Progress to Date in ATP1A3 Disease Research

Progress to Date in ATP1A3 Disease Research







Thanks to Erin Heinzen of Columbia for providing this summary:

In 2012, mutations in ATP1A3 were identified as the major cause of alternating hemiplegia of childhood (AHC), thereby expanding the phenotypic spectrum of this gene previously associated with rapid-onset dystonia-parkinsonism (RDP). Following this discovery, the research, clinical, and advocacy communities met in December 2012 in Brussels, Belgium for the inaugural International Symposium on ATP1A3 in disease (organized by Tsveta Schyns and David Goldstein). Researchers and patient advocacy leaderscollaborated to plan how to share information and cooperate to facilitate drug discovery and progress on the understanding of ATP1A3 disease pathophysiology across the globe.

Since that time the phenotypic spectrum of ATP1A3 mutations has expanded even further connecting disorders that would have never been linked based on clinical presentation alone, and significant progress has been made in advancing our understanding of these diseases. Since 2012, a yearly symposium has been held including a meeting in 2013 in Italy (organized by Fiorella Gurrieri and Giovanni Neri), and then in 2014 in the Netherlands (organized by Jan Koenderink and Thomas Friedrich). These meetings have served to drive research and facilitate collaborations in ATP1A3 diseases and have led to remarkable progress in the understanding of these very rare diseases. To continue this progress, the 4th Symposium of ATP1A3 in disease [organized by Erin Heinzen (Columbia University) and Jeff Wuchich (Cure AHC)] was held this year in Bethesda, Maryland, with the following objectives:

  • Recruiting new researchers into the collaborative group
  • Informing patient advocacy groups and clinicians to current knowledge of ATP1A3 diseases and what can be done now to help individual patients.
  • Laying groundwork for preparing for clinical trials in ATP1A3 diseases
  • Planning for a rapid expansion of work using differentiated induced pluripotent stem cells (iPSCs) from patients and from isogenic iPSCs genome-edited to have disease-causing ATP1A3 mutations to study the effects of the mutations in human neurons
  • Continuing the search for novel mutations in ATP1A3 and related genes in patients who are phenotypically similar to patients with ATP1A3 diseases yet no mutation has been found

The meeting was attended by 28 families with children affected by ATP1A3 diseases from 11 different countries (USA, The Netherlands, Canada, Iceland, Belgium, UK, Germany, Ireland, Italy, Spain, France). There were also over 50 clinicians and scientists from around the world, including USA, UK, France, Italy, Denmark, Australia, Japan, The Netherlands, and Germany.  Walter Koroshetz started the meeting with a talk on the benefits and future of rare disease research. This was followed by a sessions discussing the experiences with clinical trials in other rare diseases and what is needed to prepare for clinical trials in ATP1A3 diseases, a session on the expanding phenotypic spectrum of ATP1A3 mutations and gene discovery in ATP1A3 negative patients, and finally a session on the molecular characterization of ATP1A3 mutations that included a talk from Dr. Kevin Eggan, a leader in using iPSCs to study the effects mutations that give rise to neurological diseases in human neurons. In addition to these research-intensive sessions, Sigurður H. Jóhannesson and Agusta Fanney Snorradottir showed a moving documentary they directed on Alternating Hemiplegia of Childhood, including first hand accounts of living with this debilitating disease (

The group formulated several research recommendations to help guide efforts over the next year to lead up to the 5th Symposium of ATP1A3 in Disease in 2016 that will be held in London (organized by Helen Cross and Sanjay Sisodiya), including:

  1. To assemble a phenotypic standards for patients with ATP1A3 mutation diseases to prepare for future clinical trials and natural history studies
  2. To implement a plan to make readily available standardized iPSCs and uniform differentiation protocols to all interested researchers for the purpose of studying the effects of ATP1A3 mutations in neurons and other relevant cell types through the NIMH Stem Cell Center as part of the Rutgers RUCDR Infinite Biologics Core facilities. By providing standardizing the cells lines for researchers will ensure that all have access to cells to perform studies, and importantly, because all researchers will be using the same cells, results can be compared across labs to ensure reproducibility of relevant results.
  3. To engage in collaborative research projects with mouse models of ATP1A3 in disease, including treatment approaches and underlying physiology and molecular structure.
  4. This effort will be lead by several researchers and by CURE AHC and other family advocate groups worldwide.
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