Alfred George, Jr., M.D.
The 6th ATP1A3 Meeting took place in Tokyo, Japan on September 21 and 22.
The conference was the most well-attended of all ATP1A3 conferences in 2017 with 190 attendees comprised mostly of physicians, trainees and researchers from Japan who are new to the field. The host, Dr Masayuki Sasaki
of the National Center of Neurology and Psychiatry, received a standing ovation at the conclusion of the meeting for his outstanding hospitality and organization. Highlights of the meeting are summarized in this report; because many researchers presented unpublished results, only the general nature of some presentations can be reported.
The opening talk on Day 1 was given by Dr Sasaki
who presented the history of major milestones in the field including the original clinical description of AHC, discovery of the gene and the expanding spectrum of neurological disorders associated with ATP1A3. Following the overview, Dr Hendrik Rosewich
of the Georg August Medical University in Göttingen, Germany discussed specific challenges and dilemmas associated with diagnosing AHC and related disorders. He emphasized the diagnostic framework presented in the 2017 Neurology Genetics
paper from the AHCF-sponsored workshop, which called for standardized definitions of neurological features of ATP1A3-related disorders. Next, Dr Allison Brashear
of the Wake Forest University School of Medicine, provided an update on clinical studies on RDP including preliminary findings from an ongoing NIH-funded study of brain imaging. These studies are seeking to identify and validate diagnostic features of RDP that can be acquired by MRI and other imaging tools available in the clinic. Additional presentations by Drs Yasunari Sakai
(Kyusu University, Japan) and Naoko Ishihara
(Fujita Health University, Japan) described cases with atypical clinical presentations including that of an infant with catastrophic epilepsy in which ATP1A3 mutations have been discovered.
Two presenters discussed progress in analyzing data from large patient registries. Dr Elena Panaiotakaki
from University Hospitals of Lyon in France reported on the International AHC Consortium, which has so far enrolled 155 subjects. She discussed findings on clinical features of patients with the most common mutations, some natural history and clinical outcome data, and further evidence supporting the association of the E815K mutation with generally more severe features. Dr Kathryn Swoboda
from Massachusetts General Hospital updated the conference on her efforts to curate the AHCF registry comprised of approximately 300 subjects and more than 1000 biospecimens gathered mostly from North and South America. She further described her current collaborations with investigators at the Broad Institute at MIT to examine gene expression in blood samples, which they hope will uncover novel biomarkers of the disease. Throughout the conference, there were discussions of the importance of finding biomarkers to augment efforts to evaluate treatment success and follow the progress of the disease. Dr Balestrini
reported a follow-up of their study showing evidence of abnormal heart activity (e.g., abnormal electrocardiographs) in AHC. They now have 116 patients enrolled in the study (96 AHC cases).
Dr Kathleen Sweadner
of Massachusetts General Hospital presented an advanced analysis of the location of mutations within the ATP1A3 protein structure and contrasted this with ATP1A2 mutations. There were general correlations between the location of mutations within the protein and the clinical severity of the disease. She shared an in-depth analysis of mutations that were localized to a specific protein region called the P-domain, which has essential functions. Later in the conference, Dr Sweadner offered caution about the naming of ATP1A3 mutations and emphasized the importance of using a specific reference sequence of the gene to allow so that mutations are designated consistently. Unfortunately, as she pointed out, some genetic testing laboratories and population genetic resources (e.g., the Exome Aggregation Consortium or ExAC) use a different reference sequence. Dr Arn van den Maagdenberg of Radbound University
in the Netherlands gave an update on efforts to find additional AHC genes to help explain why 15-20% of AHC cases do not have obvious ATP1A3 mutations. Their efforts have revealed that some ATP1A3-negative cases, in fact, do have mutations in this gene revealed upon futher analysis. He reviewed evidence supporting involvement of at least two other genes but cautioned about the need to verify the diagnosis in these cases.
Dr Atsushi Ishii
from Fukuoka University reported on the apparent effects of oral ATP therapy in flunarizine-refractory AHC, which was published previously. The specific case was that of a Chinese boy with onset of hemiplegic attacks after age 2 years who was treated with escalating doses of an over-the-counter preparation of ATP. The clinical response to the therapy was notable for reduced attack frequency, improved motor function and improved performance in school. There was no pharmacological data provided on the treatment leaving many in the audience uncertain about the rationale and mechanism for using ATP in AHC. Drs Rosewich and Mohamad Mikati
of Duke University commented that attempts to treat patients in their clinics with ATP had not been effective although admittedly the doses tried were lower than that used in the Chinese boy. There were many unanswered questions leaving most attendees with the sense that more fundamental knowledge is needed before recommending this therapy.
The conference transitioned from clinical and genetic themes toward a more basic science emphasis including 3 lectures highlighting ground breaking research on neurological diseases being performed in Japan given by Drs Hideyuki Okano
(Keio University), Minako Hoshi
(Kyoto University) and Noriyuki Matsuda
(Tokyo Metropolitan Institute of Neuroscience. A very special lecture on the structure of ion transporting ATPases was given by Dr Chikashi Toyoshima
of Tokyo University.
The second day of the conference included talks on mouse models, cellular models, structural and functional investigations. Three groups reported on their progress in modeling AHC in mice with a focus on testing various strategies to alleviate major neurological features. Dr Steven Clapcoate
of Leeds University in the UK
summarized his group’s efforts to exploit three independent strategies including a genetic strategy, an ATP1A3 modulator (rosafuroxin) and a proprietary diet. Dr Karin Lykke-Hartmann
from Aarhus University, Denmark, reported on neurophysiological studies of the D801Y mouse model and showed previous data demonstrating the ability of flunarizine to attenuate cold-water induced hemiplegic and dystonic attacks in the mice. Dr Mikati
of Duke University showed new data on the effectives of flunarizine and an undisclosed investigational compound on mice with the E815K mutation. Flunarizine was effective at shortening the duration of hemiplegic attacks but didn’t prevent seizures or long term behavioral deficits. He commented that these mice are extremely fragile and have a high mortality rate thus limiting the extent to which pharmacological studies can be performed.
Three groups presented their findings on the functional properties of various ATP1A3 mutations. Dr Steven Petrou
of the University of Melbourne in Australia demonstrated unique functional features of the E818K mutation associated with CAPOS syndrome and presented detailed information about the mechanism for the dysfunction of this and other mutations. Dr Jan Koenderink
(Nijmegen, The Netherlands) discussed his findings on ATPase activity of several mutations and offered to study the function of all known ATP1A3 mutations provided that research funding were available. The last presentations of the conference were by Drs Kevin Ess
of Vanderbilt University and Alfred George, Jr.
of Northwestern University who reported their findings using patient-derived induced pluripotent stem cells (iPSCs) to create nerve cells for laboratory investigation of AHC. They presented their data showing successful use of this ‘disease in a dish’ approach to determine fundamental cellular dysfunction of the G947R mutation as well as a novel mutation causing abnormal gene splicing.
A special evening event was hosted by the Japanese AHC Foundation and featured presentations by representatives of CURE-AHC and the French AHC foundation. Several Japanese families were present as well as parents from many other countries. An emphasis was made on the important role of family organizations in raising awareness of the disease in communities, and raising funds to support research. Much of the research presented at this conference has been made possible by generous donations of these and other foundations.
Symposium on ATP1A3 in Disease will be held in October 2018 in Chicago. The AHCF will serve as the host organization.