Clinical and Genetic Spectrum of <i>ATP1A3</i>-Related Disorders: A Multicenter Cross-Sectional Study.
This study highlights the substantial clinical overlap among ATP1A3-related disorders, indicating a need for a unified diagnostic framework.
Where it sits
this study against the rest of the leuprorelin corpusSummary and findings
This study measured the phenotypic and genotypic spectrum of ATP1A3-related disorders in a Brazilian cohort of 41 patients with ATP1A3 variants. Seven phenotypic categories were identified, including rapid-onset dystonia-parkinsonism and alternating hemiplegia of childhood. The study found substantial clinical overlap among the phenotypes.
Abstract
<h4>Background and objectives</h4><i>ATP1A3</i>-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 <i>ATP1A3</i> Study Group to comprehensively characterize the phenotypic and genotypic spectrum of <i>ATP1A3</i>-related disorders in a Brazilian cohort.<h4>Methods</h4>We conducted a multicenter, cross-sectional study of individuals with <i>ATP1A3</i> 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).<h4>Results</h4>A total of 41 patients with <i>ATP1A3</i> 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 <i>ATP1A3</i> 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 <i>ATP1A3</i> spectrum. ECG abnormalities were rare in our cohort (1/20).<h4>Discussion</h4>Our findings expand the clinical and genetic landscape of <i>ATP1A3</i>-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.
Background
ATP1A3-related disorders include a range of rare neurologic conditions, with a known association to specific phenotypes like rapid-onset dystonia-parkinsonism and alternating hemiplegia of childhood. Previous studies have suggested a broader phenotypic spectrum, but comprehensive characterization has been limited. This study aims to expand the understanding of ATP1A3-related disorders in a Brazilian cohort, which may provide insights into their clinical and genetic diversity.
Methods
This multicenter, cross-sectional study recruited individuals with ATP1A3 variants from reference centers across 9 Brazilian states. A total of 41 patients were included, with standardized data extraction covering demographics, genetics, neuroimaging, EEG, ECG, and clinical features. The study utilized multiple correspondence analysis to explore symptom clustering.
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 were fatal.
Interpretation
The findings indicate substantial clinical overlap among the phenotypes associated with ATP1A3 variants, which aligns with previous literature suggesting a continuous spectrum rather than discrete categories. While the study provides valuable insights, the small sample size and potential biases limit the generalizability of the results. The implications for clinical practice include the need for a unified diagnostic approach for ATP1A3-related disorders.
Key findings
- 41 patients with ATP1A3 variants included.
- 17/41 had alternating hemiplegia of childhood (AHC).
- 10/41 had rapid-onset dystonia-parkinsonism (RDP).
- 7/41 had CAPOS syndrome.
- Cognitive impairment and seizures occurred across all phenotypes.
Limitations
- small sample size of 41 patients
- potential selection bias due to multicenter design
- no discrete clustering by classical phenotype observed
- ECG abnormalities were rare in the cohort