One of the missions of the ERN EpiCARE is to promote clinical research and the production of cross-border collaborative work on genetic epilepsies. Our field is confronted with an extremely large number of new genes, for which the clinical spectrum and/or natural history is often barely known; usually, the number of patients published is limited to a handful, their recruitment may be strongly biased towards a few clinical features, and their clinical description is often limited.
Through this section, we share the opportunity of collaborative calls for European series of patients carrying variants in already known genes but with limited knowledge that need to be expanded.
The main aim of this initiative is to recruit cohorts of patients carrying rare variants in genes without a well-defined phenotypic spectrum, where single centre studies would not yield significant series. EpiCARE can facilitate this type of studies by connecting several centers across Europe involved in the study of genetic epilepsies.
The principle behind this initiative is simple:
You will find the submission template both here, or on the EpiCARE Genetic Epilepsies Platform.
Please follow the instructions in the template and send it back to Sébile Tchaicha, EpiCARE research manager. She will contact you after review of the project.
If you are instead interested in collaborative research on novel genes within the EpiCARE community, please use the EpiCARE Genetic Epilepsies Platform that has been developed specifically for this purpose.
Please find below the list of current calls. Click on the + sign for more information and contact details.
Phenotype of individuals with bi-allelic variants in FRRS1L
Bi-allelic variants in FRRS1L are associated with an epileptic-dyskinetic encephalopathy. Loss-of-function variants of FRRS1L disrupt synaptic AMPA reception function, resulting in a devastating neurological condition. We have collected more than 40 new cases, and are looking for more! We would like to collect clinical, neurophysiological and neuroimaging information.
Clinical, molecular and functional characterization of CLCN3-associated neurodevelopmental disorder
CLCN3 (OMIM 600580)
CLCN3 has recently been associated with neurodevelopmental disorder with hypotonia and brain abnormalities. Currently, there are only two publications describing CLCN3-associated disease (PMID: 34186028; PMID: 36536096). Most of the described patients have heterozygous de novo gain-of-function variants causing dominant disorder, and only one family had homozygous loss-of-function variant responsible for more severe recessive disease. We recently identified a patient with homozygous CLCN3 missense variant with a phenotype compatible with previously reported patients. In this project, we are looking for other patients with mono- and bi-allelic CLCN3 variants, to collect clinical and genetic data and further delineate the full clinical spectrum of this recently described disorder. The functional testing of human CLCN3 variants are on transfected cells, so there is no need for human samples.
Clinical and functional characterization of GRIA-related disorders: translating genetic diagnostics into personalized treatment
GRIA1 (#138248), GRIA2 (#618917), GRIA3 (#300699), and GRIA4 (#617864)
GRIA genes encode AMPAR receptors which are important for the function of excitatory neurons. Disease-causing variants in GRIA, GRIA2, GRIA3, and GRIA4 cause a neurodevelopmental disorder (NDD) with mild-profound developmental and cognitive impairment, behavioral difficulties, early-onset and treatment-resistant seizures. Only few patients have been reported leaving phenotypical spectrum and genotype-phenotype correlations ill-defined.
We want to:
Genetic and environmental modifiers associated with KCNQ2-related disorders
KCNQ2 (OMIM: 613720 and 121200; ORPHA: 439218)
KCNQ2 encodes for a voltage gated potassium channel subunit that has a critical role in controlling neuronal excitability. KCNQ2-related disorders are associated with a spectrum of phenotypes ranging from self-limiting (familial) neonatal epilepsy at the mild end to developmental and epileptic encephalopathy at the severe end. Neonatal seizures are the main features, but patients without neonatal seizures are described. Although phenotype-genotype correlations are good, phenotypic variability exists even among carriers of recurrent variants.
We hypothesize that some of the phenotypic variability in KCNQ2-related disorders can be explained by the existence of genetic and environmental modifiers. By identifying these modifiers, we hope to improve counseling for individual patients, and to identify biological pathways that can be targeted by novel disease-modifying treatment strategies.
In this study, all patients with a proven pathogenic KCNQ2 variant can be included after signature of an informed consent document. Detailed clinical data on all participants will be collected through the treating (child) neurologist, in addition to a DNA aliquot.
Genotype-phenotype characterization of GABAAR-related epilepsies: translating genetic diagnostics into personalized treatment
GABRA1 (#137160), GABRA2 (#137140), GABRA3 (#305660), GABRA5 (#137142), GABRB2 (#600232), GABRB3 (#137192), GABRG2 (#137164), GABRD (#137163)
GABA-A receptor (GABAAR) gene family encode for the major inhibitory ion channels of the mammalian brain. Recently, a large number of pathogenic variants has been identified in GABRA1, GABRA2, GABRA3, GABRA5, GABRB2, GABRB3, GABRG2 and GABRD that causes developmental and epileptic encephalopathy (DEE).
1.to establish specific correlations between phenotype, genotype, functional effects and therapeutic response of patients with GABAAR variants to translate genetic diagnostics into treatment;
2.to determine the pathogenicity of selected variants, classify these into loss and gain of function variants in order to define whether GABAergic drugs could be used or not.
no OMIM or ORPHA code, causative gene(s) unknown.
“Sunflower syndrome is a rare photosensitive epilepsy characterized by highly stereotyped seizures. Patients with Sunflower syndrome look toward a light source, often the sun, and wave one hand with abducted fingers in front of their face. Often, there is associated eye fluttering or blinking during these episodes. Additionally, these handwaving episodes can occasionally evolve into other seizure types including generalized tonic-clonic seizures. Unfortunately, these handwaving episodes are often initially misdiagnosed as tics or behaviors associated with obsessive–compulsive disorder.” (Geenen et al., 2020, Developmental Medicine & Child Neurology 2021, 63: 259–262)
Together with the group of professor Kluger (Austria), professor Striano (Italy) and professor Lagae (Belgium); we are aiming to create awareness of Sunflower syndrome in Europe and the UK (and beyond). Moreover, we are aiming to unravel a potential genetic basis of this highly stereotyped epilepsy syndrome.
We would first start with a short questionnaire (for (the parents of) the person with Sunflower syndrome) to evaluate which medicines are effective. This questionnaire has been recently updated and could be assessed via the following link: https://redcap.patre.info/surveys/?s=N9EHWLED9A
If we would be able to bring enough patients and/or their parents together and gather their contact details, we would then perform a larger questionnaire (conform with PATRE and NETRE, Network for Therapy in Rare Epilepsies (NETRE): Lessons From the Past 15 Years. Front Neurol. 2021 Jan 14;11:622510. doi: 10.3389/fneur.2020.622510. PMID: 33519703).
ATP1A3/ all phenotypes (Alternating Hemiplegia of Childhood (AHC) #614820, Rapid Onset Dystonia Parkinsonism (RDP) #128235, CAPOS #601338, Relapsing Encephalopathy with Cerebellar Ataxia (RECA), Developmental and Epileptic Encephalopathy #619606 etc.
ATP1A3 is associated with a broad neurological disorder spectrum. Out of 168 ATP1A3 variants published so far, 2/3 of published patients carry only 8 (c.2401G>A, c.2443G>A, c.2839G>A/C, c.2452G>A, c.1838C>T, c.2273T>G, c.2267G>A and c.2267G>T), for which there is clear genotype/phenotype correlation, as they are each associated with a specific phenotype (AHC/ RDP/ CAPOS/ RECA). We call these common variants.
It remains unknown whether genotype/phenotype correlation exists for the other (rare) variants, as for most only 1-2 patients have been described. This might be due to rarity or patients are not recognized as having an ATP1A3-related condition.
Within the International AHC Research Consortium we have started an online survey of the phenotypic characteristics of patients carrying rare ATP1A3 variants to:
We would love to invite collaborators across the EPICARE network to join us in this effort and I am very happy to be contacted with any questions.
Characterization of epilepsy in children with encephalopathy SPATA5 and response to ketogenic diet.
The SPATA5 gene (NM_145207.2), located in the chromosomal region 4q28.1, encodes the spermatogenesis-associated protein (SPATA5, OMIM *613940), an 892-amino acid AAA Protein (ATPase associated with diverse activities). Bi-allelic mutations in SPATA5 gene are associated with epilepsy, hearing loss and mental retardation syndrome (EHLMRS). SPATA5 mutations cause an encephalopathy, which mimic a primary mitochondrial disorder, probably related to SPATA5 role in mitochondrial dynamics. Ketogenic diet (KD) is a metabolism-based treatment used in specific epileptic syndromes as mitochondrial related epilepsies. A few patients have been published, and epilepsy characteristics are not yet well described.
The aim of this project is to characterize the electro-clinical phenotype in children with SPATA5 mutations, and response to Ketogenic diet in case is used. Clinical data as well as treatments received and their response will be collected.
Genotype-phenotype characterization of DLG4-related synaptopathy
DLG4 (OMIM #602887)
DLG4 encodes PSD-95, a protein fundamental for the organization of the post-synaptic density (PSD), a dynamic network of hundreds of proteins responsible for the modulation of strength and plasticity of the glutamatergic synapses. While this protein has been studied for many years from the molecular point of view, it is only in recent years that a neurodevelopmental disorder was linked to DLG4 . The so called DLG4-related synaptopathy is characterized by intellectual disability, sleep disturbances, hypotonia, epilepsy and encephalopathy with status epilepticus during sleep (ESES) (Rodríguez-Palmero et al. 2021, PMID: 33597769).
The aim of this project is to identify new individuals with DLG4 variants and update the clinical phenotype for a better genotype phenotype correlation. We will have a special focus on epilepsy and collect electroencephalographic data.
The project will be carried out in close collaboration with ERN-ITHACA.
Genetic and phenotypic spectrum of FZR1 related disorders
We recently described that de novo pathogenic variants in FZR1 lead to a developmental and epileptic encephalopathy associated with a spectrum of early onset seizures. Since very few patients have been described so far, the phenotypic spectrum is still unclear. This complicates classification of variants identified during diagnostic genetic testing, especially since there is no high-throughput testing system available to functionally evaluate variant effects.
With the help of the EpiCARE network, we hope to collect information on more individuals with ultrarare variants in FZR1 that are considered (likely) pathogenic or of unknown significance. Combining detailed clinical, genetic results and in silico modelling, we hope to better define the clinico-genetic spectrum associated with FZR1 related disorders.
Sarah Weckhuysen - email@example.com
Natural history study in patients with epilepsy in infancy with focal migrating seizures
KCNB1 pathogenic variants can give a spectrum of developmental encephalopathies. Indeed, over half of reported patients present seizures. Epilepsy can present as a developmental and epileptic encephalopathy where both the etiology and the epilepsy (in this case with early onset) can impact the developmental trajectory of the individual or as developmental encephalopathy, where epilepsy occur later in life. In both, epilepsy is often pharmacoresistant and can add to the burden of this disease.
We described an international cohort of KCNB1-DE/DEE. We also reported the specific neurodevelopmental characteristics (D Breuillard, neuropsychologist). This study is ongoing with longitudinal follow-up of a cohort of almost 40 patients. KCNB1 association initiated as a French PAG but allowed the contact with patients all over Europe that are actively involved in the research and the registry support.
The goal of this project is to define natural history and possible biomarkers for these 2 distinct (to some extent) presentations with a more severe outcome in the DEE group.
Our team is establishing a prospectrive follow-up of this cohort and some of your patients are or would like to participate in this work that is supported by a basic research program at Institut Imagine (PhD, L. Robichon).
The protocol will collect clinical, EEG, imaging and developmental data as collected during clinical good practice based on a minimal clinical setting follow-up with 2 visits per year in patients under 3 years group, 1 per year for older patients.
The group interested in this study will have available the questionnaires for the developmental FU.
Natural history study in patients with epilepsy in infancy with focal migrating seizures
Epilepsy with migrating focal seizures is a rare Developmental and epileptic encephalopathy due to genetic aetiology. KCNT1 is the major gene with pathogenic variants reported in almost 50% of cases. Many patients with EIMFS present with drug resistant epilepsy and developmental delay with an acquired microcephaly in severe cases.
Other phenotypes are reported with mutations in KCNT1 mimicking ADNFLE and other focal epilepsies with some milder degrees of Intellectual disability. The diagnosis of EIMFS is based on the seizures aspect that needs a long-lasting video-EEG recording to “catch” the migration aspect, and this might sometimes not available in all cases.
We and other groups described the classical clinical and EEG aspects of EIFMS at onset and proposed 2 EEG biomarkers, however, these biomarkers need validation in a larger cohort and the natural history still lacking in this syndrome.
Our project aims to collect retrospectively data of patients with EIMFS due to KCNT1 pathogenic variant, to perform a deep phenotyping based on the available data, to collect EEGs done in the first year of the diseases and during follow-up and to structure a prospective cohort of 25-30 patients with a confirmed diagnosis of EIMFS with KCNT1 pathogenic variants.
The protocol will collect clinical, EEG, imaging and developmental data as collected during clinical good practice follow-up with 2 visits per year in the under 3 years group, 1 per year for older patients.
The group interested in this study will be invited to a remote meeting to harmonise the developmental items to collect for each age group during the clinical FU. The goal is to stay the closest to the clinical practice.
PS: The group of Filadelfia, Denmark (Dr E Gardella) and of Bambino Gesu, Rome, Italy, are involved in this project and we are keen to have additional groups following patients with the different phenotypes caused by KCNT1 pathogenic mutations joining.
A budget will be available for the different meetings of the group.
Genotype phenotype correlations and phenotypic description of patients with bi-allelic of SLC12A5 (encoding KCC2)
OMIM # 606726
SLC12A5 encodes KCC2, is a neuron-specific chloride potassium symporter responsible for establishing the chloride ion gradient in neurons through the maintenance of low intracellular chloride concentrations. It is a critical mediator of synaptic inhibition, cellular protection against excitotoxicity and may also act as a modulator of neuroplasticity. Bi-allelic mutations have been reported in a few patients with EIDEE (PMID: 28477354, 27436767 and 26333769). In this study we are collecting patients with bi-allelic mutations of SLC12A5 to better delineate the phenotypic range, the genetic bases, and the phenotype-genotype correlations. We would be interesting in collecting clinical history, EEGs, and brain MRIs.
This project is connected to basic and translational research programs that aim at improving our understanding of the functional consequences of mutations on KCC2 function and interactions.
DNM1L mutations leading to severe epileptic encephalopathy including FIRES
DNM1L p.Arg403Cys variant
The p.Arg403Cys variant on the DNM1L gene has been reported in 12 children with previously normal/near-normal development who presented with severe childhood refractory status epilepticus, several of whom had a clinical picture consistent with FIRES. All patients reported in the literature and our own experience suggests very poor functional and epilepsy outcomes, including recurrent episodes of status epilepticus.
DNM1L plays a role in division of mitochondria and peroxisomes and mutations are associated with abnormal mitochondrial fission. The identification of this mutation highlights the role that a mitochondrial etiology may have in a subset of patients presenting with refractory status epilepticus in childhood including FIRES, which are often attributed to a fulminant inflammatory response.
The aim of this project is to characterize the clinical phenotype in children with the p.Arg403Cys variant on the DNM1L gene. We will collect details on children’s previous background, their presentation, EEG and neuroimaging findings, long term outcomes and their response to anti-seizure medications and ketogenic diet.
Genotype-phenotype characterization of SCN2A associated disorders
Pathogenic variants in SCN2A – encoding the voltage-gated sodium channel NaV1.2 – have been associated with a spectrum of neurologic disorders including self-limited epilepsies as well as developmental and epileptic encephalopathies (DEEs). Current therapeutic strategies aim at dampening NaV1.2 activity by using sodium channel blockers in case of gain-of-function mutations. Yet, the impact on neurocognitive outcome is very limited. Targeted disease-modulating therapies that aim at improving both epilepsy and development are urgently needed and are about to enter clinical trials.
Our aim is to better understand the genetic and phenotypic spectrum of SCN2A associated disorders and to identify prognostic biomarkers that could predict future neurocognitive and epilepsy outcome. In addition, we want to describe the genetic and phenotypic landscape of adult SCN2A patients. Finally, similarities across sodium channelopathies incl. SCN2A will be investigated. Please contact us if you have pediatric and/or adult patients with a (likely) pathogenic variant in SCN2A and any symptoms of a neurologic disorder.
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The medical team members of the European Reference Network EpiCARE, in collaboration with patient advocates, develop and deliver highly-specialized diagnostics and care to improve interventions and outcome in individuals with rare and complex epilepsies.
The ERN EpiCARE was created in 2017 and is co-funded by the European Union.
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