Ponghatai Boonsimma 1, Marius Michael Gasser 2, Wiracha Netbaramee 3, Thanin Wechapinan 4, Chalurmpon Srichomthong 1, Chupong Ittiwut 1, Matias Wagner 5, Martin Krenn 6, Fritz Zimprich 7, Angela Abicht 8, Saskia Biskup 9, Timo Roser 2, Ingo Borggraefe 10, Kanya Suphapeetiporn 11, Vorasuk Shotelersuk 1.
Abstract
Background: Mutations in the ATP1A3 gene are known to be the cause of three distinct neurological syndromes including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP) and cerebellar ataxia, arefexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS). Recent studies have suggested the broader diversity of ATP1A3-related disorders. This study aimed to investigate the clinical spectrum in patients carrying causative mutations within the ATP1A3 gene.
Method: The medical histories of nine unrelated patients with diverse phenotypes harboring variants in ATP1A3 were retrospectively analyzed after they were referred to a tertiary epilepsy center in one of the two different health care systems (Germany or Thailand). Clinical features, neurophysiological data, imaging results, genetic characteristics and treatments were reviewed.
Results: Three patients harbor novel mutations in the ATP1A3 gene. Atypical clinical features and imaging findings were observed in two cases, one with hemiplegia-hemiconvulsion-epilepsy syndrome, and the other with neurodegeneration with brain iron accumulation. All nine patients presented with intellectual impairment. Alternating hemiplegia of childhood (AHC) was the most common phenotype (67%). Flunarizine and topiramate led to symptom reduction in 83% and 25% of AHC cases administered, respectively.
Conclusion: The present case series expands the clinical and genetic spectrum of ATP1A3-related disorders.
- Division of Medical Genetics and Metabolism, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok 10330, Thailand.
- Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Haunersches Childrens Hospital, Ludwig Maximilians University of Munich, Germany.
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
- Division of Neurology, Department of Pediatrics, Faculty of Medicine, Queen Sirikit National Institute of Child Health, Bangkok 10400, Thailand.
- Institute of Human Genetics, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute for Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
- Institute of Human Genetics, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany; Department of Neurology, Medical University of Vienna, Vienna, Austria.
- Department of Neurology, Medical University of Vienna, Vienna, Austria.
- Medical Genetic Center Munich, Munich, Germany; Department of Neurology, Friedrich-Baur-Institute, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany.
- Praxis für Humangenetik und CeGaT GmbH, Paul-Ehrlich-Str. 23, Tuebingen, Germany.
- Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Haunersches Childrens Hospital, Ludwig Maximilians University of Munich, Germany; Comprehensive Epilepsy Center, Ludwig Maxiliams University of Munich, Germany.
- Division of Medical Genetics and Metabolism, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok 10330, Thailand. Electronic address: kanya.su@chula.ac.th.