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Revising rapid‐onset dystonia–parkinsonism: Broadening indications for ATP1A3 testing
Author(s) -
Haq Ihtsham U.,
Snively Beverly M.,
Sweadner Kathleen J.,
Suerken Cynthia K.,
Cook Jared F.,
Ozelius Laurie J.,
Miller Charlotte,
McCall William V.,
Whitlow Christopher T.,
Brashear Allison
Publication year - 2019
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.27801
Subject(s) - dystonia , parkinsonism , age of onset , proband , family history , medicine , pediatrics , psychology , psychiatry , mutation , disease , genetics , biology , gene
Background and Objectives Rapid‐onset dystonia–parkinsonism (RDP) is caused by mutations in the ATP1A3 gene, which codes for the α‐3 subunit of the Na + /K + ATPase. It has been characterized by rapid‐onset bulbar dysfunction, limb dystonia, bradykinesia, and a rostrocaudal spatial gradient of expression, usually after a physiologic trigger. We reexamined whether these features were in fact characteristic. Methods We characterized phenotypic variation within a cohort of 50 ATP1A3 mutation‐positive individuals (carriers) and 44 mutation‐negative family members (noncarriers). Potential participants were gathered through referral for clinical suspicion of RDP or alternating hemiplegia of childhood. Inclusion criteria were having a ATP1A3 mutation or being a family member of such an individual. Results We found RDP is underdiagnosed if only “characteristic” patients are tested. Rapid onset and bulbar predominance were not universally present in carriers. Among those with at least mild symptoms of dystonia, rostrocaudal severity gradient was rare (7%). Symptoms began focally but progressed to be generalized (51%) or multifocal (49%). Arm (41%) onset was most common. Arms and voice were typically most severely affected (48% and 44%, respectively). Triggers preceded onset in 77% of the participants. Rapid onset, dystonia, parkinsonism, bulbar symptoms, headaches, seizures, frontal impairment, and a history of mood disorder and a history of psychosis were more common in carriers. Approximately half of the proband mutations occurred de novo (56%). Conclusions Our findings suggest that patients should not be excluded from ATP1A3 testing because of slow onset, limb onset, absent family history, or onset in middle adulthood. RDP should be strongly considered in the differential for any bulbar dystonia. © 2019 International Parkinson and Movement Disorder Society