Clinical and Genetic Spectrum of ATP1A3-Related Disorders: A Multicenter Cross-Sectional Study.
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Rebelo Procaci Victor, da Hora Raphael Pinheiro Camurugy, Gomes Anna Maria, Silva Thiago Yoshinaga Tonholo, Embiruçu Emilia Katiane, Silva Thiago Oliveira, Van Der Linden Vanessa, Estephan Eduardo De Paula, Oliveira Fabio Nazare, de Goes Fernanda Veiga, de Freitas Marcela Rodriguez, Horovitz Dafne Dain Gandelman, Domingues José Darlan Pinheiro, Möller Patricia Dumke da Silva, Poswar Fabiano Oliveira, Krueger Mariana Braatz, van der Linden Hélio, Torres Bruna Ribeiro, Loutfi Karina Soares, Kauark Roberta Borges Gomes, Inuzuka Luciana Midori, Cabral Katiane Sayão Souza, Oliveira Isabela, Rocha Maria Sheila G, Camargos Sarah, Maia Debora Palma, Maciel Ricardo Oliveira Horta, Cardoso Francisco, da Penha Ananias Morita Maria, Coelho Érica Nogueira, França Marcondes C, Lima Pedro Lucas Grangeiro de Sá Barreto, Pessoa André Luiz Santos, Barsottini Orlando G P, Nóbrega Paulo Ribeiro, Pedroso José Luis, as the ATP1A3 Study Group
Аннотация
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.