Report by dr. Al Georg
The Third Symposium on ATP1A3 in Disease was held August 29-30, 2014 in Lunteren, The
Netherlands. The meeting was held jointly with the first day of the 14th International Conference
on Na/K ATPase. This joint arrangement was designed to stimulate discussions between
clinicians, geneticists and scientists working on these genes and related disorders. During the
two-day conference, there was clear evidence of intermingling of researchers who are experts in
the more basic scientific aspects of ATP1A3 with others more focused on AHC and related
diseases. Overall, the conference was deemed highly successful.
Progress has been made in several important areas including advances in recognizing an
expanded range of clinical disorders associated with ATP1A3 mutations, development and
characterization of various mouse models of AHC, continued progress toward understanding
the basic molecular defect underlying AHC and RDP, and preliminary work toward identifying
The evening before the conference, a group dinner followed by a short program allowed parents
and researchers to exchange ideas. There was brief discussion about the potential value of
medicinal marijuana or cannabidiols in treating AHC, an idea stimulated by current trends in
epilepsy therapy. Additional topics receiving attention were the need for more research into
behavioral aspects of AHC, the basis for relief of symptoms by sleep and the need to
understand the mechanisms of triggers. The program ended with the showing of videos
produced by the AHC International Alliance to raise awareness about this condition.
Progress in defining the clinical spectrum of ATP1A3 disease
New clinical subsets of ATP1A3 were revealed at the conference. The disorder called CAPOS
has been diagnosed in several families. All families have the same ATP1A3 mutation. Unlike
AHC and RDP in which most mutations are de novo, this mutation can be transmitted within
families. Although CAPOS was described as a distinct entity, there is also evidence of clinical
overlap with AHC and RDP.
There may be other clinical entities associated with ATP1A3 mutations Three cases were
presented with a wide range of neurological symptoms that had been brought to the researchers
attention because of incidental discovery of ATP1A3 mutations. These new cases suggest a
wider clinical spectrum of ATP1A3-associated disease.
One presenter discussed the possible occurrence of abnormal electrical activity in hearts of
AHC patients. An extensive study of electrocardiographs (ECG) revealed some consistent
abnormalities among patients, although the clinical significance of these findings is unclear.
There are now more than 70 known ATP1A3 mutations and a suggestion to build a web site to
collect information about these findings was embraced by the group. There remains a small
subset of AHC and RDP patients in whom no ATP1A3 mutation has been found and there are
efforts to look for a second AHC gene in these families.
Progress in understanding the molecular defect
Several groups have employed various cellular models to understand the basic molecular
defects caused by ATP1A3 mutations. The emerging consensus appears to be that mutations
associated with AHC and RDP are predominantly loss-of-function. Additionally, there may be
some properties of the ATP1A3 pump protein that are preserved in some cases and this fueled
speculation of mechanisms responsible for greater clinical severity of certain mutations such as
E815K. There have been preliminary efforts to identify drugs that can restore ATP1A3 function.
Progress with mouse models
Exciting work was presented at the conference related to the development and characterization
of mouse models of AHC. Three different groups are working on various studies involving
mouse models and hopefully will have more to report in the future.
Progress in working as a team
Throughout the conference, there was a consistent emphasis by presenters and participants to
work together as much as possible. These efforts included developing consensus guidelines for
genetic testing and clinical management, and defining measurable indices of symptoms and
clinical outcomes. Dr. Rosewich informed the group about the effort started at the AHCF Family
Conference held in June 2014 to write a consensus paper about AHC and RDP management
then invited the rest of the research community to contribute. There was a spirited discussion
about fund raising strategies but no specific recommendations were made.
Planning is underway for the 4th Symposium on ATP1A3 in Disease to be held in Bethesda the
last week of August 2015. A small grant has been submitted to the NIH to help fund the
Dr Al George