IAHCRC UPDATE - FALL 2023
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Overview | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Alternating Hemiplegia of Childhood (AHC) is an ultra-rare neurodevelopmental disease. The prevalence is 1 in a million, and it was first reported in the medical literature in 1971.[1] AHC is a life-long condition, in spite of its name suggesting a childhood disease. However, the first symptoms classically begin in childhood before the age of 18 months.[4, 5] |
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Signs and Symptoms | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Whilst the name of the disease highlights its most characteristic symptom (recurrent attacks of hemiplegia that alternates between limbs and can include full body quadriplegia), this condition encompasses a vast and wide-ranging complex constellation of neurological symptoms.[4, 5] These neurological symptoms will vary and fluctuate during an individual’s life. Episodes There are many types of paroxysmal symptoms in AHC including:
Any and all of these types of paroxysmal symptoms occurring in an AHC person, are referred to as ‘episodes.’ An episode can be a combination of several types of symptoms in one time period and vary greatly in frequency, severity, intensity and duration between individuals as well as with age and with different seasons, without a specific pattern. Epileptic seizures and seizure-like episodes may appear at different ages, from early infancy to late adulthood.[7] Sleep plays a peculiar and critical role in AHC. A key part of the clinical diagnositc criteria is resolution of the plegic attacks during sleep. Therefore, inducing sleep during an attack is paramount to ending it. However, it is recognised that on waking the attacks can re-occur within the first hour. Parents usually take advantage of this short time of relief after a long-lasting attack, to feed and hydrate their children. Unfortunately, for some who have prolonged or frequent AHC episodes this is not adequate and supplemental feeding via a gastrostomy is required. The triggers for episodes in AHC are vast and wide-ranging.[5, 8] This makes it a very complex condition to manage in everyday life. Common triggers include excitement, fatigue, temperature change, water, pain, constipation, fever or illness, sunlight …… Many attacks, however, appear without a specific trigger and are totally unpredictable. Comorbidities In addition to all these types of episodes, AHC is also a neurodevelopmental condition, characterized by many permanent symptoms, ranging from mild to severe physical and cognitive disabilities.[5, 9] Some people with AHC also have Autism Spectrum Disorder, and other behavioural disorders.[10] Additionally, the ATP1A3 gene is expressed in the heart leading to risk of arrthymias and possible sudden death.[11] Gastroinestinal disorders[12], breathing complications and sleep apnoea have also been shown in AHC.[13] |
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Genetic Cause | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
In 2012 a group of mutations in the ATP1A3 gene (located on chromosome 19) was identified as causing AHC in approximately 70-80% cases[2, 14, 15] The ATP1A3 gene encodes a protein functioning as sodium-potassium ion pump at the neuronal level (Na+,K+-ATPase)[3] and has a critical role in regulation of the nervous system. Recently, it has also been found to be expressed in the heart.[11, 16] Prior to this, the cause of AHC was unclear with many theories hypothesised. This genetic mutation is now included in rare epilepsy genetic panels, no doubt leading to more individuals being correctly diagnosed. Several large-scale genotype-phenotype studies have been carried out showing that some ATP1A3 mutations are associated with more severe phenotypes (E815K, pGlu815Lys), some intermediate phenotypes (D801N, pAsp801Asn) and some milder phenotypes (G947R , pGly947Arg).[6, 23, 24, 25, 34] However, the variation in the different mutations does not fully explain the clinical variation with the varied phenotypes, leaving researchers with many unanswered questions about the possible role of other genes/variation across the whole genome or epigenetic factors influencing pathogenic variation or protein misfolding/varied ratio of normal to mutant ATP1A3 proteins.[26, 27] |
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Diagnosis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Clinical diagnosis is based on diagnostic criteria clearly defined in literature since 1980 [4, 5, 28]. For about 70-80% of cases the clinical diagnosis is confirmed by the presence of a mutation in the ATP1A3 gene. Some diagnosed cases are classified as "atypical", either not fulfilling all the clinical diagnostic criteria or overlapping with other ATP1A3 neurological disease. Indeed, there is an expanding spectrum of ATP1A3 neurological diseases, with overlapping symptoms: rapid-onset dystonia-parkinsonism (RDP, DYT12, OMIM #128235), CAPOS Syndrome (OMIM #601338) and more recently, early infantile epilepsy with encephalopathy (EIEE), recurrent encephalopathy with cerebellar ataxia (RECA), Fever-Induced Paroxysmal Weakness and Encephalopathy (FIPWE), and D-DEMØ.[4, 29, 30, 31, 32, 33] For the remaining 20% cases with no mutation in the ATP1A3 gene, the clinical diagnosis can be confirmed after excluding any other differential diagnosis with extensive examinations and investigations, all typically normal for AHC. |
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Treatment and Management | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
There is no regulatory approved treatment for AHC. Antiepileptic drugs are used for those patients with confirmed seizures and episodes of status epilepticus. In addition to pharmacological treatment, with the aim to reduce their frequency, a preventive measure can be to limit the exposure to the most known triggering factors for AHC episodes. A multispecialty reference centre with the availability of various specialists with considerable experience in AHC should take in charge patients, directly or through a local centre.
They should also coordinate and support any other involved local service: rehabilitation, education and schooling, social and home assistance, psychologic support, emercency services for treatment of prolonged dystonic/plegic attacks and seizures/episodes of status epilepticus ... |
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Joint Effort for Research and Care | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Charity support services and collaboration AHC is a neglected disease, still unknown and ignored by most public health, scientific and education institutions, by pharma companies and public in general. The AHC associations play an essential role also in the creation of clinical reference centres for AHC in many countries worldwide; the development of Clinical Registries and Biobanks; the organisation of the annual International Symposium on ATP1A3 in disease since 2012 for scientists, clinicians and families to learn together; the creation and management of the IAHCRC (International AHC Research Consortium).[44] The clinical reference centres provide opportunity for a correct and early diagnosis as well as continuous follow-up treatment and family support. In Europe, most of these centres are now member of EpiCARE-ERN, the European Reference Network for Rare and Complex Epilepsies www.epi-care.eu. Research and Care to improve the future of people with AHC The establishment of the IAHCRC Consortium in 2014[44], enabled multi-centre collaborative studies. Since then, research studies into AHC genotype-phenotype correlations, cardiac disturbances, secondary genes for AHC, and testing candidate compounds for AHC treatment (using in-vitro and in-vivo models) have been initiated. Furthermore, the OBSERV-AHC Study is investigating the natural history of AHC, the efficacy of current therapies, as well as validating some new specific scales to use as indicators for future clinical trials. Additionally, other research centres are involved in projects investigating AAV gene therapy as a new treatment for AHC, and creating induced pluripotent stem cells (iPSCs) derived neuronal models of AHC to investigate possible mechanisms underlying disease pathogenesis.[45] All these research projects are driven and largely funded by AHC patient associations with hope for an improved future for those living with this cruel disease. |
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Acknowledgements | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Some Facts on AHC
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An interesting webinar on AHC was organized by the European Reference Network Epicare-ERN. The content is very educational, mainly for clinicians and researchers, but also for families and caregivers, covering all aspects of the disease, from diagnostics and genetics to therapy and management. TITLE: Alternating Hemiplegia of Childhood: a multi-faceted neurological disorder, new discoveries and new perspectives.
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
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last update 27 December 2021 |
The IAHCRC Consortium is a network of clinical centres, research labs and scientific organizations producing and collecting the patient data according to unique common formats, protocols and procedures, in order to share them for collaborative studies about AHC and the other ATP1A3 diseases.
Based on the results of such studies, it also produces public documentation to be used as guidelines and recommendations for the health and social care of the AHC and all the ATP1A3 patients.
The activities of the Consortium are organized in three levels:
A Clinical Centre in the Consortium is usually the Reference Centre for the care for AHC and/or other ATP1A3 diseases, at the national level; there can be more than one Reference Centre member of the Consortium in each country.
A Node is a cluster of Clinical Centres and serving Labs that has in charge a single cohort of patients; it collects the patient data in its Node-Database that may also have a linked biobank.
The IAHCRC Charter contains the rules for the work among all the member centers to carry out their collaborative studies, and in particular the rights and obligations of the members. It also describes the organizational structure of the Consortium, in terms of functional bodies and their mutual relationships.
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The IAHCRC Consortium aims to accelerate clinical and basic science research in the field of AHC to improve the quality of life of the patients affected by the ATP1A3 diseases and of their families.
Its specific objectives are:
To actively involve in the IAHCRC network all the clinical centres, research labs and scientific organizations willing to contribute to the search for an effective treatment and better standards of care for all the patients affected by AHC and all the ATP1A3 diseases, also working in close collaboration with patient associations and related structures and Institutions.
All the Clinical Centres, Research laboratories and Scientific organizations in the world with active involvement in the research and in the care for AHC or for any other ATP1A3 diseases, and with an interest to be involved and work in collaboration with the other members, can be a member of the Consortium.
IAHCRC-US Consortium, USA (Node US01) |
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IAHCRC-FR Consortium, France (Node FR01) |
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IAHCRC-IT Consortium, Italy (Node IT01) |
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IAHCRC-CZ-SLO Consortium, Czech Republic and Slovakia (Node CZ01) |
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IAHCRC-AU Consortium, Australia (Node AU01) |
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IAHCRC-GR Consortium, Greece (Node GR01) |
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IAHCRC - International Consortium for the Research on Alternating Hemiplegia of Childhood and other ATP1A3 related diseases