Objective: To describe and compare the clinical phenotype and frequency of symptom presentation of p.Glu831Lys variant associated syndrome within the ATP1A3 gene, adding the first mexican case to the literature, while proposing a new classification  for this entity.

Background: Pathogenic variants in the ATP1A3 gene have been mainly related to alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and  cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. However, other syndromes continue to be described, adding to the phenotypic expression of these entities.[1,2]

Method: A review of the literature with descriptive and comparative analysis was performed and 65 patients were included. Given the variability in symptom presentation, patients were categorized into two groups –complete (CAPOS) and incomplete CAPOS (CAPOS-) depending on the fulfillment of the classical symptoms; in addition, we propose CAPOS+ for those cases that presented other clinical features.

Results: The mean age of onset was 2.32±1.90y, 95.4% developed after a febrile episode. Sensorineural hearing loss was observed in 95.4% (mean onset 4.26y), ataxia in 90.8% (mean onset 4.42y), areflexia in 89.2% (mean onset 4.21y), optic atrophy in 81.5% (mean onset 8.15y), and Pes Cavus in only 32.3%. Other neurological manifestations were present in 83.1%, including oculomotor abnormalities (49.2%; mean onset 10.48y), speech impairment (35.4%; mean onset 6.18y), and vision impairment (29.2%; mean onset 6.47y) (Graph 1][Table 1]. Other movement disorders were identified in 32.3% of cases, such as tremor (13.8%), dystonia (12.3%), and chorea (6.2%). Psychiatric symptoms were reported in 16.9% of cases.  Only 30.8% met the criteria for complete CAPOS, which notably had a higher frequency of Pes Cavus, Optic Atrophy, and psychiatric symptoms [Table 2]. Only 1 patient from the CAPOS- group presented Pes Cavus. There was no significant difference in age of onset between both groups (p = 0.705).

Conclusion: A comprehensive literature review plays a crucial role in refining the characterization of clinical syndromes by mapping the full spectrum of associated symptoms. We expect  this review facilitates a more comprehensive understanding of this heterogeneous entity.

Graph 1.

Table 1.

Table 2.

References: 1. Brashear A, Sweadner KJ, Haq I, Napoli E, Ozelius L. ATP1A3-related disorder. In: GeneReviews. Seattle (WA): University of Washington, Seattle; 1993.
2. Vezyroglou A, Akilapa R, Barwick K, Koene S, Brownstein CA, Holder-Espinasse M, et al. The phenotypic continuum of ATP1A3-related disorders. Neurology 2022;99(14):e1511–26.
3. Tranebjærg L, Strenzke N, Lindholm S, Rendtorff ND, Poulsen H, Khandelia H, et al. The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management. Hum Genet 2018;137(2):111–27.
4. Nicolaides P, Appleton RE, Fryer A. Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS): a new syndrome. J Med Genet 1996;33(5):419–21.
5. Demos MK, van Karnebeek CD, Ross CJ, Adam S, Shen Y, Zhan SH, et al. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis 2014;9(1):15.
6. Rosewich H, Weise D, Ohlenbusch A, Gärtner J, Brockmann K. Phenotypic overlap of alternating hemiplegia of childhood and CAPOS syndrome. Neurology 2014;83(9):861–3.
7. Heimer G, Sadaka Y, Israelian L, Feiglin A, Ruggieri A, Marshall CR, et al. CAOS-episodic cerebellar ataxia, areflexia, optic atrophy, and sensorineural hearing loss: A third Allelic disorder of the ATP1A3 gene: A third Allelic disorder of the ATP1A3 gene. J Child Neurol 2015;30(13):1749–56.
8. Potic A, Nmezi B, Padiath QS. CAPOS syndrome and hemiplegic migraine in a novel pedigree with the specific ATP1A3 mutation. J Neurol Sci 2015;358(1-2):453–6.
9. Maas RPPWM, Schieving JH, Schouten M, Kamsteeg EJ, van de Warrenburg BPC. The genetic homogeneity of CAPOS syndrome: Four new patients with the c.2452G>A (p.Glu818Lys) mutation in the ATP1A3 gene. Pediatr Neurol 2016;59:71–5.e1.
10. Duat Rodriguez A, Prochazkova M, Santos Santos S, Rubio Cabezas O, Cantarin Extremera V, Gonzalez-Gutierrez-Solana L. Early diagnosis of CAPOS syndrome before acute-onset ataxia-review of the literature and a new family. Pediatr Neurol 2017;71:60–4.
11. Duat-Rodríguez A, Prochazkova M, Sebastian IP, Extremera VC, Legido MJ, Palero SR, et al. ATP1A3-related disorders in the differential diagnosis of acute brainstem and cerebellar dysfunction. Eur J Paediatr Neurol 2021;34:105–9.
12. Han KH, Oh DY, Lee S, Lee C, Han JH, Kim MY, et al. ATP1A3 mutations can cause progressive auditory neuropathy: a new gene of auditory synaptopathy. Sci Rep 2017;7(1):16504.
13. Chang IJ, Adam MP, Jayadev S, Bird TD, Natarajan N, Glass IA. Novel pregnancy-triggered episodes of CAPOS syndrome. Am J Med Genet A 2018;176(1):235–40.
14. Hayashida T, Saito Y, Ishii A, Hirose S, Hiraiwa R, Maegaki Y, et al. Further characterization of CAPOS/CAOS syndrome with the Glu818Lys mutation in the ATP1A3 gene: A case report. Brain Dev 2018;40(7):576–81.
15. Paquay S, Wiame E, Deggouj N, Boschi A, De Siati RD, Sznajer Y, et al. Childhood hearing loss is a key feature of CAPOS syndrome: A case report. Int J Pediatr Otorhinolaryngol 2018;104:191–4.
16. Schirinzi T, Graziola F, Nicita F, Travaglini L, Stregapede F, Valeriani M, et al. Childhood rapid-onset ataxia: Expanding the phenotypic spectrum of ATP1A3 mutations. Cerebellum 2018;17(4):489–93.
17. Atilgan A, Yuksel M, Ciprut A. Cochlear implantation in a case of auditory neuropathy spectrum disorder with CAPOS syndrome. Medeni Med J 2019;34(3):318–23.
18. Hashimoto A, Kuki I, Fukuoka M, Kim K, Inoue T, Nukui M, et al. Chronological dynamic changes in cortico-subcortical imbalance of cerebral blood flow in a boy with CAPOS syndrome. Brain Dev 2019;41(7):625–9.
19. Stenshorne I, Rasmussen M, Salvanos P, Tallaksen CME, Bindoff LA, Koht J. Fever-related ataxia: a case report of CAPOS syndrome. Cerebellum Ataxias 2019;6(1):2.
20. Sharawat IK, Kasinathan A, Suthar R, Sankhyan N. CAPOS syndrome: A rare ATP1A3-related disorder. Ann Indian Acad Neurol 2020;23(3):397–8.
21. Chouksey A, Pandey S. ATP1A3 mutation presenting as CAPOS syndrome + dystonia phenotype. Parkinsonism Relat Disord 2020;78:192–4.
22. Lax DN, Bieri P, Patel P. The diagnostic spectrum of ATP1A3-related disorders: 3 new patients. J Neurol Sci 2021;430(120003):120003.
23. Wang W, Li J, Lan L, Xie L, Xiong F, Guan J, et al. Auditory neuropathy as the initial phenotype for patients with ATP1A3 c.2452 G > A: Genotype-phenotype study and CI management. Front Cell Dev Biol 2021;9:749484.
24. Huang D, Song X, Ma J, Li X, Guo Y, Li M, et al. ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA. Eur J Pediatr 2023;182(2):825–36.
25. Kaneshiro S, Hiraumi H, Kobayashi Y, Kanno T, Akasaka M, Shiga K. Childhood fever and hearing loss associated with CAPOS syndrome. Auris Nasus Larynx 2024;51(4):724–7.
26. González Plata A, Marcos Toledano MM, Correa Martínez L, Fernández-Burriel Tercero M. Un nuevo caso de síndrome CAPOS/CAOS. Neurología 2020;35(8):612–4.
27. Gao Y, Li F, Luo R, Chen G, Li D, Wang D, et al. Clinical features of CAPOS syndrome caused by maternal ATP1A3 gene variation: a case report. Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2024;38(1):73–6.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/capos-phenotypic-spectrum-capos-capos-and-capos-within-the-p-glu831lys-variant-of-the-atp1a3-gene-case-report-and-literature-review/