Revising rapid‐onset dystonia–parkinsonism: Broadening indications for ATP1A3 testing

Abstract

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

Unraveling Targetable Systemic and Cell-Type-Specific Molecular Phenotypes of Alzheimer’s and Parkinson’s Brains With Digital Cytometry

“…We were thereby able to discriminate genes with a strong disease effect ( Figure 5B ) from those essentially altered by neuronal loss ( Figure 5D ). In fact, according to our analysis, genes reported as playing a role in PD [ ABL1 ( Mahul-Mellier et al, 2014 ), COMT ( Jiménez-Jiménez et al, 2014 ), GRK5 ( Liu et al, 2010 ), and APT1A3 ( Haq et al, 2019 )] were found associated with neuronal loss rather than the disease itself ( Figures 5A,C ).…”

ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum

“…RDP is an autosomal dominant disorder with variable penetrance, although some cases may appear sporadic due to de novo pathogenic variants, with an onset most commonly in the teens to twenties ( 15 ). Approximately half of the pathogenic variants occurred de novo ( 16 ).…”

Misfolding, altered membrane distributions, and the unfolded protein response contribute to pathogenicity differences in Na,K-ATPase ATP1A3 mutations

“…Heterozygous mutations in the genes for three Na,K-ATPase catalytic subunit isoforms can result in debilitating neurologic syndromes, but the presentations vary widely in severity. The mildest syndromes have onset in adults or youth and are often inherited: axonal Charcot-Marie-Tooth neuropathy (CMT2) in ATP1A1 ( 1 ), familial hemiplegic migraine (FHM2), epilepsy, or both in ATP1A2 ( 2 ), and rapid-onset dystonia-parkinsonism (frequently triggered by stress) in ATP1A3 ( 3 ). In ATP1A3 there are also three fever-induced syndromes, typically with childhood onset: relapsing encephalopathy with cerebellar ataxia ( 4 ), fever-induced paroxysmal weakness and encephalopathy ( 5 ), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness ( 6 ).…”