| Title: |
The phenotypic continuum of ATPLA3-related disorders |
| Authors: |
Vezyroglou, A.; Akilapa, R.; Barwick, K.; Koene, S.; Brownstein, C.A.; Holder-Espinasse, M.; Fry, A.E.; Nemeth, A.H.; Tofaris, G.K.; Hay, E.; Hughes, I.; Mansour, S.; Mordekar, S.R.; Splitt, M.; Turnpenny, P.D.; Demetriou, D.; Koopmann, T.T.; Ruivenkamp, C.A.L.; Agrawal, P.B.; Carr, L.; Clowes, V.; Ghali, N.; Holder, S.E.; Radley, J.; Male, A.; Sisodiya, S.M.; Kurian, M.A.; Cross, J.H.; Balasubramanian, M. |
| Publisher Information: |
Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology |
| Publication Year: |
2022 |
| Collection: |
White Rose Research Online (Universities of Leeds, Sheffield & York) |
| Description: |
Background and objectives: ATP1A3 is associated with a broad spectrum of predominantly neurological disorders, that continues to expand beyond the initially defined phenotypes of Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss syndrome (CAPOS). This phenotypic variability makes it challenging to assess pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurological disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process. Methods: Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders (DDD) study with additional cases contributed by collaborators internationally. Detailed clinical data was collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term “ATP1A3” from 2004 to 2021. Results: Twenty-four individuals with a previously undiagnosed neurological phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurological features were common including microcephaly (7;29%), ataxia (13;54%), dystonia (10;42%) and hypotonia (7;29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| ISSN: |
0028-3878 |
| Relation: |
https://eprints.whiterose.ac.uk/id/eprint/189437/9/WNL.0000000000200927.pdf; Vezyroglou, A., Akilapa, R., Barwick, K. et al. (26 more authors) (2022) The phenotypic continuum of ATPLA3-related disorders. Neurology, 99 (14). e1511-e1526. ISSN: 0028-3878 |
| Availability: |
https://eprints.whiterose.ac.uk/id/eprint/189437/; https://eprints.whiterose.ac.uk/id/eprint/189437/9/WNL.0000000000200927.pdf |
| Rights: |
cc_by_4 |
| Accession Number: |
edsbas.DB5AF81B |
| Database: |
BASE |