Call for collaborative genetic research on rare and complex epilepsies.

• Short title: Characterization of the Clinical and Natural History of UFSP2-Related Developmental and Epileptic-Dyskinetic Encephalopathy
• Targeted gene(s)/phenotype under study (to be quoted in the newsletter): OMIM#620028- UFSP2-Related Developmental and Epileptic-Dyskinetic Encephalopathy

• Summary (1000 characters max):

In 2021, a homozygous missense variant (p.Val115Glu) in UFSP2 was identified in three families with developmental and epileptic-dyskinetic encephalopathy. Since then, we've identified over 100 additional families across multiple continents, highlighting a significant global prevalence. We are spearheading deep phenotyping, natural history studies, and developing models in C. elegans, flies, zebrafish, and mice. Our work also includes patient-derived cell studies and plans for iPSC-derived neurons. We invite you to contribute cases with biallelic UFSP2 variants to collaboratively advance our understanding and explore potential treatments, including gene therapy.

• Coordinating clinician: Dr. Reza Maroofian, Dr. Amy McTague, Dr. Henry Houlden.
• Institution (dept, hospital, city, country): The UCL Queen Square Institute of Neurology, London, UK. Developmental Neurosciences Dept, UCL GOS Institute of Child Health, London, UK
• Contact email: maroofian@ucl.ac.uk, mctague@ucl.ac.uk, houlden@ucl.ac.uk

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

• Short title: DECADE-Deciphering the CACNA1E developmental and epileptic encephalopathy
• Targeted gene(s)/phenotype under study (to be quoted in the newsletter): CACNA1E (OMIM # 601013 ) / DEE69 (OMIM# 618285)
• Summary (1000 characters max):

CANCA1E-DEE is a severe and rare disorder comprising developmental delay, epilepsy and/or a complex movement disorder mainly caused by gain of function variants in the CACNA1E gene, encoding the R-Type voltage-gated calcium channel. Our current knowledge about the disease is restricted to few cohorts and good treatment options are scarce.

DECADE (Deciphering the CACNA1E Developmental and Epileptic Encephalopathy) is a RedCap-based natural history study to better understand the course of disease and to identify effective treatment options.

Participants should carry a likely pathogenic or pathogenic variant in CACNA1E and suffer from at least one of the core symptoms of CACNA1E-DEE (developmental delay, epilepsy, movement disorder).

DECADE consists of yearly interviews of patients and caregivers by treating physicians with the possibility to submit video recordings to better understand the movement disorder. In the first part, we aim to collect data retrospectively for patients alive and deceased.

Inclusion into the study is also possible through an online visit at our department.

• Coordinating clinician: Dr. Robert Lauerer-Braun & Prof. Holger Lerche.
• Institution (dept, hospital, city, country): Dpt. of Neurology and Epileptology, University Hospital Tübingen, Germany (Prof. Holger Lerche)
• Contact email: decade@med.uni-tuebingen.de
• Specific requirements beyond clinical and genotype data:
  1- Re-analysis of DNA samples: N
  2- Resampling of patients: Y
  3- Linked to a translational/basic research project? N

• Short title: The neurological (and immunological) phenotype of patients with biallelic loss-of-function variants in DIAPH1
• Targeted gene(s)/phenotype under study (to be quoted in the newsletter):  DIAPH1. OMIM #616632 or ORPHA code 477814
• Summary (1000 characters max):

DIAPH1 encodes for the mammalian diaphanous-related formin protein, mDia1, which plays a role in the regulation of cell morphology and cytoskeletal organization. Homozygous or compound heterozygous variants in DIAPH1 have been associated with early-onset epilepsy, cortical blindness, microcephaly, delayed psychomotor development and short stature. Furthermore, some patients exhibit immune deficiencies and develop lymphoma.
The aim of this collaborative study is to provide a more detailed description of the neurological (and immunological) phenotype, including the course of epilepsy.
In addition, to clinical and genetic data, we also request neurophysiological and neuroimaging data, if available.

• Coordinating clinician:
  Birna Ásbjörnsdóttir, Jonna Komulainen-Ebrahim and Rikke Steensbjerre Møller.
• Institution (dept, hospital, city, country):
  Department of Epilepsy Genetics and Personalised Medicine, Danish Epilepsy Centre, Filadelfia, Denmark (Prof. Rikke S Møller) and
  Department of Children and Adolescents, Division of Pediatric Neurology, Oulu University Hospital, Oulu, Finland
• Contact email:
  birna.asbjoernsdottir@regionh.dk 
• Specific requirements beyond clinical and genotype data:
  1- Re-analysis of DNA samples: N
  2- Resampling of patients: N
  3- Linked to a translational/basic research project? N

• Short title: Further expanding our knowledge on SLC6A1-neurodevelopmental disorders
• Targeted gene(s)/phenotype under study (to be quoted in the newsletter): SLC6A1
• Summary (1000 characters max):

SLC6A1-neurodevelopmental disorders (SLC6A1-NDDs) are one of the more common causes of monogenic epilepsy. SLC6A1-NDDs are mainly characterized by mild to moderate developmental delay, epilepsy, often with myoclonic-atonic or absence seizures, and neuropsychiatric comorbidities such as ADHD and autism spectrum disorder. Previous studies have focused on the epilepsy phenotypes as well as assessment of the functional effect of the larger number of missense variants in SLC6A1-NDDs. Our continued studies on SLC6A1-NDDs will focus on deep phenotyping, developmental milestones, recurrent variants and correlations between degree of functional impairment and severity of phenotype under the umbrella term of “clinical trial readiness”.

• Coordinating clinician:
  Katrine M Johannesen
• Institution (dept, hospital, city, country):
  Department of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre, Dianalund, Denmark
• Contact email:
  kamaa@filadelfia.dk
• Specific requirements beyond clinical and genotype data:
  1- Re-analysis of DNA samples: N
  2- Resampling of patients: N
  3- Linked to a translational/basic research project? N

• Short title: Epilepsy spectrum in individuals with pathogenic KDM5C variants: a  genotypephenotype characterisation.
• Targeted gene(s)/phenotype under study (to be quoted in the newsletter): KDM5C (OMIM # * 314690)
• Summary (1000 characters max):

Pathogenic variants in the KDM5C (JARID1C) gene are associated with X-linked intellectual disability (XLID). Furthermore, individuals with pathogenic KDM5C variants present with considerable clinical heterogeneity, including severe intellectual disability (ID), short stature, microcephaly, hyperreflexia and aggressive behaviour. Female patients are known to have a milder phenotype. Recently, we identified a hemizygous de novo variant in the KDM5C gene in a male patient with ID, autism, epilepsy, optic nerve atrophy and leukomalacia. A review of the literature revealed a
gap in knowledge regarding epilepsy in individuals with pathogenic KDM5C variants. Therefore, we are planning a natural history study in collaboration with external partners to describe the epilepsy syndrome(s) and therapeutic strategies in affected individuals.

• Coordinating clinician:
  Dr. med. Rahel Burger
• Institution (dept, hospital, city, country):
  Department of Pediatric Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany
• Contact email:
  rahel.burger@charite.de
• Specific requirements beyond clinical and genotype data:
  1- Re-analysis of DNA samples: N
  2- Resampling of patients: N
  3- Linked to a translational/basic research project? Y

• Short title: Phenotype spectrum of patients with biallelic CACNA2D2 variants.
• Targeted gene(s)/phenotype under study (to be quoted in the newsletter):CACNA2D2 (OMIM # * 607082)
• Summary (1000 characters max):

Following the first publication of three siblings with early infantile epileptic encephalopathy (EIEE) and biallelic variants in the CACNA2D2 variants in 2013, only six individuals have been reported. We recently identified a biallelic variant in the CACNA2D2 gene in a girl with a
developmental and epileptic encephalopathy (DEE) characterized by developmental delay and drug-resistant focal/generalized epilepsy, dysmorphic features, dystonic movements and infratentorial parenchymal atrophy/hypoplasia. There is a knowledge gap regarding the phenotype spectrum associated with CACNA2D2 variants. In a natural history study, we aim to provide an overview of the phenotype, with a particular focus on the epilepsy syndrome(s) and the effect of therapeutic strategies in collaboration with external partners.

• Coordinating clinicians: Dr. Gaetan Lesca
• Institution (dept, hospital, city, country):

Hospices Civils de Lyon, Lyon, France

• Contact email: gaetan.lesca@chu-lyon.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

• Short title: Mapping clinical, EEG, and MRI signatures in STX1B epilepsies
• Targeted gene(s)/phenotype under study (to be quoted in the newsletter): STX1B; OMIM #601485
• Summary (1000 characters max):

Background:

STX1B encodes syntaxin-1B, a presynaptic protein that is part of the SNARE complex mediating the process of calcium-dependent synaptic vesicle release. Variants in STX1B are associated with a wide spectrum of epilepsies, ranging from GEFS+ to DEE (1). Our previous research indicated a genotype-phenotype correlation, where truncating variants were associated with milder and missense variants with more severe phenotypes (2).

Objectives:

This study aims to deepen the understanding of STX1B-associated epilepsies by expanding the database of clinical information. Our goals are:

• To enhance the understanding of the phenotype-genotype relationship, which will aid in the counseling of affected individuals
• To investigate whether affected individuals exhibit specific EEG patterns, using EEG post-processing methods such as connectivity and spectral power analyses.
• To identify STX1B-specific patterns using MRI post-processing techniques. We will compare MRI scans of affected individuals to age-matched controls, where MRI data is available.

Besides clinical and genotype data, we therefore request EEG and MRI data, if available.

• Coordinating clinicians: Stefan Wolking, Rikke S Møller and Niels Focke
• Institution (dept, hospital, city, country):

SW: Dept. of Epileptology, Aachen University Hospital, Germany;

RM: Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark

NF: Dept. of Clinical Neurophysiology, University Medical Center Göttingen, Germany

• Contact email: swolking@ukaachen.de or 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? N
• If available: raw EEG data (EDF) and 3D-T1-MRI sequences (DICOM)

1. Schubert J, Siekierska A, Langlois M, May P, Huneau C, Becker F, et al. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nature Genetics. 2014;46(12):1327-32.
2. Wolking S, May P, Mei D, Møller RS, Balestrini S, Helbig KL, et al. Clinical spectrum of STX1B -related epileptic disorders. Neurology. 2019:10.1212/WNL.0000000000007089.

• Short title: Variants of RNU4-2
• Targeted gene(s)/phenotype under study:RNU4-2 (no OMIM # or ORPHA code yet).
• Summary:

Dear Colleagues,

We are looking for patients with de novo variants in the RNU4-2 gene (hg38; chr12:120,291,763-120,291,903), encoding a small nuclear RNA involved in splicing. Patients with variants of this gene typically have severe ID, microcephaly, epilepsy, and other frequent but variable malformations (skeletal, cardiac...). Variants in this gene can only be identified from genome data.

We are also interested in collecting data on variants in other RNU genes not yet associated with a human pathology and on inherited RNU4-2 variants in patients with other phenotypes (e.g. neurodegenerative, e.g. ataxia, spasticity).

Thank you in advance for your collaboration,

Christel Depienne, Caroline Nava, Julien Thévenon

• Coordinating clinician: Christel Depienne, Caroline Nava, Julien Thévenon.
• Institution (dept, hospital, city, country): UK Essen, APHP Pitié-Salpêtrière, CHU Grenoble
• Contact email: christel.depienne@uk-essen.de; caroline.nava@uk-essen.de; JThevenon@chu-grenoble.fr
• Specific requirements beyond clinical and genotype data:
• Re-analysis of DNA samples: Possible
• Resampling of patients: Not necessary (DNA or genome data sufficient)
• Linked to a translational/basic research project? Y

• Short title: Clinical, Electroencephalographic and Genetic characterization of theHDAC4-related epilepsy

• Targeted gene(s)/phenotype under study: HDAC4 (MIM : 605314)
• Summary:

De novo variants in HDAC4 (histone deacetylase 4), a gene with a widespread distribution throughout the brain which modulates the expression of genes key to synaptic plasticity and memory formation (PMID: 23141539), have been reported in a limited number of patients with global developmental delay, epilepsy, hypotonia, and dysmorphic features (PMID: 33537682). The epilepsy phenotype manifested by these patients remains ill defined. Our centre’s experience suggests HDAC4-related disorders might at times configure as a developmental and epileptic encephalopathy.

Through this call we wish to gather a wide cohort of HDAC4-related epilepsy patients, aiming at refining the clinical epilepsy and EEG phenotype and addressing possible genotype-phenotype correlations.

• Coordinating clinician: Alice Dainelli, Prof. Renzo Guerrini
• Institution (dept, hospital, city, country): Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
• Contact email: dainelli@meyer.it; renzo.guerrini@meyer.it

• 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: Clinical and Genetic characterization of the DMXL2-related DEE
•  Targeted gene(s)/phenotype under study: MIM 618663
• Summary :

Biallelic variants of DMXL2, a gene expressed in the brain have been reported recently in a limited numbers of patients with early-onset DEE and Experimental studies have suggested a role for this gene in autophagy (PMID: 31688942).

The aim of the present collaborative study, open to the ERN Epicare who are interested in contributing, is to constitute a larger series of patients, to refine the electroclinical phenotype of the DMXL2-related DEE and to investigate more in depth the pathophysiological mechanisms, especially concerning its impact on autophagy.

• Coordinating clinicians: Gaetan Lesca / Renzo Guerrini
• Institution : University Hospitals of Lyon / Children’s Hospital A. Meyer
• Contact email: gaetan.lesca@chu-lyon.fr / renzo.guerrini@meyer.it
• Specific requirements beyond clinical and genotype data:
  • Re-analysis of DNA samples: N
  • Resampling of patients: possible
  • Linked to a translational/basic research project? Y - Dr Julien Courchet, Neuromyogene institute, Claude Bernard Lyon 1 University.

• Short title

Phenotype of individuals with bi-allelic variants in FRRS1L

• Targeted gene(s)/phenotype under study 

FRRS1L

• Summary 

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.

• Coordinating clinicians:
  Reza Maroofian (UCL) Sarah Weckhuysen (UZA); Matthias De Wachter (UZA)
• Institution (dept, hospital, city, country):
  UCL, Antwerp University Hospital, University of Antwerp
• Contact email: r.maroofian@ucl.ac.uk; sarah.weckhuysen@uza.be; Matthias.dewachter@uza.be 
  

• Specific requirements beyond clinical and genotype data 
  • Re-analysis of DNA samples: Y, in selected cases (variants of specific interest) 
  • Resampling of patients: N
  • Linked to a translational/basic research project? N

• Short title

Clinical, molecular and functional characterization of CLCN3-associated neurodevelopmental disorder

• Targeted gene(s)/phenotype under study 

CLCN3 (OMIM 600580)

• Summary 

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.

• Coordinating clinicians:
  Dr. Tinatin Tkemaladze¹
  Dr. Allan Bayat²
  Dr. Reza Maroofian³
  Dr. Thomas Jentsch⁴
• Institution (dept, hospital, city, country):
  ¹Department of Genetics, Tbilisi State Medical University, Tbilisi, Georgia
  ²Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center,  Dianalund, Denmark
  ³Department of Neuromuscular Disorders, UCL Institute of Neurology, Queen Square, London, UK
  ⁴NeuroCure Centre of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany
• Contact email: t.tkemaladze@tsmu.edu; abaya@filadelfia.dk; r.maroofian@ucl.ac.uk; Jentsch@fmp-berlin.de
  

• 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

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 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

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: seor@filadelfia.dk;  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. Find here the publication. 

• 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

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

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 

• Short title

 DNM1L mutations leading to severe epileptic encephalopathy including FIRES

• Targeted gene(s)/phenotype under study

DNM1L p.Arg403Cys variant

• Summary 

   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.

• Coordinating clinician: Leo Arkush
• Institution (dept, hospital, city, country): Pediatric Neurology Unit, Sheba Medical Center, Ramat Gan, Israel

• 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 SCN2A associated disorders

• Targeted gene(s)/phenotype under study 

SCN2A

• Summary 

   Pathogenic variants in SCN2A – encoding the voltage-gated sodium channel Na_V1.2 – 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 Na_V1.2 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.

• Coordinating clinician: Walid Fazeli
• Institution (dept, hospital, city, country): Dept of Pediatric Neurology, University Hospital Bonn, Germany in collaboration with the Danish Epilepsy Centre, Filadelfia, Denmark (Prof. Rikke S Møller)

• 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