IAHCRC Public Communication N. 3/2023 - 2023.10.06

Fall 2023 Update

Dear all,
I hope that you and your families are always doing well.

Together with the IAHCRC Scientific Coordinators, Prof. Mohamad Mikati and Dr. Eleni Panagiotakaki, I am pleased to send you here below a brief update about the activities of the IAHCRC Consortium in this first part of the year. 

In spite of the chronic lack of funds for its internal activities and its services to the members, the Consortium is proving more and more effective in developing the collaborative international research on AHC and all ATP1A3-related diseases.

Do not hesitate to contact us for further details and for possible collaborations.

Thank you very much for your kind attention and best regards.


Dr. Eng. Rosaria Vavassori
IAHCRC-CLOUD Project Coordinator and IAHCRC Data Manager
The IAHCRC-CLOUD Platform is a Project of
I.E.ME.S.T Institute of Science and Technology
Website www.iemest.eu
IAHCRC International Consortium
research and care for the ATP1A3 diseases
Website www.iahcrc.net

Patient Advocate for the European Reference Network 
EpiCARE-ERN for Rare and Complex Epilepsies
Website www.epi-care.eu

IAHCRC Studies
"... A study which has been proposed by a member and approved by the Assembly, has been designed in compliance with the IAHCRC Questionnaires and according to the IAHCRC protocols, and is using the internal resources and services of the Consortium,  is considered a Study of the IAHCRC Consortium.
The member that proposed the Study is its Coordinator...."
(from the IAHCRC Charter)

Since its creation in 2014, many multicentric studies have been carried out and are currently in progress within the collaborative framework of the IAHCRC Consortium, proposed and led by its member centers.

Most of these studies take advantage of the data collection and sharing service offered by the IAHCRC-CLOUD Platform, a project carried out by the I.E.ME.S.T. Institute (Palermo, Italy) and coordinated by the IAHCRC Data Manager. 

We heartily thank all those that are supporting the IAHCRC Studies and in particular the AHC patient associations, in Europe and in the USA, for their financial and logistical contributions.

This overview describes the past IAHCRC Studies, already published on scientific journals, and the ongoing Studies at different stages of their timelines. 

The Studies and Projects of the IAHCRC Consortium
this overview is available in pdf on the IAHCRC official website at this link 
(Scientific Coordinator Prof. Mikati, Duke University, USA)
The three years data collection by the nine participating centers, in the US, Spain, France, UK and Italy has been closed on March 2023, with 110+ patients included. 

Data analysis is in progress, by the Statistics Team of the Duke University, whose preliminary results will be presented at the next "ATP1A3 in Disease" Symposium (Chicago, October 2023).

In the meanwhile, most sub-studies, each of them specifically aimed to one of the many and complex OBSERV-AHC objectives, have already been published or submitted for publication.
  • The results of the COURSE-AHC Study, the pilot phase of the OBSERV-AHC Study aimed to determine the potential predictors for long-term outcome, have been published in BRAIN Communications, June 2021.
  • The sub-project Event Calendar and  E-Diary has been published in the European Journal of Pediatric Neurology, August 2023.
  • The article about the OBSERV-AHC methodology, describing the procedures developed for multicenter prospective data collections that could be used in future controlled trials, has been published on the Journal of Child Neurology, September 2023.
  • The CBD-AHC Study led by Prof. Mohamad Mikati (Duke University, Durham, NC, USA) as an OBSERV-AHC sub-study, aims to determine the efficacy of CBD in AHC. Its preliminary results have been submitted for publication. The Study, carried out in a small coohort of patients from the USA and France, is a pilot study precursor to a large-scale prospective study within the IAHCRC Consortium.
  • The KETO-AHC Study aimed to determine the efficacy of ketogenic diet in AHC, has just been launched as a IAHCRC Study, coordinated by Dr. Carmen Fons and Dr. Jennifer Anticona, at the San Juan de Deu Hospital, in Barcelona, Spain.
The last workgroup meeting for the closing of data collection and the start of data analysis took place online last June 2023.
(a sub-project of the OBSERV-AHC Study)
The COURSE-AHC Study led by Prof. Mohamad Mikati (Duke University, Durham, NC, USA) as an OBSERV-AHC  sub-study, aimed to investigate the disease progression and to determine potential early-life clinical predictors .

The clinical findings of this study, published in BRAIN Communications, June 2021,  provide a basis for counseling patients and for designing therapeutic trials.
Animal findings confirm a mouse model for investigation of underlying mechanisms of disease progression, and are also consistent with known mechanisms of ATP1A3-related neurodegeneration.

The full text of the article published in BRAIN Communications can be downloaded as pdf from this link
Event Calendar App and Caretaker Training for Spells Identification
(a sub-project of the OBSERV-AHC Study)
An article has been published on the European Journal of Pediatric Neurology, August 2023, about the development and testing of Methods to Record and Follow up Spells in Patients with Alternating Hemiplegia of Childhood (OBSERV-AHC Sub-Project "Event Calendar and E-Diary").

The methods include the use of an app by the caretakers to record their patients' episodes on the IAHCRC-CLOUD Platform and a survey, also implemented on the Platform, to train the caretakers to identify the episodes to record correctly. 

The training procedure uses the videos uploaded by the patients in the Videolibrary hosted on the Platform, classified by 5 AHC experts of the IAHCRC Standardization Workgroups.

As we read in the Conclusions of the article, "Video-library training improved spell identification. Calendar with weekly reviews resulted in a sustained and consistent record keeping. Caregivers’ e-Diary feedback was encouraging with long-term usage in many. These approaches could be helpful for AHC and, potentially, in similar disorders."


The article and its supplemental material are available at this link
An article has been published on the Journal of Child Neurology, September 2023, titled "Methodology of a Natural History Study of a Rare Neurodevelopmental Disorder: Alternating Hemiplegia of Childhood as a Prototype Disease".

The article describes the process of development of the methodology for the OBSERV-AHC Study, an international multicenter natural history study of alternating hemiplegia of childhood as a prototype disease for rare neurodevelopmental disorders.
The relevant questions about alternating hemiplegia of childhood natural history and expected challenges were first identified.
Then solutions were defined to address these questions.

Specifically, these solutions included development and standardization of alternating hemiplegia of childhood–specific spell video-library, spell calendars, adoption of tailored methodologies for prospective measurement of nonparoxysmal and paroxysmal manifestations, unified data collection protocols, centralized data platform, adoption of specialized analysis methods including, among others, Cohen kappa, interclass correlation coefficient, linear mixed effects models, principal component, propensity score, and ambidirectional analyses. 
You can read the synopsys of the article written by the first author, Dr. Shital Patel (Duke University, USA) at this link.
The article about the OBSERV-AHC Methodology is available at this link
(Scientific Coordinators Dr. Carmen Fons and Dr. Jennifer Anticona, Hospital San Juan de Deu, Barcelona, Spain)
The KETO-AHC Study focuses on efficacy of Ketogenic Diet (KD) in AHC patients, by further pursuing  one of the objectives of the OBSERV-AHC Study. 
Based on the potential mechanisms of action of this therapeutic option, in fact, the Scientific Coordinators hypothesize that in AHC, KD could have impact in several pathways: (i) the effect on transient glucose hypometabolism in AHC, (ii) reduction in glycolytic ATP production might enable the opening of K+ATP channels and thus could reduce the electrical excitability of central neurons.

The main objective of the Study is to evaluate efficacy of the KD in a cohort of patients with AHC. Secondary objectives are to describe the characteristics of patients with a positive effect to the KD, to analyze the changes of  the disability indexes after KD implementation, to describe other effects observed in the patients with KD (cognitive, behaviour, etc)

The center recruitment phase  will be closed at the end of October 2023
All centers worldwide are invited to participate. The IAHCRC membership is not mandatory for participation.
Retrospective and prospective data about the use of ketogenic diet are collected in the KETO-AHC Study Database on the IAHCRC-CLOUD Platform.
Deadline for data collection is set to the end of December 2023.

The Study presentation is available at this link.
Interested centers should contact Dr. Jennifer Anticona asap, at this This email address is being protected from spambots. You need JavaScript enabled to view it.   

Centers interested to participate in the KETO-AHC Study, also non-IAHCRC, should contact the Scientific Coordinators asap at this This email address is being protected from spambots. You need JavaScript enabled to view it.    

Scientific Coordinator Dr. Simona Balestrini (National Institute of Neurology and Neurosurgery, University College of London, UK)

This qualitative and quantitative EEG study of sleep is aimed to further understand the mechanisms of benefit of sleep in AHC, and of the sleep disorder in AHC and its association with epilepsy, by further analyzing sleep disruption, assessing EEG changes associated with epileptic and other non-epileptic paroxysmal spells, and searching for EEG biomarkers of disease severity and outcome.

Data collection in the IAHCRC-CLOUD Platform has been completed with the inclusion of 80+ patients from more than 12 centers, in America, Europe and Australia. Analysis of the collected data is in progress.
Scientific Coordinator: Dr. Katharina Vezyroglou, Great Ormond Street Children Hospital, University College of London, UK

The aim of this study is to establish the actual width of the ATP1A3-related disease spectrum and whether genotype/phenotype correlation exists for the rarer ATP1A3 variants.
If successful, this study will help doctors and researchers give families a more accurate prognosis early on and support patients with appropriate therapies.
The knowledge gained by this study might be helpful to diagnose patients with atypical AHC earlier.

Data collection in the IAHCRC-CLOUD Platform is going to be closed soon, with 60+ patients included from 15 centers. Analysis of the collected data will start by the end of the year.

QTc-AHC Study
Scientific Coordinator: Dr. Andrew Landstrom, Duke University, Durham NC, USA

This quantitative study uses electrocardiogram (ECG) data to further understand the impact of AHC genotype in relation to cardiac repolarization, specifically the resetting electrical activity of the heart after a heartbeat.
The goal of this new project is to expand upon and validate the previous findings about differences in the electrical activity of the hearts of patients with different variations in the ATP1A3 gene, by including other centers worldwide and increasing the power to detect an association between AHC genotype and cardiac phenotype.

Patients' data collection in the QTc-AHC Study Database on the IAHCRC-CLOUD Platform has been closed at the end of 2021, with more than 150 patients included. Its results has been presented  at the Congress of the American Heart Association in November 2022 and are currently in pubblication.

GEN2-AHC Study (AHC2 Hunt)
Scientific Coordinators: Arn van den Maagdenberg (Leiden University, Holland) and Erin Heinzen (Columbia University, USA)

In this study, the DNA's of ATP1A3-negative patients are sequenced with the hope to identify the genetic cause of AHC in them.
Identifying these mutations will not only allow the families of ATP1A3-negative patients to better understand why their child is suffering from the disease, but it will also teach how AHC is brought about. The identification of new mechanisms, beside sodium potassium pumps that are affected by ATP1A3 mutations, will give new opportunities to identify treatments for children with AHC.

30 exomes have been sequenced so far and some significant variants have been identified. An article with the results has just been approved for publication by the European Journal of Human Genetics.

(Scientific Coordinator Dr. Danilo Tiziano, Università Cattolica, Rome, Italy)
The TREAT-AHC Study is carried out by member centers of the IAHCRC Consortium, both clinical and genetic, after being approved for funding at the 2019 edition of La Marató de TV3, in Spain.
Beside the contribution of La Marató, this study has been mainly funded since 2013, when its first phase of creation of the in-vitro model started, by the Italian association AISEA, also with the support of the Spanish association AESHA.

Dr. Tiziano reports that the study is now ready for the clinical phase: the first molecule will enter phase I study upon finalizing the agreement with the potential industrial partner identified.
This compound has been proved effective in reducing significantly frequency and duration of epileptic and dystonic crises in mutated mice. This part of the study has been performed in collaboration with Professor Mohamad Mikati at Duke University, Durham, NC USA. Several compounds have been proven effective in vitro, on the cellular model of AHC developed at the CAtholic University in Rome.

In parallel to the lab activities, an AHC specific scale for clinicians has been designed by the experts of three main clinical reference centers, in Italy (G. Gaslini Institute, Genoa), France (University Hospitals of Lyon) and Spain (Hospital San Juan de Deu, Barcelona), and revised by other 2 experts in movement disorders.
Besides of being of key relevance in the evaluation of the efficacy of candidate compounds during forthcoming clinical trials, the AHC scale will allow clinicians worldwide to evaluate the rate of disease severity, the semeiology of the disease, the genotype-phenotype correlation, the natural evolution of the AHC during the lifespan of a patient.

As reported by Dr. Michela Stagnaro of the Gaslini Institute, the scale addresses all the disease domains, embracing the complex phenotype of the syndrome, and it is divided into 4 scores: Paroxysmal Manifestation Score (PMS), Epilepsy Score (ES), Non – Paroxysmal Manifestation Score (NPMS), Adaptive Capacities Score (ACS).

The scale is currently being tested and validated on Italian, French and Spanish AHC patients. All patients are examined and filmed according to a standardized video protocol. The different Patient Advocacy Organizations (Italian (AISEA), Spanish (AESHA) and French (AFHA)) have been actively involved in the design, management, and logistic support for the project.  
Oxygen Therapy: an acute treatment for Paroxysmal Motor Events in Alternating Hemiplegia of Childhood?
The first report of successful use of oxygen therapy in an AHC patient was published on Movement Disorders, February 2023, by Dr. Eleni Panagiotakaki and other French members of the IAHCRC Consortium.

In this second article published on Movement Disorders in July 2023, they expand their observation and report the positive effect of high-flow oxygen administration in two children with ATP1A3-related AHC who had dystonic, plegic, or mixed attacks.

According to the authors, "controlled studies are mandatory to confirm our observation. However, considering the major impact of paroxysmal motor events on the quality of life of the AHC patients and the burden for caregivers, this therapeutic strategy might be life changing for both patients and families."

All IAHCRC contacts will be invited soon to participate in an international survey to evaluate the feasibility of a multicentric study about the efficacy of this therapy, using the same methodology developed for the OBSERV-AHC Study.

Link to the first article on Movement Disorders, February 2023
Link to the second article ion Movement Disorders, July 2023 
11th International Symposium on ATP1A3 in Disease
Chicago, 26 - 28 October 2023
The 11th Symposium on ATP1A3 in Disease will take place on Friday and Saturday, October 27-28, 2023 at the premises of Northwestern University, Feinberg School of Medicine, Chicago, USA. 

There will be a poster session and free time for discussion during the meeting, and a dinner event on Saturday evening after conclusion of the conference.

The Scientific Program Committee includes Al. George (Chair), Kathy Sweadner, Arn van den Maagdenberg. 

Participation is also possible  on line. The schedule and all information on registration, abstract submission, hotel, venue etc. are available at www.atp1a3-disease-symposium.org.

For any questions on the organisation of the Symposium, please contact the event hosts at This email address is being protected from spambots. You need JavaScript enabled to view it.

As showed in the program here below, this edition of the Symposium will feature an international panel of speakers addressing:

•    Disease Natural History
•    Quantifying Phenotypes and Clinical Trial Readiness
•    Basic Mechanisms and Neurophysiology
•    Therapeutic Advances

Many presentations will be given by IAHCRC members about the OBSERV-AHC Study on natural history and therapy for AHC, and all its  related studies, as well as about other IAHCRC studies. 
An overview will also be presented about the IAHCRC Consortium and the IAHCRC-CLOUD Platform, the data collection and sharing service for its multicentric studies.

Looking forward to meeting you all, in person to Chicago or online, for this unique 2-day event in October!
The IAHCRC-CLOUD Platform | a service for National Registries and International Studies in the IAHCRC cooperative network
(Project Coordinator Dr. Rosaria Vavassori, I.E.ME.S.T. Institute, Italy)
The IAHCRC-CLOUD Platform implement an international network for the data collection and sharing for the collaborative studies of the Clinical and Basic Research Centers belonging to the IAHCRC Consortium, involved in research and treatment of the rare neurological diseases caused by mutations in the ATP1A3 gene.

The network is composed of international Study Databases and of national Disease Registries (Node Databases), in which the centers of a national IAHCRC Node, as well as their patients, can collect and keep their data securely for their own, private use (for example for the clinical practice), and share them for any IAHCRC Study served by the Platform in which they freely decide to participate.

Data collected in the Platform are managed in full compliance with the rules defined in the Charter of the IAHCRC Consortium, based on international ethical standards and national and international regulations on data privacy and security.

Thanks to the implemented workflow, based on principles and methods of platform cooperativism and patient engagement, data can be collected in the Platform and shared in an ethical and informed way by all actors involved in the biomedical research process (patients, clinicians and basic researchers, scientific and health institutions, and eventually pharma and biotech organizations).
From Dr. Jennifer Anticona's presentation on the ongoing IAHCRC studies, during the webinar organized by the association AESHA in September 2022, for Spanish and Latin American families.
Interactive workshop on designing, conducting and managing Real World studies
22 June 2023 | Politechnics University, Milan Italy
The IAHCRC-CLOUD Platform was presented by the IAHCRC Data Manager Dr. Rosaria Vavassori at the Workshop on Real World Data and Evidence in health governance, for observational studies, clinical trials and care pathways. 
The Workshop was organized last June by the Politechnics University of Milan, together with some biotech companies and CRO's.

Next January 2023, Dr. Vavassori has been invited as a teacher to a Master Degree organized by the Politechnics University of Milan on Innovation Management in Clinical Reasearch and Health Systems, to present the IAHCRC Consortium as an organizational model for rare and complex diseases.
Translations of AHC Information Leaflet and Patient Journey available on the EpiCARE-ERN website
With the contribution of the patient associations of AHCFE, the European Federation for AHC
The Information Leaflet and Patient Journey for AHC, originally developed in English by Rosaria Vavassori (IAHCRC Data Manager and AHC18+ e.V. member) and Katherine Behl (President AHC-UK), are now also available in Croatian, Spanish and Italian on the EpiCARE-ERN official website.

Two more translations, in French and German, will soon be also available, thanks to the collaboration of the Patient Associations member of AHCFE, the European Patient Federation for AHC www.ahcfe.eu 

Both the English version and all the translations are reviewed and validated by the EpiCARE-ERN members, expert in AHC and in all rare and complex epilepsies www.epi-care.eu.

The aim of the Patient Journey and of the Information Leaflet for healthcare professionals and for families, is to provide homogeneous and scientifically sound information about diagnosis, treatment and management of AHC, for all patients in Europe and eventually worldwide.

We sincerely thank the European patient Associations for taking charge of the translation into their own languages, and for involving their AHC and EpiCARE-ERN experts  for the validation of the translation.

Many thanks also to the Coordination and Management Team of EpiCARE-ERN for endorsing this project of its ePAG (Patient Advocacy Group) and for collaborating in the creation, publication, and dissemination of the Patient Journeys and Information Leaflets for AHC and all Rare and Complex Epilepsies. 
The original English version and all the translations of the AHC Information Leaflet and Patient Journey can be downloaded from the EpiCARE-ERN website at this link
December 2023
The members of the IAHCRC General Assembly will have their annual meeting in December 2023. In that occasion, the new membership applications will be approved.

All centers interested to join the IAHCRC Consortium, and to contribute to the progress of collaborative research on ATP1A3 diseases by proposing new studies or by participating in studies proposed by other Consortium members, are kindly invited to contact the IAHCRC Data Manager asap at this This email address is being protected from spambots. You need JavaScript enabled to view it., to initiate the application procedure.
Some IAHCRC members from UK, Italy and France, presenting a poster about the "Event Calendar and 
E-Diary" project at the10th Symposium on ATP1A3 in Disease (Edinburgh, October 2022).
On the left, Prof. Sanjay Sisodiya, chair of the Symposium Scientific Committee.

The updated list of the IAHCRC members is available on the IAHCRC official website  link
IAHCRC on FAcebook
IAHCRC Official Website
IAHCRC on LinkedIn
IAHCRC International Research Consortium
research and care for the ATP1A3 diseases

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IAHCRC - International Consortium for the Research on Alternating Hemiplegia of Childhood and other ATP1A3 related diseases