT could not.

Background to proposal

Mutations in ATP1A3, the gene that encodes the Na+/K+-ATPase α3 subunit, have been identified as the cause of alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism (RDP), CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) and an increasing range of intermediate phenotypes. These rare conditions are on a spectrum of ATP1A3-related disease, and share common features. For example in both AHC and RDP, a strikingly asymmetric, predominantly dystonic movement disorder with a rostrocaudal gradient of involvement is observed, while all three phenotypes share physical, emotional, or chemical stressors as triggers. Even though case reports and small case series of distinct and intermediate ATP1A3 phenotypes are frequently published, larger cohort studies illuminating the anticipated course of the disease, ideally further divided into its genetic subpopulations, are lacking. The one natural history study that has been published including only AHC patients relied solely on questionnaires and the conclusion reached, that AHC is a non-progressive disease, seems to be disputed as further cases and phenotypes emerge. A more systematic approach is needed to better understand this complex phenotypic spectrum. Even though the genetic basis is clear, the pathophysiology of ATP1A3 diseases remains elusive and, consequently, no rational treatments are available. Multiple symptomatic therapeutic approaches have been trialed, but, except for flunarizine showing some benefit for hemiplegic episodes, results have been largely disappointing. Furthermore the role of flunarizine in changing the course of the disease, and especially the cognitive outcome, is still uncertain, not least because of the lack of available biomarkers marking disease progression. Such biomarkers, together with solid natural history data from a carefully phenotyped cohort, would be invaluable to assess efficacy of novel treatments that may start emerging soon.

Rationale for proposal

We propose a natural history study of ATP1A3-related disease combining retrospective (questionnaires; home videos) and prospective design. This will include deep phenotyping and genotyping, by utilizing traditional and novel methodology. We thus aim to:

    • Elucidate the natural history of the disease and its phenotypic and genetic subpopulations.
    • Better understand pathophysiology by utilizing novel investigations and identify potential biomarkers to monitor treatment efficacy and disease progression.
    • Provide the basis to support novel treatment options.

Study Design

We are planning an observational cohort study combining retrospective (questionnaires; home videos) and prospective design. This will include deep phenotyping and genotyping of included patients by utilizing traditional (detailed history taking, examination, EEG, MRI) and novel (broadband-NIRS, TMS, genomics) methodology.

Study setting/location

The children participating in the study will be seen at Great Ormond Street Hospital for Children, whilst the adult visits will take place at the National Hospital for Neurology and Neurosurgery or the affiliated Epilepsy Society. Patients that are treated in other centers throughout the UK and are not able to travel to London for participation in the study will partake in the study activities that can be administered remotely (questionnaires, home videos, clinical history, collection of clinical data). Study Population Between Great Ormond Street Hospital and the National Hospital for Neurology and Neurosurgery, we already have 30 patients with ATP1A3-related disease. We will utilize the British Paediatric Neurology and British Neurology Surveillance Units in collecting all further cases from around the UK: based on previous prevalence estimates we would expect to at least double our cohort to 60.

Investigators and Contact Details:

Lead Investigator

Professor J Helen Cross (1)
Tel 0207 905 2981 Email:

Co-Investigator: Dr Aikaterini Vezyroglou (1)
Co-Investigator: Professor Sanjay Sisodiya (2)
Co-Investigator: Dr Rachel Thornton (3)
Co-Investigator: Dr Ilias Tachtsidis (4)

    1. UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, UK.
    2. UCL, Institute of Neurology, Queen Square, London, UK
    3. Great Ormond Street Hospital for Children, Great Ormond Street, London, UK.
    4. UCL, Medical Physics and Biomedical Engineering, Malet Place Engineering Building Gower Street, London, UK.

Inclusion Criteria:
    • Children and adults of any age carrying a mutation in the ATP1A3-gene.
    • Children and adults of any age matching an ATP1A3-related disease phenotype without a mutation in the gene.
    • Written informed consent given by patient and/or parent/guardian.

Exclusion Criteria:
    • Patients with a phenotype not fitting ATP1A3-related disease and no mutation in the ATP1A3 gene.

Additional Information: