The Movement Disorder Spectrum of ATP1A3-Related Disorders: Cross-Sectional Analysis and Video Archive of 88 Patients.
The Movement Disorder Spectrum of ATP1A3-Related Disorders: Cross-Sectional Analysis and Video Archive of 88 Patients.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Boston, US · Author affiliation
Movement Disorders Program, Department of Neurology & F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.Location evidence
Beijing, CN · Author affiliation
Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.Location evidence
Barcelona, ES · Author affiliation
Pediatric Neurology Research Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.Location evidence
Athens, GR · Author affiliation
Parkinson's Disease and Movement Disorders Department, HYGEIA Hospital, Athens, Greece.Location evidence
Calgary, CA · Author affiliation
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.Location evidence
Norton, US · Author affiliation
Department of Pediatrics, Division of Pediatric Neurology, Norton Children's Medical Group, University of Louisville, Louisville, Kentucky, USA.Location evidence
Chicago, US · Author affiliation
Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern Feinberg School of Medicine, Chicago, Illinois, USA.Location evidence
Philadelphia, US · Author affiliation
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.Location evidence
Lübeck, DE · Author affiliation
Department of Pediatrics, University Hospital Medical Center Schleswig-Holstein, Lübeck, Germany.Location evidence
DE · Author affiliation · country only
Department of Neurology, University Hospital of Ulm, Ulm, Germany.Location evidence
Toronto, CA · Author affiliation
Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.Location evidence
Houston, US · Author affiliation
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.Location evidence
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Original abstract
BACKGROUND: ATP1A3-related disorders are characterized by genetic heterogeneity and phenotypic pleiotropy, posing significant challenges for classification. Although canonical phenotypes have traditionally guided decision-making, increasing evidence highlights their limitations in capturing the clinical complexity. OBJECTIVE: The aims of this study were to characterize movement disorders, paroxysmal features, and genotype-phenotype relationships; to build a curated video archive; and to assess alignment with canonical phenotypes. METHODS: This is an observational study of 88 individuals with pathogenic or likely pathogenic variants in ATP1A3 who were evaluated in specialized movement disorders programs. RESULTS: Age at last clinical follow-up ranged from 0.1 to 63 years; 80.7% were pediatric patients. Chronic movement disorders were present in 68 of 88 individuals (75%); most had two or more coexisting phenomenologies. Dystonia was most common (47/88, 53%), followed by spasticity (28/88, 32%) and ataxia (28/92, 32%). Paroxysmal events occurred in 78 of 88 (88%) patients, including dystonic spells (45/78, 58%), abnormal eye movements (39/78, 50%), and hemiplegic episodes (37/78, 47%). Common comorbidities included epilepsy (21/88, 24%), cognitive impairment (41/88, 47%), and neuropsychiatric disorders. Only 22 of 88 (25%) fulfilled criteria for a single canonical phenotype; 28 of 88 (32%) met canonical criteria plus additional features, 18 of 88 (20%) satisfied criteria for ≥2 canonical phenotypes, and 20 of 88 (23%) fit no canonical category. We identified 43 distinct ATP1A3 variants; recurrent variants (eg, p.Arg756His, p.Asp801Asn, p.Glu818Lys) showed variable expressivity across categories. CONCLUSIONS: The extensive clinical heterogeneity in ATP1A3-related disorders challenges rigid phenotypic classifications. The predominance of patients with overlapping or atypical features supports a shift toward flexible, symptom-based clinical approaches rather than strict reliance on canonical phenotype recognition. © 2026 International Parkinson and Movement Disorder Society.