Clinical and Genetic Spectrum of ATP1A3 -Related Disorders

Background and ObjectivesATP1A3-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. MethodsWe 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). ResultsA 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). DiscussionOur 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.

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Journal
Neurology Genetics
Published
2026-08-27
DOI
https://doi.org/10.1212/nxg.0000000000200429
Primary Topic
Ion Transport and Channel Regulation
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article
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article

Clinical and Genetic Spectrum of ATP1A3 -Related Disorders

Érica Nogueira Coelho, Marcondes C. França, Francisco Cardoso, Fernanda Veiga de Góes et al.
Neurology Genetics
Ion Transport and Channel Regulation
article

Clinical and Genetic Spectrum of ATP1A3 -Related Disorders

Érica Nogueira Coelho, Marcondes C. França, Francisco Cardoso, Fernanda Veiga de Góes, Sarah Camargos, Bruna Ribeiro Torres, Emília Katiane Embiruçu de Araújo Leão, Thiago Yoshinaga Tonholo Silva, Maria da Penha Ananias Morita, Pedro Lucas Grangeiro de Sá Barreto Lima, Orlando Graziani Póvoas Barsottini, Ricardo Maciel, Eduardo de Paula Estephan, Fabiano de Oliveira Poswar, Hélio van der Linden, Débora Palma Maia, Paulo Ribeiro Nóbrega, Victor Rebelo Procaci, José Luiz Pedroso, Luciana Midori Inuzuka, Mariana Braatz Krueger, Roberta Borges Gomes Kauark, Patricia Dumke da Silva Moller, Thiago Oliveira Silva, André Luiz Santos Pessoa, Dafne Dain Gandelman Horovitz, Karina Soares Loutfi, Maria Sheila Guimarães Rocha, Vanessa van der Linden, José Darlan Pinheiro Domingues, Katiane Souza-Cabral, Fábio N. Oliveira, Raphael Pinheiro Camurugy da Hora, Isabela Caldeira de Oliveira, Anna Maria Gomes, Marcela Rodriguez de Freitas, as the ATP1A3 Study Group
article en

Abstract

Background and ObjectivesATP1A3-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. MethodsWe 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). ResultsA 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). DiscussionOur 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.

Neurology GeneticsVol. 12(5)
Universidade Federal da Bahia (BR), Faculdade de Medicina de São José do Rio Preto (BR), Universidade de São Paulo (BR), Universidade Estadual de Campinas (UNICAMP) (BR), Universidade Federal do Ceará (BR), Hospital Israelita Albert Einstein (BR), Complexo Hospitalar Universitário Professor Edgard Santos (BR), Hospital de Clínicas de Porto Alegre (BR), Centro de Estudos e Sistemas Avançados do Recife (BR), Hospital das Clínicas da Universidade Federal de Minas Gerais (BR), Instituto Nacional de Saúde (MZ), Hospital Universitário de Brasília (BR), Hospital Infantil Joana de Gusmão (BR), Hospital Infantil Albert Sabin (BR), Hospital do Coração (BR), Faculdade de Medicina de Jundiaí (BR), Hospital Santa Marcelina (BR), Hospital Sírio-Libanês (BR), Hospital de Clínicas (UY), Universidade Federal de São Paulo (BR)
Biogen, Universidade de São Paulo
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