NEWS - YEAR 2021
1 July 2021
IAHCRC GENERAL ASSEMBLY 2021
"The IAHCRC Consortium is an international network of research and healthcare providing centers specifically created to carry out collaborative studies on AHC and all the ATP1A3-related diseases.
Next July 15th, the member centers will gather online for their annual General Assembly, to approve some modifications in the IAHCRC Charter, ratify the new memberships and define the research and treatment strategy for the next five years.
An update will also be given by the Scientific Coordinators of the current IAHCRC Studies and the results reported in the most recent scientific publications will be discussed.
A report will be published here, soon after the meeting.
Download the PRELIMINARY AGENDA in pdf.
31 May 2021
EARLY PROFOUND EPILEPTIC ENCEPHALOPATHY AND BRAIN MALFORMATION AS A NEW PHENOTYPE ASSOCIATED WITH ATP1A2 AND ATP1A3 MUTATIONS
"A new multicentric study led by Professor Renzo Guerrini (University of Florence, Italy) has just been published in the scientific journal ‘BRAIN’.
Twenty-two individuals were included in the study, including six with ATP1A2 mutations and 16 with ATP1A3 mutations. A new specific very severe clinical presentation was found in seven individuals who had epilepsy, abnormalities of cerebral cortex, i.e. polymicrogyria, or progressive reduction of cerebral volume, and early mortality. Most individuals had severe seizures with early onset, often in the neonatal period; not all of them had brain structural malformations. The effect of the mutations was studied at the cellular level, showing that the cellular protein pump encoded by the two genes lost its function due to the mutations. The more the pump function was impaired, the more severe was the phenotype. They also looked at the brain tissue of two individuals who were deceased and found that there were neuronal abnormalities together with blood vessel disruption. The authors provide an estimate of the incidence of these severe phenotypes in about 5% of individuals with ATP1A2 mutations and about 12% of individuals with ATP1A3 mutations.
This study further expands the spectrum of ATP1A2 and ATP1A3-related disease and provides a correlation between protein function and disease severity."
by Prof. Renzo Guerrini
The article will soon be available on BRAIN at this link doi.org/10.1093/brain/awab052
Prof. Guerrini's department at the MEYER Hospital in Florence is a clinical reference center for AHC in Italy. Recently Prof. Guerrini joined the IAHCRC Consortium, to contribute to its multicentere studies on AHC and all the ATP1A3-related diseases. He is also member of EpiCARE-ERN, the European Reference Network for Rare and Complex Epilepsies that includes also AHC.
15 February 2021
DUKE RESEARCHERS ACHIEVE FAVORABLE RESPONSE TO GENE THERAPY IN ALTERNATING HEMIPLEGIA OF CHILDHOOD (AHC) MOUSE MODEL
In this study the Duke research group of the Mikati Lab used an adeno-associated virus serotype 9 (AAV9) vector expressing the human ATP1A3 gene to add a normal copy of the ATP1A3 gene to the brain of AHC mice by injecting that vector into the cisterna magna (space within the skull just outside the base of the brain that has cerebrospinal fluid) and into the two lateral cerebral ventricles (spaces within the brain substance that are filled with cerebrospinal fluid).
The injections were performed in mice carrying the D801N mutation (Mahlool AHC mice). One group of these mice received the above active vector and another received a control vector without ATP1A3. Also control normal mice were injected.
Mice received the injections at age 10 days (P10) which corresponds to early infancy in human terms, the age at which AHC is usually diagnosed. The mice were then tested at age 40 days (P40, early adulthood) and 70 days (P70, mid adulthood).
The findings were the following:
- Treatment increased ATP1A3 expression and function: There was strong expression of the injected gene in brain areas close to the injection sites (see Figure 1) with increase in the enzyme activity of the ATP1A3 ATPase.
- Treatment improved survival: It is already known that without treatment about half of the D801N mice die by around the age of 70 days. In this study, all the D801N mice treated with the active vector survived during the study period. On the other hand, as expected, half of the D801N mice who did not receive the active vector died.
- Treatment improved neurological function: At P40 there was reduction of inducible hemiplegia spells, and a significant improvement in balance of the mice who received the active vector.
- Improvement in neurological function was only partial: At age 70 days only a minimal effect on balance persisted and an effect on hemiplegia spells was not observed. Also, not all neurological function improved at either age (including inducible dystonia, strength and memory at either age 40 days or 70 days which did not differ between the treated group and the control mice).
Figure 1: Green Stain shows expression of ATP1A3. The illustration shows strong expression in an area close to the active vector injections site.
This study demonstrates that, as a proof of concept, gene therapy can induce favorable effects in mice carrying the most common mutation causing AHC in humans. This encourages future research to improve the vector to allow more expression of ATP1A3 in all the brain (not just in areas close to the injection sites) for longer periods of time to get even more effects allowing translation to human trials.
by Prof. Mohamad Mikati (Duke University, Durham NC, USA)
read the report in pdf
Reference: Hunanyan AS, Kantor B, Puranam RS, Elliott C, McCall A, Dhindsa J, Pagadala P, Wallace K, Poe J, Gunduz T, Asokan A, Koeberl DD, ElMallah MK, Mikati MA.Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood. Hum Gene Ther. 2021 Feb 12. doi: 10.1089/hum.2020.191. Epub ahead of print. PMID: 33577387. link
11 February 2021
AN EDUCATIONAL WEBINAR ON AHC ORGANIZED BY EPICARE-ERN, THE EUROPEAN REFRENCE NETWORK FOR RARE AND COMPLEX EPILEPSIES
The recording is now available at this link
Registration is mandatory in order to watch the webinar.
ORGANIZER: EpiCARE-ERN www.epi-care.eu
SPEAKERS: Dr. Eleni Panagiotakaki and Prof. Gaetan Lesca, Epilepsy, Sleep and Pediatric Neurophysiology Unit, University Hospital of Lyon, France
CHAIR: Prof. Alexis Arzimanoglou, Sleep and Pediatric Neurophysiology Unit, University Hospital of Lyon, France
DATE: 11 February 2021
19 January 2021
THE COLLABORATIVE STUDY TREAT-AHC CARRIED OUT BY THE CENTERS OF THE IAHCRC CONSORTIUM RECEIVES FUNDING
Warmest congratulations to the TREAT-AHC team, and best wishes for a profitable and rapid completion of their Study.
18 January 2021
INTERNATIONAL AHC DAY