Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature.

Ataxia Epilepsy Febrile seizures Intellectual disability YWHAG

Journal

European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society
ISSN: 1532-2130
Titre abrégé: Eur J Paediatr Neurol
Pays: England
ID NLM: 9715169

Informations de publication

Date de publication:
09 Oct 2024
Historique:
received: 15 05 2024
revised: 17 09 2024
accepted: 06 10 2024
medline: 17 10 2024
pubmed: 17 10 2024
entrez: 16 10 2024
Statut: aheadofprint

Résumé

Developmental and epileptic encephalopathy 56 (DEE-56) is caused by pathogenic variants in YWHAG and is characterized by early-onset epilepsy and neurodevelopmental delay. This study reports on a cohort of DEE-56 individuals, correlating antiseizure medication usage and comorbidities, to aid in understanding disease evolution. We analyzed data from thirty-nine individuals aged 3-40 years with YWHAG variants, including 12 previously unreported individuals (2 of these with recurrent distal 7q11.23 deletions) and 27 previously published cases (21 families, including 3 adult individuals reported in a family case). Our assessments encompassed clinical, radiological, and genetic evaluations. All procedures adhered to standardized protocols for patient approvals, registrations, and data collection. Individuals with YWHAG variants exhibited variable psychomotor delay, with the majority experiencing mild intellectual disability. Early-onset seizures, particularly febrile seizures, were common, with various seizure types reported. Valproic acid has emerged as an effective antiseizure medication. Movement disorders were present in a subset of individuals, primarily manifesting as ataxia and tremor. Comorbidities such as autism spectrum disorders and attention deficit-hyperreactivity disorder were observed in a proportion of individuals. We identified a novel YWHAG variant (c.634_645del/p.Asn212_Ser215del) and expanded the genotypic spectrum of the disease. We provide insights into the clinical, radiological, and genetic features of YWHAG-related epileptic encephalopathy. Despite mild clinical symptoms, affected individuals face challenges in daily functioning, underscoring the need for comprehensive care. Valproic acid has been used for seizure control with variable results.

Sections du résumé

BACKGROUND AND OBJECTIVES OBJECTIVE
Developmental and epileptic encephalopathy 56 (DEE-56) is caused by pathogenic variants in YWHAG and is characterized by early-onset epilepsy and neurodevelopmental delay. This study reports on a cohort of DEE-56 individuals, correlating antiseizure medication usage and comorbidities, to aid in understanding disease evolution.
METHODS METHODS
We analyzed data from thirty-nine individuals aged 3-40 years with YWHAG variants, including 12 previously unreported individuals (2 of these with recurrent distal 7q11.23 deletions) and 27 previously published cases (21 families, including 3 adult individuals reported in a family case). Our assessments encompassed clinical, radiological, and genetic evaluations. All procedures adhered to standardized protocols for patient approvals, registrations, and data collection.
RESULTS RESULTS
Individuals with YWHAG variants exhibited variable psychomotor delay, with the majority experiencing mild intellectual disability. Early-onset seizures, particularly febrile seizures, were common, with various seizure types reported. Valproic acid has emerged as an effective antiseizure medication. Movement disorders were present in a subset of individuals, primarily manifesting as ataxia and tremor. Comorbidities such as autism spectrum disorders and attention deficit-hyperreactivity disorder were observed in a proportion of individuals. We identified a novel YWHAG variant (c.634_645del/p.Asn212_Ser215del) and expanded the genotypic spectrum of the disease.
CONCLUSIONS CONCLUSIONS
We provide insights into the clinical, radiological, and genetic features of YWHAG-related epileptic encephalopathy. Despite mild clinical symptoms, affected individuals face challenges in daily functioning, underscoring the need for comprehensive care. Valproic acid has been used for seizure control with variable results.

Identifiants

DOI: 10.1016/j.ejpn.2024.10.005 PMID: 39413657
pubmed: 39413657
pii: S1090-3798(24)00158-2
doi: 10.1016/j.ejpn.2024.10.005
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

63-72

Informations de copyright

Copyright © 2024 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest None of the authors has any conflict of interest to disclose.

Auteurs

Maria Eugenia Amato (ME)

Movement Disorders Unit, Pediatric Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain.

Sol Balsells (S)

Department of Statistics Institut de Recerca Sant Joan de Déu Barcelona, Barcelona, Spain.

Loreto Martorell (L)

Department of Genetic and Molecular Medicine-IPER Institut de Recerca Sant Joan de Déu , Barcelona, Spain; U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Salud Carlos III Health Institute, Barcelona, Spain.

Adrián Alcalá San Martín (A)

Department of Genetic and Molecular Medicine-IPER Institut de Recerca Sant Joan de Déu , Barcelona, Spain.

Karen Ansell (K)

Department of pediatric neurology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Malene Landbo Børresen (ML)

Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

Heather Johnson (H)

Department of Paediatric Neurology, CNP Sanford Children's, South Dakota, USA.

Christian Korff (C)

Pediatric Neurology Unit, Geneva University Hospitals, 1205 Geneva, Switzerland.

Stephanie Garcia-Tarodo (S)

Pediatric Neurology Unit, Geneva University Hospitals, 1205 Geneva, Switzerland.

Jeremie Lefranc (J)

Pediatric Neurophysiology Department, CHU de Brest, Brest, 29200, France.

Anne-Sophie Denommé-Pichon (AS)

INSERM UMR1231 GAD "Génétique des Anomalies Du Développement", FHU-TRANSLAD, University of Burgundy, Dijon, France; Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, University Hospital, Dijon, Bourgogne, France.

Elisabeth Sarrazin (E)

Caribbean Reference Center for Neuromuscular Diseases, University Hospital, Fort de France, Martinique, France.

Nora Zsuzsanna Szabo (NZ)

Saint John's Hospital, Epilepsy-neurology Outpatient Clinic, Child Epilepsy Center, Budapest, Hungary.

Jorge M Saraiva (JM)

Medical Genetics Department, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal; University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, Portugal; Clinical Academic Center of Coimbra, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal.

Dorota Wicher (D)

Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.

Anne Goverde (A)

Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Karen G C B Bindels-de Heus (KGCB)

Department of Pediatrics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Tahsin Stefan Barakat (TS)

Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands; European Reference Network for Rare Neurological Diseases (ERN-RND), Barcelona, Spain; U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain.

Juan Darío Ortigoza-Escobar (JD)

Movement Disorders Unit, Pediatric Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain; European Reference Network for Rare Neurological Diseases (ERN-RND), Barcelona, Spain; U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain. Electronic address: juandario.ortigoza@sjd.es.

Classifications MeSH