We now report two new patients, a Japanese boy and his mother with a pathogenic mutation (c.2452G>A) in ATP1A3, who were diagnosed with CAPOS syndrome.
CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is a rare neurological disorder, recently associated with the c.2452G > A hotspot mutation in the ATP1A3 gene, with sensorineural hearing loss as a prominent feature.
ATP1A3 mutations are related to a wide spectrum of clinical conditions, including several defined syndromes as rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), together with many other intermediate phenotypes.
Growing evidence suggests that AHC, RDP and CAPOS syndrome are part of a large and continuously expanding clinical spectrum and share some recurrent clinical features, such as abrupt-onset, asymmetric anatomical distribution and the presence of triggering factors, which are highly suggestive of ATP1A3 mutations.
Mutations in the ATP1A3 gene, which encodes the alpha<sub>3</sub>-subunit of sodium-potassium ATPase, are related to a spectrum of neurological diseases 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.
The genetic testing revealed a de novo heterozygous mutation of c.2452G > A (p.Glu818Lys) in the ATP1A3 gene, which was compatible with the clinical phenotype of CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss)/CAOS syndrome.
Through whole exome sequencing and subsequent bioinformatics analysis, two out of the three were found to share a de novo variant, p.E818K of ATP1A3, which had been reported to cause exclusively CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome.
De novo mutations in ATP1A3 cause three types of neurological diseases: AHC; rapid-onset dystonia-Parkinsonism (RDP); and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndromes.
Mutations in ATP1A3 have previously been linked to rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and CAPOS syndrome.
This study confirms that the specific c.2452G>A mutation in the ATP1A3 gene is associated with the CAPOS syndrome in pedigrees of different ethnic backgrounds.
Existing literature on ATP1A3-related disorders in the pediatric population were reviewed, with attention to clinical features and associated genotypes among those with RDP, AHC, or CAPOS syndrome phenotypes.
The phenotypic spectrum of ATP1A3-related neurological disorders continues to expand beyond the distinct yet overlapping phenotypes in patients with AHC, RDP, and CAPOS syndromes.