Ayelet Zerem1, Kazuhiro Haginoya2, Dorit Lev1,3, Lubov Blumkin1,3, Sara Kivity1, Ilan Linder1, Cheryl Shoubridge4, Elizabeth Emma Palmer5,6,7, Michael Field5,6, Jackie Boyle5,6, David Chitayat7,8, William D Gaillard9, Eric H Kossoff10, Marjolaine Willems11, David Geneviève11, Frederic Tran-Mau-Them11, Orna Epstein12, Eli Heyman12, Sarah Dugan13, Alice Masurel-Paulet14, Ame'lie Piton15,16, Tjitske Kleefstra17, Rolph Pfundt17, Ryo Sato2, Andreas Tzschach18,19, Naomichi Matsumoto20, Hirotomo Saitsu20, Esther Leshinsky-Silver1,3, Tally Lerman-Sagie1,3. 1. Pediatric Neurology Unit, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Institute of Medical Genetics, Holon, Israel. 2. Department of Neurology, Takuto Rehabilitation Center for Children, Miyagi Children's Hospital, Sendai, Japan. 3. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 4. Department of Paediatrics, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia. 5. GOLD Genetics of Learning Disability Service, Waratah, New South Wales, Australia. 6. University of New South Wales, Sydney, New South Wales, Australia. 7. Department of Obstetrics and Gynecology, The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. 8. Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital of Sickkids, University of Toronto, Toronto, Ontario, Canada. 9. Pediatrics and Neurology, Division Epilepsy and Neurophysiology, Comprehensive Pediatric Epilepsy Program, Center for Neuroscience Research, Children's National Medical Center, George Washington University, Washington, District of Columbia, U.S.A. 10. Departments of Pediatrics and Neurology, The Johns Hopkins Hospital, Baltimore, Maryland, U.S.A. 11. Department of Medical Genetics, Rare Diseases and Personalized Medicine, Faculty of Medicine, Unit INSERM 1183, CHU Montpellier, University of Montpellier, Montpellier, France. 12. Pediatric Neurology Department, Pediatric Epilepsy Service, Asaf Harofeh Medical Center, Zerifin, Israel. 13. Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, U.S.A. 14. Reference Center for Developmental Anomalies and Syndromes, Children's Hospital, CHU Dijon, Dijon, France. 15. Department of Translational Medicine and Neurogenetics, IGBMC, CNRS UMR 7104/INSERM U964/Strasbourg University, Strasbourg, France. 16. Genetic Diagnostic Laboratory, University Hospitals of Strasbourg, Strasbourg, France. 17. Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands. 18. Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany. 19. Institute of Clinical Genetics, Technische Universität Dresden, Dresden, Germany. 20. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Abstract
OBJECTIVE: IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants. METHODS: Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians. RESULTS: Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features. SIGNIFICANCE: The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy. Wiley Periodicals, Inc.
OBJECTIVE:IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants. METHODS: Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians. RESULTS: Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features. SIGNIFICANCE: The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy. Wiley Periodicals, Inc.
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