ATP1A3 – CAPOS Syndrome

CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is an autosomal dominant disorder caused by heterozygous variants in ATP1A3, encoding the neuron‐specific Na+/K+‐ATPase α3 subunit. Affected individuals typically present in early childhood with fever‐triggered episodes of cerebellar ataxia and encephalopathy, followed by persistent multisystem neurologic deficits including ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing impairment.

A recurrent heterozygous missense variant, c.2452G>A (p.Glu818Lys), has been identified in all reported CAPOS patients. In a literature review encompassing 25 individuals from multiple unrelated families, this variant segregated in an autosomal dominant manner with complete penetrance ([PMID:28483396]). Segregation analysis across three pedigrees demonstrated 7 additional affected relatives carrying the same ATP1A3 allele ([PMID:24468074]).

Functional studies support a dominant‐negative mechanism. Single‐photon emission computed tomography during acute episodes revealed hyperperfusion in frontal cortex, basal ganglia, and thalamus, and hypoperfusion in occipital and temporal lobes, with partial improvement in the chronic phase, reflecting episodic encephalopathy due to ATP1A3 dysfunction ([PMID:30904181]).

No conflicting evidence has been reported; population screening has not identified c.2452G>A in healthy controls, and the phenotype is highly specific and reproducible across ethnic backgrounds.

In summary, heterozygous ATP1A3 c.2452G>A (p.Glu818Lys) is definitively associated with CAPOS syndrome. Genetic testing for this variant should be considered in patients presenting with fever‐induced ataxia and sensorineural hearing loss to enable early diagnosis and management.

Key Take‐home: ATP1A3 sequencing is clinically indicated for individuals with paroxysmal ataxia and multisystem neurologic features consistent with CAPOS syndrome.

References

• Orphanet journal of rare diseases • 2014 • A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. PMID:24468074
• Pediatric neurology • 2017 • Early Diagnosis of CAPOS Syndrome Before Acute‐Onset Ataxia-Review of the Literature and a New Family. PMID:28483396
• Brain & development • 2019 • Chronological dynamic changes in cortico‐subcortical imbalance of cerebral blood flow in a boy with CAPOS syndrome. PMID:30904181

Evidence Based Scoring (AI generated)