title: The expanding clinical and genetic spectrum of ATP1A3-related disorders.
abstract: OBJECTIVE
  We aimed to delineate the clinical and genetic spectrum of ATP1A3-related disorders and recognition of a potential genotype-phenotype correlation.
  
  
  METHODS
  We identified 16 new patients with alternating hemiplegia of childhood (AHC) and 3 new patients with rapid-onset dystonia-parkinsonism (RDP) and included these as well as the clinical and molecular findings of all previously reported 164 patients with mutation-positive AHC and RDP in our analyses.
  
  
  RESULTS
  Major clinical characteristics shared in common by AHC and RDP comprise a strikingly asymmetric, predominantly dystonic movement disorder with rostrocaudal gradient of involvement and physical, emotional, or chemical stressors as triggers. The clinical courses include an early-onset polyphasic for AHC, a later-onset mono- or biphasic for RDP, as well as intermediate forms. Meta-analysis of the 8 novel and 38 published ATP1A3 mutations shows that the ones affecting transmembrane and functional domains tend to be associated with AHC as the more severe phenotype. The majority of mutations are located in exons 8, 14, 17, and 18.
  
  
  CONCLUSIONS
  AHC and RDP constitute clinical prototypes in a continuous phenotypic spectrum of ATP1A3-related disorders. Intermediate phenotypes combining criteria of both conditions are increasingly recognized. Efficient stepwise mutation analysis of the ATP1A3 gene may prioritize those exons where current state of knowledge indicates mutational clusters.
authors: From the Department of Pediatrics and Adolescent Medicine (H.R., A.O., P.H., L.S., R.S., J.G., K.B.), Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University; Department of Pediatrics (M.B.), Hospital Dritter Orden, Munich, Germany; Departments of Pediatric Neurology (I.C.), Hospital Maria Pia do Centro Hospitalar do Porto, Portugal; 4IRCCS Stella Maris (S.F.), Calambrone, Pisa; Department of Clinical and Experimental Medicine (S.F.), University of Pisa, Italy; Neurogenetics Unit (C.M.L.), Department of Neurology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil; and Children's Hospital of Eastern Ontario (S.S.), Ottawa, Canada.
authors: Hendrik
authors: H
authors: Rosewich
authors: Andreas
authors: A
authors: Ohlenbusch
authors: Peter
authors: P
authors: Huppke
authors: Lars
authors: L
authors: Schlotawa
authors: Martina
authors: M
authors: Baethmann
authors: Inês
authors: I
authors: Carrilho
authors: Simona
authors: S
authors: Fiori
authors: Charles Marques
authors: CM
authors: Lourenço
authors: Sarah
authors: S
authors: Sawyer
authors: Robert
authors: R
authors: Steinfeld
authors: Jutta
authors: J
authors: Gärtner
authors: Knut
authors: K
authors: Brockmann
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D020821:Dystonic Disorders / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006429:Hemiplegia / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D015201:Meta-Analysis as Topic; D009154:Mutation / Q000235:genetics*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*; D055815:Young Adult
chemical_list: C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase