Dravet syndrome: From neurodevelopmental to neurodegenerative disease?
Arunan Selvarajah, Andrea Sabo, Carolina Gorodetsky, Paula T Marques, Ilakkiah Chandran, Miles Thompson, Quratulain Zulfiqar Ali, Mary Pat McAndrews, Maria Carmela Tartaglia, Victor S T Lira, Linda Huh, Mary Connolly, Arezoo Rezazadeh, Farah Qaiser, Tadeu A Fantaneanu, Monica Duong, Karen Barboza, Lysa Boiss�� Lomax, Luciana Inuzuka Nakaharada, Kette Valente, Jack Arbinuch, Mariana Espindola, Eliana Garzon, Gianluca Sorrento, Mary Anne Meskis, Nicole Villas, Veronica Hood, Marta Gonzalez, Elena Cardenal-Mu��oz, Jose Angel Aiba, Lauraine McKenna, Christine Linehan, Sophine Hohn, St��phane Auvin, Orrin Devinsky, Ryan Yuen, Anne T Berg, Babak Taati, Alfonso Fasano, Danielle M Andrade
Author Information
Arunan Selvarajah: Adult Genetic Epilepsy Program, Division of Neurology, Krembil Research Institute, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. ORCID
Andrea Sabo: Kite Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada. ORCID
Carolina Gorodetsky: Division of Neurology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. ORCID
Paula T Marques: Adult Genetic Epilepsy Program, Division of Neurology, Krembil Research Institute, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. ORCID
Ilakkiah Chandran: Adult Genetic Epilepsy Program, Division of Neurology, Krembil Research Institute, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. ORCID
Miles Thompson: Adult Genetic Epilepsy Program, Division of Neurology, Krembil Research Institute, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. ORCID
Quratulain Zulfiqar Ali: Institute of Medical Sciences, University of Toronto, University of Toronto, Toronto, Ontario, Canada. ORCID
Mary Pat McAndrews: Division of Brain, Imaging, & Behaviour, Department of Neuropsychology, Krembil Neurosciences Institute, University of Toronto, University Health Network, Toronto, Ontario, Canada. ORCID
Maria Carmela Tartaglia: Division of Neurology, Department of Medicine, Toronto Western Hospital Krembil Neuroscience Centre, University of Toronto, Toronto, Ontario, Canada. ORCID
Victor S T Lira: Adult Genetic Epilepsy Program, Division of Neurology, Krembil Neurosciences Institute, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. ORCID
Linda Huh: Division of Neurology, Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
Mary Connolly: Division of Neurology, Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
Arezoo Rezazadeh: Division of Neurology, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada. ORCID
Farah Qaiser: Institute of Medical Sciences, University of Toronto, University of Toronto, Toronto, Ontario, Canada. ORCID
Tadeu A Fantaneanu: Division of Neurology, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada. ORCID
Monica Duong: Adult Genetic Epilepsy Program, Division of Neurology, Krembil Research Institute, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
Karen Barboza: Adult Genetic Epilepsy Program, Division of Neurology, Krembil Neurosciences Institute, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. ORCID
Lysa Boiss�� Lomax: Division of Neurology, Kingston General Hospital, University of Kingston, Kingston, Ontario, Canada.
Luciana Inuzuka Nakaharada: S��o Paulo Integrated Neurology Institute, S��o Paulo, Brazil. ORCID
Kette Valente: Pediatric Neurology, Hospital das Cl��nicas, Faculty of Medicine of the University of S��o Paulo, S��o Paulo, Brazil. ORCID
Jack Arbinuch: David and Judi Proctor Department of Mathematics, University of Oklahoma, Norman, Oklahoma, USA.
Mariana Espindola: S��o Paulo Instituto de Neurologia, S��o Paulo, Brazil.
Eliana Garzon: Instituto de Neurologia Integrada de S��o Paulo, S��o Paulo, Brazil.
Gianluca Sorrento: Edmond J. Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, UHN, Toronto, Ontario, Canada.
Mary Anne Meskis: Dravet Syndrome Foundation, Cherry Hill, New Jersey, USA.
Nicole Villas: Dravet Syndrome Foundation, Cherry Hill, New Jersey, USA. ORCID
Veronica Hood: Dravet Syndrome Foundation, Cherry Hill, New Jersey, USA. ORCID
Marta Gonzalez: Dravet Syndrome Foundation, Madrid, Spain.
Elena Cardenal-Mu��oz: Dravet Syndrome Foundation, Madrid, Spain. ORCID
Jose Angel Aiba: Dravet Syndrome Foundation, Madrid, Spain. ORCID
Christine Linehan: School of Psychology, University College Dublin, Dublin, Ireland. ORCID
Sophine Hohn: Cognition and Behaviour Department, Institut des Neurosciences Paris-Saclay, Gif-sur-Yvette, France. ORCID
St��phane Auvin: Department of Pediatric Neurology, H��pital Robert Debr��, Universit�� de Paris, Paris, France. ORCID
Orrin Devinsky: Division of Neurology, New York University Langone Epilepsy Center, New York, New York, USA. ORCID
Ryan Yuen: Department of Molecular Genetics, Genetics & Genome Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. ORCID
Anne T Berg: Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern Feinberg School of Medicine, Chicago, Illinois, USA. ORCID
Babak Taati: Kite Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Alfonso Fasano: Edmond J. Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Centre, Division of Neurology, Krembil Neuroscience Centre, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. ORCID
Danielle M Andrade: Adult Genetic Epilepsy Program, Division of Neurology, Krembil Research Institute, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. ORCID
OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency in the majority of cases. Caregivers of adults with DS often complain about the loss of previously acquired skills. We set out to explore these perceptions and determine whether abnormalities reported were detectable in validated tests. We also investigated possible correlations between symptoms, age, and exposure to sodium channel blockers (SCBs). METHODS: This cross-sectional, multicenter study used the Vineland Adaptive Behavior Scales, 3rd edition (raw scores) for behavior analyses and Moss-Psychiatric Assessment Schedules checklist to screen for psychiatric symptoms. The Social Communication Questionnaire screened for social communication deficits. Parkinsonian features were evaluated with the modified Unified Parkinson's Disease Rating Scale. For gait evaluation, we validated the use of home videos, using instrumental gait analysis in a subgroup of patients, and then used the home videos for the remainder. RESULTS: A total of 92 patients were enrolled (age range���=���18-51���years, mean���=���27.93��������8.59���years). Sixty percent of caregivers observed a decline in previously acquired skills, including intelligence, speech, interaction with others, ability to climb stairs and walk without support, and hand coordination. Adaptive skills, parkinsonian symptoms, and gait were worse in older patients and those exposed to SCBs for longer periods of time. Fourteen percent of patients screened positive for affective disorders, 11.6% for dementia, and 10.5% for a psychotic disorder. Fifty-three percent screened positive for social communication deficits. SIGNIFICANCE: This is the largest group of adults with DS to be systematically evaluated. They had severe nonseizure symptoms. Older age and longer use of SCBs were associated with worse adaptive skills, gait, and parkinsonism. Some older adults screened positive for depression and dementia. Caregivers identified functional decline in activities of daily living (ADLs). Taken together, the risk of dementia, parkinsonian gait, and decline in ability to perform previously mastered ADLs support that some adults with DS may be developing a neurodegenerative disorder.
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