Objective: To describe a case series of patients with ATP1A3 variants, analyzing their phenotypic presentation and genetic characteristics in Brazil.

Background: ATP1A3-related disorders exhibit a complex clinical spectrum. Patients may present with ataxia, hemiparesis, parkinsonism, dystonia, fever-induced episodes, encephalopathy, epileptic seizures, and psychiatric symptoms, among other features. Describing the clinical spectrum in a Brazilian cohort is essential for improving disease characterization and understanding the distribution of ATP1A3 variants in the Brazilian population.

Method: This retrospective case series analyzed medical records from the neurology outpatient clinics of multiple Brazilian universities, and private neurology practices of the authors. Patients with a confirmed ATP1A3 variant were included, regardless of their clinical phenotype.

Results: We identified 24 cases with a known mutation in ATP1A3, 15 males and 9 females. Age of onset varied from less than a year to 17-year-old. We have found five phenotypes: 11 alternating hemiplegia of childhood (AHC); 5 cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome (CAPOS); 3 rapid-onset dystonia parkinsonism (RDP); 2 developmental and epileptic encephalopathy 99 (DEE99); 2 fever-induced paroxysmal weakness and encephalopathy (FIPWE); 1 relapsing encephalopathy with cerebellar ataxia (RECA). Seizure was present in 8 AHC patients, 2 CAPOS, 2 DEE99, 1 FIPWE. Dystonia was present in all phenotypes. Fever induced symptoms were present in all phenotypes, except RECA. EEG showed abnormalities in seven patients (1 DEE99, 1 CAPOS and 5 AHC). Brain MRI showed abnormalities in six patients (2 DEE99, 1 CAPOS, 1 AHC, 1 RDP and 1 RECA). We found that p.(Asp801Asn) variant was the most common in our cohort, followed by p.(Gly947Arg) and p.(Arg756Cys).

Conclusion: Our cohort highlights the phenotypic heterogeneity and overlap of classic phenotypes in ATP1A3 related disorders, emphasizing the need to consider a combination of neurological symptoms instead of classifying phenotypes in separate syndromes. While some variants have been frequently reported in the literature, our findings reveal a broader spectrum of genetic diversity within the Brazilian population. Further research is needed to clarify the spectrum of this disorder and phenotypical implications from different variants reported.

References: A summarized version of this research was presented at the Brazilian Neurogenetics Conference on March 15, 2025.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-phenotypic-spectrum-of-atp1a3-related-disorders-a-brazilian-cohort/