Report from 5th ATP1A3 Meeting London UK August 25-26th 2016
The Fifth Symposium on ATP1A3 in Disease was held in London UK August 25-26th 2016. The conference was very successful with lots of exciting results and sense of increasing teamwork and collegiality with groups throughout the world.
The opening talk on Day 1 was given by Dr. Brashear who provided a clinical review of typical and atypical ATP1A3-associated disorders. Presented brain MRI data from RDP patients, looking at cerebellum, basal ganglia, and thalamus volume along with performance during card sorting tasks. Dr. Sweadner then reviewed mouse models representing different genetic disorders of Na, K-ATPases with an emphasis on potential disease mechanisms. She also discussed the spectrum of known mutations in ATP1A2 and ATP1A3 with an emphasis on what can be learned by comparing the locations of these mutations between the two genes.
Drs. Doummar, Rosewich, Bhatia and Scharf reported on unique features of ATP1A3-associated diseases. ATP1A3 can cause an early onset epileptic encephalopathy without hemiplegic attacks. There are now 22 known cases of CAPOS syndrome and they all have the same ATP1A3 mutation (E818K). A potential new mechanism to explain optic atrophy in this disorder was discussed. A case with painful dyskinesia and dystonia was presented. Finally, there was evidence discussed that ATP1A3 can be the target of an autoimmune disorder in adults that is associated with cancer. Dr. Caski discussed cardiac involvement in AHC emphasizing his 2015 publication reporting ECG abnormalities.
A video review session was led by Dr. Mikati to seek consensus for describing movements and seizure manifestations of ATP1A3 disorders. There was specific discussion of spells of altered consciousness in AHC that are not accompanied by abnormal EEG findings. A comment about the similarity of clinical presentations to anti-NMDA encephalitis led to a stimulating discussion about testing ATP1A3 mutation-negative kids for anti-NMDA and anti-alpha3 antibodies. There was consensus to generate a video library for review by experts in the field.
Two presentations focused on different aspects of genetics related to AHC. Dr. van den Maagdenberg gave an informative update on the search for a possible second AHC gene. In ATP1A3 mutation negative patients, further sequencing identified a few patients with ATP1A3 mutations (false-negative initial sequencing). In other families, new gene variants were discovered but further validation is needed. Dr. Kearney reviewed related work in Dravet Syndrome using mouse models to discover genetic modifiers. A similar strategy using ATP1A3 mouse models is feasible to discover genetic pathways and disease modifying therapies.
Mouse models continue to provide novel information about ATP1A3-related disorders. Dr. Lykke-Hartmann provided an update on the ATP1A3 D801Y mouse model. She focused her presentation on abnormal gait and balance evident in the mice and the corresponding defects in cerebellar neuron function. Dr. Piggins presented data on the Myshkin mouse (mutation ATP1A3-I810N) focusing on circadian rhythms. These animals are hyperactive with poor circadian control and quicker adaptation to alterations in day-night changes (e.g., they “don’t have jet lag”). A discussion ensued about whether patients with AHC also have day/night issues. Dr. Clapcote discussed other published work on the Myshkin mouse.
Two presentations focused attention on other proteins that may interact with ATP1A3. Dr. Hoshi presented data that ATP1A3 interacts with amyloid beta protein and discussed possible involvement of the protein in Alzheimer’s disease. Dr. Melki presented other data reporting interactions between ATP1A3 and a protein (α-synuclein) involved in Parkinson disease.
There were presentations focusing on the structure and function of ATP1A3. Dr. Vilson reviewed structural and functional aspects of Na,K-ATPases focusing on perturbation to sodium ion binding. Dr. Koenderink discussed his research findings from work that was supported in part by AHCF. He illustrated different molecular mechanisms that stem from ATP1A3 mutations. There does not appear to be a clear correlation of pump function within phenotype or severity. Dr. George outlined AHCF funded work being done at Vanderbilt and Northwestern using patient-specific induced pluripotent stem cells made into neurons. Functional data on these neurons were presented.
The keynote presentation of Day 2 was given by Dr. Muntoni. He shared decades of experience of mechanistic discovery and therapeutic search in Duchenne Muscular Dystrophy. The difficult and often prolonged journey from gene discovery to effective therapy was stressed, as lessons learned may apply to ATP1A3 related disease manifestations.
Additional presentations discussed different treatment strategies. Dr. Fedosova discussed the binding of cardiotonic steroids to Na, K-ATPases and speculated that it may be feasible to develop ATP1A3-selective drugs. Dr. Cross discussed the use of a ketogenic diet in AHC. Dr. de Grandis reviewed studies on flunarizine and antiepileptic drugs for AHC. Several studies have been done but all had small numbers of subjects and suboptimal experimental designs. Finally, Dr. Roze reviewed his on-going clinical trial experience in AHC involving 10 patients. His clinical trial explores the use of the fatty acid analog triheptanoin based on a hypothesis of altered energy usage in the brain underlying AHC. Findings from this clinical trial may be revealed by the end of 2016.
The 6th Symposium on ATP1A3 in Disease will be held 21-22 September 2017 in Tachikawa City Tokyo, Japan. The Steering Committee for the 2017 meeting will consist of Drs. Ess, Mikati, Rosewich and Schyns, and Mr. Wuchich.