Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome is a rare chronic neurological disorder named for its unique constellation of symptoms.
CAPOS syndrome was first described in the literature in 1996 by Nicoladies when three family members were found to each have early onset cerebellar ataxia, progressive optic atrophy, areflexia, and a pes cavus deformity (6). Having no clear etiology, Nicoladies described this constellation of symptoms as “a separate syndrome of early onset cerebellar ataxia with associated features (cerebellar ataxia plus)” (6).
The number of people with CAPOS disease is estimated to be fewer than 1,000 (1). As of 2020, 33 cases of CAPOS syndrome have been reported in the English literature (4). Symptoms of this disease may begin as early as infancy (1).
CAPOS syndrome is caused by a mutation in the ATP1A3 gene on chromosome 19q13 which affects the alpha-3 polypeptide of ATPase, Na+/K+ transporte (2). This leads to a distortion of electrochemical gradients across membranes.
Diagnosis of CAPOS syndrome can be made clinically or by identifying the ATP1A3 variant on genotyping. ATP1A3 variants can be inherited or occur de novo, meaning that a family history is not required to make the diagnosis (5). CAPOS syndrome is inherited in an autosomal dominant fashion, meaning that each child of an affected individual has a 50% chance of inheriting the disease. Prenatal testing for fetuses is possible (5).
ATP1A3 mutations are associated with three neurological disorders; CAPOS syndrome, rapid onset dystonia parkinsonism, and alternating hemiplegia of childhood (2, 3). There is consideration that these represent a clinical spectrum of disorders. Unifying features include an abrupt onset of symptoms in the presence of triggering factors and an asymmetric anatomical distribution (9).
|Cerebellar Ataxia||Loss of coordination of muscle movement due to inflammation of the cerebellum|
|Areflexia||Absence of deep tendon reflexes|
|Pes Cavus||High arched feet|
|Optic Atrophy||Death of the retinal ganglion cell axons that comprise the optic nerve|
|Sensorineural hearing loss||Hearing loss resulting from damage to the inner ear or auditory nerve|
Other less common symptoms may include the following: hypotonia or dystonia, myoclonus, bradykinesia, irregular eye movements (nystagmus or strabismus), dysarthria (difficulty speaking), dysphagia (difficulty swallowing), hyporeflexia (decreased reflexes), autistic behavior, intellectual disability, cardiac conduction blocks, and cognitive impairment. Loss of consciousness, seizure, or onset of coma may occur during an episode in rare circumstances (1, 4).
Progressive vision loss due to optic atrophy or episodic abnormal eye movements such as nystagmus or strabismus may be observed (1,2).
Symptoms are typically triggered by an infection-induced fever or childbirth (1). Initial manifestations of CAPOS syndrome are typically episodic ataxia and encephalopathy (1). Sensorineural hearing loss and optic atrophy may occur at onset or later in the course of the disease. Although symptoms typically resolve once the infection has cleared, neurologic sequelae of the disease such as movement problems, vision loss, and hearing loss may persist (1, 2). Permanence of these symptoms vary (3) . People diagnosed with CAPOS syndrome experience 1-3 episodes on average during their lifetime (1).
There is no definitive treatment for CAPOS syndrome. Treatment primarily focuses on symptomatic control and preventative measures. For movement-related symptoms, physical, occupational, and speech therapy are recommended. Vision and hearing loss are controlled with standard treatment (5). Preventative measures include avoiding triggers that can lead to acute attacks as well as the following medications and countermeasures: flunarizine, topiramate, a ketogenic diet, and sleep. Additionally, Acetazolamide may be considered to prevent episodes of ataxia. Being a carbonic anhydrase inhibitor, acetazolamide creates a state of metabolic acidosis which reduces ion leakage and may normalize neuron excitability (8). Case studies however have shown limited success (7).
(1) U.S. Department of Health and Human Services. (2023, February). Cerebellar ataxia, areflexia, PES cavus, optic atrophy and sensorinural hearing loss - about the disease. Genetic and Rare Diseases Information Center. Retrieved February 28, 2023, from https://rarediseases.info.nih.gov/diseases/1188/cerebellar-ataxia-areflexia-pes-cavus-optic-atrophy-and-sensorinural-hearing-loss
(2) Vernon, H. J. (2022, December 1). Entry - #601338 - cerebellar ataxia, areflexia, pes cavus, Optic ... - OMIM. Online Mendelian Inheritance in Man. Retrieved March 1, 2023, from https://www.omim.org/entry/601338
(3) Demos, M. K., van Karnebeek, C. D. M., Ross, C. J. D., Adam, S., Shen, Y., Zhan, S. H., Shyr, C., Horvath, G., Suri, M., Fryer, A., Jones, S. J. M., & Friedman, J. M. (2014). A novel recurrent mutation in ATP1A3 causes capos syndrome. Orphanet Journal of Rare Diseases, 9(1), 15. https://doi.org/10.1186/1750-1172-9-15
(4) Sankhyan, N., Sharawat, I. K., Kasinathan, A., & Suthar, R. (2019). Capos syndrome: A rare ATP1A3-related disorder. Annals of Indian Academy of Neurology. https://doi.org/10.4103/aian.aian_41_19
(5) Brashear, A., Sweadner, K. J., Cook, J. F., Swoboda, K. J., & Ozelius, L. (2008). ATP1A3-Related Neurologic Disorders. In M. P. Adam (Eds.) et. al., GeneReviews®. University of Washington, Seattle.
(6) 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 May;33(5):419-21. doi: 10.1136/jmg.33.5.419. PMID: 8733056; PMCID: PMC1050615.
(7) Maas RP, Schieving JH, Schouten M, Kamsteeg EJ, van de Warrenburg BP. The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene. Pediatr Neurol. 2016 Jun;59:71-75.e1. doi: 10.1016/j.pediatrneurol.2016.02.010. Epub 2016 Mar 17. PMID: 27091223.
(8) Sharawat IK, Kasinathan A, Suthar R, Sankhyan N. CAPOS Syndrome: A Rare ATP1A3-Related Disorder. Ann Indian Acad Neurol. 2020 May-Jun;23(3):397-398. doi: 10.4103/aian.AIAN_41_19. Epub 2020 Jun 10. PMID: 32606553; PMCID: PMC7313598.
(9) Carecchio M, Zorzi G, Ragona F, Zibordi F, Nardocci N. ATP1A3-related disorders: An update. Eur J Paediatr Neurol. 2018 Mar;22(2):257-263. doi: 10.1016/j.ejpn.2017.12.009. Epub 2017 Dec 21. PMID: 29291920.