Clinical and Genetic Spectrum of ATP1A3-Related Disorders
Background and Objectives ATP1A3-related disorders comprise an expanding group of ultra-rare neurologic conditions, classically including rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. However, accumulating reports suggest a broader and overlapping phenotypic spectrum. In this context, we established the ATP1A3 Study Group to comprehensively characterize the phenotypic and genotypic spectrum of ATP1A3-related disorders in a Brazilian cohort. Methods We conducted a multicenter, cross-sectional study of individuals with ATP1A3 variants. Cases were recruited across reference centers in 9 Brazilian states, with standardized extraction of demographic, genetic, neuroimaging, EEG, ECG, and clinical data. Variants were annotated using transcript NM_152296.5 (hg19). AlphaFold was used for structural visualization. Multiple correspondence analysis (MCA) was performed to explore symptom clustering. This study was approved by the Ethics Committee of Federal University of São Paulo (Approval No.: 82533124.0.0000.5505). Results A total of 41 patients with ATP1A3 variants were included. Seven phenotypic categories were represented: AHC (17/41), RDP (10/41), CAPOS (7/41), relapsing encephalopathy with cerebellar ataxia (RECA; 4/41), fever-induced paroxysmal weakness and encephalopathy (FIPWE; 1/41), developmental and epileptic encephalopathy 99 (DEE99; 1/41), and malformation of cortical development (MCD; 1/41). Two neonatal-onset cases (DEE99 and MCD) were fatal. We identified 22 distinct ATP1A3 variants, including 4 novel variants (p.Gln920His, p.Arg827Gly, p.Glu670Ala, and c.606+5G>T). Clinical overlap was substantial: Cognitive impairment and seizures occurred across all phenotypes; hypotonia was present in 6 of 7 main phenotypes; abnormal eye movements and fever-induced symptoms occurred in all except MCD; and paroxysmal symptoms were reported in all, except DEE99. MCA demonstrated no discrete clustering by classical phenotype, reinforcing the continuous nature of the ATP1A3 spectrum. ECG abnormalities were rare in our cohort (1/20). Discussion Our findings expand the clinical and genetic landscape of ATP1A3-related disorders and underscore major phenotypic overlap among classical syndromes. The results highlight the need for a unified diagnostic framework. This study also demonstrates the feasibility and scientific value of coordinated rare disease research in resource-limited settings.