Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations.
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2021-01-22
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Abstract
Background
ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments.Aim
We aimed to describe the manifestations of early onset severe ATP1A2-related epileptic encephalopathy and its underlying mutations in a cohort of seven patients.Methods
A retrospective chart review of a cohort of seven patients was conducted. Response to open-label memantine therapy, used off-label due to its NMDA receptor antagonist effects, was assessed by the Global Rating Scale of Change (GRSC) and Clinical Global Impression Scale of Improvement (CGI-I) methodologies. Molecular modeling was performed using PyMol program.Results
Patients (age 2.5-20 years) had symptom onset at an early age (6 days-1 year). Seizures were either focal or generalized. Common features were: drug resistance, recurrent status epilepticus, etc., severe developmental delay with episodes of acute severe encephalopathy often with headaches, dystonias, hemiplegias, seizures, and developmental regression. All had variants predicted to be disease causing (p.Ile293Met, p.Glu1000Lys, c.1017+5G>A, p.Leu809Arg, and 3 patients with p.Met813Lys). Modeling revealed that mutations interfered with ATP1A2 ion binding and translocation sites. Memantine, given to five, was tolerated in all (mean treatment: 2.3 years, range 6 weeks-4.8 years) with some improvements reported in all five.Conclusions
Our observations describe a distinctive clinical profile of seven unrelated probands with early onset severe ATP1A2-related epileptic encephalopathy, provide insights into structure-function relationships of ATP1A2 mutations, and support further studies of NMDAR antagonist therapy in ATP1A2-encephalopathy.Type
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Publication Info
Moya-Mendez, Mary E, David M Mueller, Milton Pratt, Melanie Bonner, Courtney Elliott, Arsen Hunanyan, Gary Kucera, Cheryl Bock, et al. (2021). Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations. Epilepsy & behavior : E&B, 116. p. 107732. 10.1016/j.yebeh.2020.107732 Retrieved from https://hdl.handle.net/10161/22374.
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Scholars@Duke
Melanie Jean Bonner
My current research efforts focus on evaluating and remediating cognitive functioning in children with illnesses that impact the central nervous system. Current projects include: 1) evaluation of a cognitive intervention for children with sickle cell disease; 2) intervention aimed at improving adherence to medication regiments in children with sickle cell disease; and 3) remediation of cognitive deficits in children undergoing treatment for pediatric tumors. I also consult on several multi-center projects aimed at evaluating cognitive functioning and quality of life in children with disease.
Joan Mary Jasien
Dr. Joan Mary Jasien completed a med-peds residency and neurodevelopmental neurology and became boarded in internal medicine, pediatrics, neurology and is board eligible for neurodevelopment. She is the co-director of the Multidisciplinary Spina Bifida and Cerebral Palsy Related Conditions Clinics and cares for children and adults with neurodevelopmental disabilities at Duke University Medical Center in Durham, NC, USA. Her research focus is on neurological aging in Spina Bifida and other neurodevelopmental disabilities.
Vandana Shashi
Undiagnosed and rare diseases cause significant emotional and financial distress to patients who suffer from these and their families. Duke is one of seven clinical sites to be part of the NIH Undiagnosed Diseases Network (UDN). As a principal investigator for the Duke UDN site, I am involved in arranging detailed clinical evaluation for children and adults with undiagnosed diseases and in the interpretation of the genome sequencing that is performed as part of the initiative to obtain a diagnosis in these individuals. I also currently serve as the Co-Chair of the UDN steering committee.
Chromosome 22q11.2 deletion syndrome (also known as velocardiofacial or DiGeorge syndrome: particular interests are in understanding the learning disabilities and the high risk of mental illness in these children as they get older, for which a research study is ongoing. As a clinician and researcher in this area, I run a clinic for children and adults with 22q11.2 deletion syndrome and am an investigator within the International Brain and Behavior Consortium for 22q11.2 deletion syndrome. The goal of the consortium is to conduct research to understand the genetic underpinnings of the serious mental illnesses such as schizophrenia that occur in ~25% of adolescents and adults with the condition.
Marie Theresa McDonald
My current research interests are in the field of Clinical Genetics, Dysmorphology, and Fabry disease.
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