Adult Phenotype of SYNGAP1-DEE

Marlene Rong; Tim Benke; Quratulain Zulfiqar Ali; Ángel Aledo-Serrano; Allan Bayat; Alessandra Rossi; Orrin Devinsky; Farah Qaiser; Anum S Ali; Alfonso Fasano; Anne S Bassett; Danielle M Andrade

doi:10.1212/NXG.0000000000200105

Adult Phenotype of SYNGAP1-DEE

Neurol Genet. 2023 Nov 17;9(6):e200105. doi: 10.1212/NXG.0000000000200105. eCollection 2023 Dec.

Affiliation

¹ From the Institute of Medical Science (M.R.), University of Toronto; Adult Genetic Epilepsy (AGE) Program (M.R., Q.Z.A., F.Q., A.S.A., D.M.A.), Krembil Neurosciences Institute, Toronto Western Hospital, University Health Network, Ontario, Canada; Department of Pediatrics, Neurology, Pharmacology and Otolaryngology (T.B.), University of Colorado School of Medicine and Children's Hospital Colorado, Aurora; Epilepsy and Neurogenetics Program (A.A.-S.), Neurology Department, Ruber Internacional Hospital, and Initiative for Neuroscience (INCE) Foundation, Madrid, Spain; Department of Drug Design and Pharmacology (A. Bayat), University of Copenhagen; Department for Genetics and Personalized Medicine (A. Bayat), Danish Epilepsy Centre, Dianalund; Institute for Regional Health Services (A. Bayat), University of Southern Denmark, Odense; Department of Epilepsy Genetics and Personalized Medicine (A.R.), Danish Epilepsy Centre, Dianalund, Denmark; Pediatric Clinic (A.R.), IRCCS San Matteo Hospital Foundation, University of Pavia, Italy; NYU Langone Epilepsy Center (O.D.), NY; Edmond J. Safra Program in Parkinson's Disease (A.F.), Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital; Division of Neurology (A.F.), University of Toronto; Krembil Brain Institute (A.F.); Clinical Genetics Research Program (A.S.B.), Centre for Addiction and Mental Health; The Dalglish Family 22q Clinic (A.S.B.), Toronto General Hospital, University Health Network; Department of Psychiatry (A.S.B.), University of Toronto; Toronto Congenital Cardiac Centre for Adults (A.S.B.), Division of Cardiology, Department of Medicine, and Department of Psychiatry, University Health Network; Toronto General Hospital Research Institute and Campbell Family Mental Health Research Institute (A.S.B.); Division of Neurology (D.M.A.), Department of Medicine, University of Toronto, Ontario, Canada.

Abstract

Background and objectives: SYNGAP1 variants are associated with rare developmental and epileptic encephalopathies (DEEs). Although SYNGAP1-related childhood phenotypes are well characterized, the adult phenotype remains ill-defined. We sought to investigate phenotypes and outcomes in adults with SYNGAP1 variants and epilepsy.

Methods: Patients 18 years or older with DEE carrying likely pathogenic and pathogenic (LP/P) SYNGAP1 variants were recruited through physicians' practices and patient organization groups. We used standardized questionnaires to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder and adaptive skills of patients. We also assessed caregiver burden.

Results: Fourteen unrelated adult patients (median: 21 years, range: 18-65 years) with SYNGAP1-DEE were identified, 11 with novel and 3 with known LP/P SYNGAP1 de novo variants. One patient with a partial exon 3 deletion had greater daily living skills and social skills than others with single-nucleotide variants. Ten of 14 (71%) patients had drug-resistant seizures, treated with a median of 2 antiseizure medications. All patients (100%) had abnormal pain processing. Sleep disturbances, social communication disorders, and aggressive/self-injurious behaviors were each reported in 86% of patients. Only half of adults could walk with minimal or no assistance. Toileting was normal in 29%, and 71% had constipation. No adult patients could read or understand verbal material at a sixth-grade level or higher. Aggressive/self-injurious behaviors were leading cause of caregiver burden. The oldest patient was aged 65 years; although nonambulant, she had walked independently when younger.

Discussion: Seventy-one percent of patients with SYNGAP1-DEEs continue to have seizures when adults. Nonseizure comorbidities, especially aggression and self-injurious behaviors, are major management challenges in adults with SYNGAP1-DEE. Only 50% of adults can ambulate with minimal or no assistance. Almost all adult patients depend on caregivers for many activities of daily living. Prompt diagnostic genetic testing of adults with DEE can inform clinical care and guide outcomes of precision therapies.