title: CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene.
abstract: We describe the molecular basis of a distinctive syndrome characterized by infantile stress-induced episodic weakness, ataxia, and sensorineural hearing loss, with permanent areflexia and optic nerve pallor. Whole exome sequencing identified a deleterious heterozygous c.2452 G>A, p.(E818K) variant in the ATP1A3 gene and structural analysis predicted its protein-destabilizing effect. This variant has not been reported in context with rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood, the 2 main diseases associated with ATP1A3. The clinical presentation in the family described here differs categorically from these diseases in age of onset, clinical course, cerebellar over extrapyramidal movement disorder predominance, and peripheral nervous system involvement. While this paper was in review, a highly resembling phenotype was reported in additional patients carrying the same c.2452 G>A variant. Our findings substantiate this variant as the cause of a unique inherited autosomal dominant neurologic syndrome that constitutes a third allelic disease of the ATP1A3 gene.
authors.affiliation: Pediatric Neurology Unit, Edmond and Lily Children's Hospital, The Chaim Sheba Medical Center, Ramat Gan, Israel The Pinchas Borenstein Talpiot Medical Leadership Program, The Chaim Sheba Medical Center, Ramat Gan, Israel Galih.md@gmail.com.
authors.forename: Gali
authors.initials: G
authors.lastname: Heimer
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Yair
authors.initials: Y
authors.lastname: Sadaka
authors.affiliation: Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lori
authors.initials: L
authors.lastname: Israelian
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Feiglin
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ruggieri
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Pediatric Neurology Unit, Edmond and Lily Children's Hospital, The Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Ganelin-Cohen
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Children's Hospital, the Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Marek-Yagel
authors.affiliation: Pediatric Neurology Unit, Edmond and Lily Children's Hospital, The Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Tzadok
authors.affiliation: Pediatric Neurology Unit, Edmond and Lily Children's Hospital, The Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Andreea
authors.initials: A
authors.lastname: Nissenkorn
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Children's Hospital, the Chaim Sheba Medical Center, Ramat Gan, Israel The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Berge A
authors.initials: BA
authors.lastname: Minassian
authors.affiliation: Pediatric Neurology Unit, Edmond and Lily Children's Hospital, The Chaim Sheba Medical Center, Ramat Gan, Israel The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Bruria Ben
authors.initials: BB
authors.lastname: Zeev
mesh_terms: D000328:Adult; D002524:Cerebellar Ataxia / Q000235:genetics*; D002675:Child, Preschool; D005190:Family; D005260:Female; D005532:Foot Deformities, Congenital / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D008958:Models, Molecular; D009896:Optic Atrophy / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012021:Reflex, Abnormal / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*
chemical_list: C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase
keywords: CAPOS; alternating hemiplegia of childhood; deafness; intermittent weakness; rapid-onset dystonia parkinsonism