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The Phenotypic Continuum of ATP1A3-Related Disorders

Aikaterini Vezyroglou¹, Rhoda Akilapa², Katy Barwick²

¹From the Developmental Neurosciences (A.V., K.B., M.A.K., J.H.C.), UCL Great Ormond Street Institute of Child Health, London, UK; Department of Neurology (A.V., L.C., M.A.K., J.H.C.), Great Ormond Street Hospital, London, UK; Department of Clinical Genetics (R.A., M.H.-E.), Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, United Kingdom; Department of Clinical Genetics (S.K., T.T.K., C.A.L.R.), Leiden University Medical Center, The Netherlands; Division of Genetics and Genomics (C.A.B., P.B.A.), the Manton Center for Orphan Disease Research, Boston Children's Hospital, MA; Department of Pediatrics (C.A.B., P.B.A.), Harvard Medical School, Boston, MA; All Wales Medical Genomics Service (A.E.F.), NHS Wales Cardiff and Vale University Health Board, Institute of Medical Genetics, University Hospital of Wales, UK; Division of Cancer and Genetics (A.E.F.), School of Medicine, Cardiff University, UK; Nuffield Department of Clinical Neurosciences (A.H.N., G.K.T.), University of Oxford, UK; Department of Clinical Genetics (E.H., A.M.), Great Ormond Street Hospital, London, UK; Department of Paediatric Neurology (I.H.), Central Manchester University Hospitals NHS Foundation Trust, UK; SW Thames Regional Genetics Service (S.M.), St George's University Hospitals NHS Foundation Trust, UK; Department of Paediatric Neurology (S.R.M.), Ryegate Children's Centre, Sheffield Children's Hospital, United Kingdom; Institute of Genetic Medicine (M.S.), Newcastle Upon Tyne, UK; Clinical Genetics (P.D.T.), Royal Devon & Exeter NHS Foundation Trust, UK; Aneurin Bevan University Health Board (D.D.), Royal Gwent Hospital, Newport, UK; Division of Newborn Medicine (P.B.A.), Boston Children's Hospital, MA; North West Thames Regional Genetics Service (V.C., N.G., S.E.H., J.R.), Northwick Park Hospital, Middlesex, UK; Department of Clinical and Experimental Epilepsy (S.M.S.), UCL Queen Square Institute of Neurology, London, UK; Department of Oncology & Metabolism (M.B.), University of Sheffield, UK; and Sheffield Clinical Genetics Service (M.B.), Sheffield Childrens NHS Foundation Trust, UK. k.vezyroglou@ucl.ac.uk.

|October 3, 2022

Summary

ATP1A3 variants cause diverse neurological disorders. Combining symptom analysis with variant data aids in diagnosing ATP1A3-related conditions, improving patient identification beyond strict criteria.

Area of Science:

Genetics
Neurology
Molecular Biology

Background:

The ATP1A3 gene is linked to various neurological disorders, including alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism.
Phenotypic variability of ATP1A3 variants complicates the diagnosis of undiagnosed patients.

Purpose of the Study:

To describe the phenotypic features of individuals with pathogenic/likely pathogenic ATP1A3 variants.
To review published ATP1A3 variants associated with human neurologic disease.
To demonstrate the heterogeneous clinical spectrum and identify phenotypic overlap for streamlined diagnosis.

Main Methods:

Collected clinical data from undiagnosed individuals with ATP1A3 variants.
Conducted a literature review of ATP1A3 variants in human neurologic disease (2004-2021).
Analyzed variant pathogenicity using Combined Annotation-Dependent Depletion (CADD) scores and variant location.

Main Results:

Twenty-four individuals with 21 ATP1A3 variants presented with diverse phenotypes, often not fitting established criteria.
Common features included paroxysmal events, cognitive impairment, ataxia, dystonia, and neuropsychiatric diagnoses.
Literature review identified 1,108 individuals with 168 ATP1A3 variants; rarer variants correlated with rarer symptoms.

Conclusions:

ATP1A3-related conditions present a wide spectrum of neurological symptoms.
Evaluating a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, cognitive impairment, CADD scores, and variant location aids diagnosis.
This approach can help identify ATP1A3-related conditions more effectively than diagnostic criteria alone.

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