Call for collaborative genetic research on rare and complex epilepsies.

• Short title

Clinical and functional characterization of GRIA-related disorders: translating genetic diagnostics into personalized treatment

• Targeted gene(s)/phenotype under study 

GRIA1 (#138248), GRIA2 (#618917), GRIA3 (#300699), and GRIA4 (#617864)

• Summary 

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:

1. collect clinical data from patients with rare GRIA variants in order to establish a database of high-quality genetic and clinical data sets.
2. Systematically evaluate the impact of GRIA variants on key parameters of AMPAR function using a combination of biochemical and functional assays and advanced electrophysiology to pinpoint exact phenotypical mutational impact on AMPAR molecular function and classify pathogenicity of variants.
3. Analyze correlations between patient disease phenotypes and specific effects on receptor function to establish genotype-phenotype patterns and perform pilot experiments to explore options for rescue pharmacology using existing AMPAR drugs.

• Coordinating clinician: Allan Bayat
• Institution (dept, hospital, city, country): Department of Epilepsy Genetics and Personalized Medicine. Danish Epilepsy Centre Filadelfia, Dianalund, Denmark
• Contact email: abaya@filadelfia.dk, bayabayabayat@hotmail.com

• Specific requirements beyond clinical and genotype data 
  • Re-analysis of DNA samples: N
  • Resampling of patients: N
  • Linked to a translational/basic research project? Y

• Short title

Genetic and clinical characterization of patients with microdeletions of KCNQ2 and EEF1A2

• Targeted gene(s)/phenotype under study (to be quoted in the newsletter):

KCNQ2 + EEF1A2

• Summary 

We aim at describing the clinical (epilepsy, neurodevelopmental,…) and EEG phenotype of patients with a microdeletion (CNV loss) including both KCNQ2 and EEF1A2 We need precise CNV coordinates, family history and parental genetic testing if available.

• Coordinating clinician: Gaëtan Lesca / Alice Bergevin / Clotilde Rivier
• Institution (dept, hospital, city, country): medical genetics, University Hospital of Lyon, France
• Contact email: lesca@chu-lyon.fr ; bergevinalice@yahoo.fr; CRivier@lhopitalnordouest.fr;       

• Specific requirements beyond clinical and genotype data :
  • Re-analysis of DNA samples: N
  • Resampling of patients: N
  • Linked to a translational/basic research project? N

• Short title

Genetic and environmental modifiers associated with KCNQ2-related disorders

• Targeted gene(s)/phenotype under study

 KCNQ2 (OMIM: 613720 and 121200; ORPHA: 439218)

• Summary 

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.

• Coordinating clinician: Sarah Weckhuysen
• Institution (dept, hospital, city, country): Department of neurology, University Hospital of Antwerp, Antwerp, Belgium
• Contact email: sarah.weckhuysen@uantwerpen.vib.be

• Specific requirements beyond clinical and genotype data :
  • Re-analysis of DNA samples: Y
  • Resampling of patients: Y (not needed if an aliquot of DNA is already available and can be shared)
  • Linked to a translational/basic research project? Y

• Short title

clinical and genetic description of a cohort of patients with RORA pathogenic variants (CN, SNV, indels, SV)    

• Targeted gene(s)/phenotype under study

All neurodevelopmental phenotypes related to RORA  (OMIM # 600825)

• Summary 

Based on our previous collaborative study demonstrating the role of RORA pathogenic variants in neurodevelopmental disorders, including epilepsy (PMID: 29656859) we are willing to collect a large cohort of patients to describe the clinical features (including EEG features and brain MRI) and the genetic variants to better delineate this condition.

• Coordinating clinician: Gaetan Lesca, Zeynep Gokce-Samar, Sebastien Küry
• Institution (dept, hospital, city, country): Department of Medical Genetics, Lyon University Hospital, Lyon, France. Department of medical genetics, Nantes University Hospital, Nates, France.
• Contact email: gaetan.lesca@chu-lyon.fr; zeynep.gokce-samar@chu-lyon.fr; sebastien.kury@chu-nantes.fr 

• Specific requirements beyond clinical and genotype data:
  • Re-analysis of DNA samples: N
  • Resampling of patients: for segregation studies (parents) if not done. We would be interested to get the DICOM files for brain MRI.
  • Linked to a translational/basic research project? N

• Short title

Genotype-phenotype characterization of GABAAR-related epilepsies: translating genetic diagnostics into personalized treatment  

• Targeted gene(s)/phenotype under study

GABRA1 (#137160), GABRA2 (#137140), GABRA3 (#305660), GABRA5 (#137142), GABRB2 (#600232), GABRB3 (#137192), GABRG2 (#137164), GABRD (#137163)

• Summary 

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).

• Aims

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.

• Coordinating clinician: Alessandra Rossi, MD, and Rikke Steensbjerre Møller, Professor, PhD
• Institution (dept, hospital, city, country): Department of Epilepsy Genetics and Personalized Medicine. Danish Epilepsy Centre Filadelfia, Dianalund, Denmark
• Contact email: alesross@hotmail.com ;  rimo@filadelfia.dk   

• Specific requirements beyond clinical and genotype data:
  • Re-analysis of DNA samples: N
  • Resampling of patients: N
  • Linked to a translational/basic research project? Y

• Short title

Sunflower syndrome

• Targeted gene(s)/phenotype under study

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)

• Summary 

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).

• Coordinating clinician: Sunflower syndrome research group: professor Kluger, professor Striano and professor Lagae.
• Institution (dept, hospital, city, country): multiple departments in/outside Europe:
  • prof Lagae: Department of Development and Regeneration, Division of Locomotor and Neurological Disorders (University of Leuven, KU Leuven, Belgium)
  • prof Striano: Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto 'G. Gaslini', Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy.
  • prof Kluger: Center for Pediatric Neurology, Neurorehabilitation and Epileptology, Schoen Klinik Vogtareuth, Vogtareuth, Germany.
• Contact email: sunflower@patre.info

• Specific requirements beyond clinical and genotype data:
  • Re-analysis of DNA samples: both are possible
  • Resampling of patients: both are possible
  • Linked to a translational/basic research project? N

• Short title

VARIA-ATP1A3 study

• Targeted gene(s)/phenotype under study

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.

• Summary

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:

• establish the width of the ATP1A3-related disease spectrum;
• establish if genotype/phenotype correlation exists for rare ATP1A3
• establish a registry of patients with rare variants.

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.

• Coordinating clinician: Dr Aikaterini Vezyroglou
• Institution (dept, hospital, city, country): Neurology, Great Ormond Street Hospital, London, UK
• Contact email: k.vezyroglou@ucl.ac.uk

• Specific requirements beyond clinical and genotype data :
  • Re-analysis of DNA samples: N
  • Resampling of patients: N
  • Linked to a translational/basic research project? N

• Short title

Characterization of epilepsy in children with encephalopathy SPATA5 and response to ketogenic diet.    

• Targeted gene(s)/phenotype under study

SPATA5, EHLMRS

• Summary

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.

• Coordinating clinician: Carmen Fons and Laia Nou-Fontanet
• Institution (dept, hospital, city, country): Pediatric Neurology Department. Sant Joan de Déu Hospital Barcelona. Barcelona. Spain. 
• Contact email: cfons@hsjdbcn.es; laia.nou@sjd.es

• Specific requirements beyond clinical and genotype data :
  • Re-analysis of DNA samples: N
  • Resampling of patients: N
  • Linked to a translational/basic research project? N

• Short title

Genotype-phenotype characterization of DLG4-related synaptopathy  

• Targeted gene(s)/phenotype under study

DLG4 (OMIM #602887)

• Summary

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.

• Coordinating clinician: Benedetta Kassabian MD, Guido Rubboli MD, Professor, Rikke Steensbjerre Møller, Professor, PhD, and Zeynep Tümer MD, PhD, DMSc, Professor, co-chair of research working group ERN-ITHACA.
• Institution (dept, hospital, city, country): Department of Epilepsy Genetics and Personalized Medicine. Danish Epilepsy Centre Filadelfia, Dianalund, Denmark, and Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet.
• Contact email: benedettakassabian@gmail.com , guru@filadelfia.dk , rimo@filadelfia.dk, zeynep.tumer@regionh.dk          

• Specific requirements beyond clinical and genotype data :
  • Re-analysis of DNA samples: N
  • Resampling of patients: N
  • Linked to a translational/basic research project? Y

• Short title

Genotype-phenotype characterization of YWHAG-related disorders  

• Targeted gene(s)/phenotype under study

YWHAG (OMIM#617665) 

• Summary

YWHAG-related disorders were described for the first time in 2017 by Guella and collaborators. YWHAG-related disorders are also known as developmental and epileptic encephalopathy, 56. This disorder is characterized by seizures of multiple types, including status epilepticus, delayed psychomotor development or intellectual disability, poor language and poor coordination, wide-based gait, ataxia, and videoEEG abnormalities. Patients also demonstrated behavioral and psychiatric manifestations, including autistic features, attention deficit, anxiety, and obsessive-compulsive traits. Onset of symptoms is usually in the first year of life. Multiple antiseizure medications with limited efficacy have been administered to patients, and in some cases, a ketogenic diet has been tried. 

The aim of this project is to identify new individuals with YWHAG-related disorders and update the clinical phenotype for a better genotype phenotype correlation. 

• Coordinating clinician:

  Juan Darío Ortigoza-Escobar, MD, PhD - juandario.ortigoza@sjd.es 

  Eugenia Amato, MD - mariaeugenia.amato@sjd.es   

• Institution (dept, hospital, city, country): Department of Pediatric Neurology, Hospital Sant Joan de Déu, Barcelona, Spain  

• Specific requirements beyond clinical and genotype data :
  • Re-analysis of DNA samples: N
  • Resampling of patients: N
  • Linked to a translational/basic research project? N

• Short title

Genetic and phenotypic spectrum of FZR1 related disorders 

• Targeted gene(s)/phenotype under study

FZR1

• Summary

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.

• Coordinating clinician:

  Sarah Weckhuysen - sarah.weckhuysen@uantwerpen.vib.be

• Institution (dept, hospital, city, country): University Hospital Antwerp, Belgium

• Specific requirements beyond clinical and genotype data :
  • Re-analysis of DNA samples: N
  • Resampling of patients: N
  • Linked to a translational/basic research project? N

• Short title

Natural history study in patients with epilepsy in infancy with focal migrating seizures

• Targeted gene(s)/phenotype under study 

KCNB1 ORPHA:442835

• Summary 

 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.

• Coordinating clinician: Maya El HABBAS, MD (fellowship program)/Rima Nabbout
• Institution (dept, hospital, city, country): Necker Hospital, Paris, France
• Contact email: rima.nabbout@aphp.fr

• Specific requirements beyond clinical and genotype data 
  • Re-analysis of DNA samples: N
  • Resampling of patients: N
  • Linked to a translational/basic research project? Y (Imagine institute GEEN-DS Chair on DEEs, PhD L Robichon)

• Short title

Natural history study in patients with epilepsy in infancy with focal migrating seizures

• Targeted gene(s)/phenotype under study 

KCNT1 ORPHA:293181

• Summary 

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.

• Coordinating clinician: M. Legras/Rima Nabbout
• Institution (dept, hospital, city, country): Necker Hospital, Paris, France
• Contact email: rima.nabbout@aphp.fr

• Specific requirements beyond clinical and genotype data 
  • Re-analysis of DNA samples: N
  • Resampling of patients: N
  • Linked to a translational/basic research project? Y (Imagine institute GEEN-DS Chair on DEEs)

• Short title

Genotype phenotype correlations and phenotypic description of patients with bi-allelic of SLC12A5 (encoding KCC2)

• Targeted gene(s)/phenotype under study 

OMIM # 606726

• Summary 

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.

• Coordinating clinician: Gaëtan Lesca / Amy McTague
• Institution (dept, hospital, city, country): University Hospital of Lyon / UCL GOSH

• Specific requirements beyond clinical and genotype data 
  • Re-analysis of DNA samples: N
  • Resampling of patients: Y may be possible, depending on the type of variants (for functional confirmation or research purpose)
  • Linked to a translational/basic research project? Y