A novel recurrent mutation in ATP1A3 causes CAPOS syndrome

Abstract

BackgroundWe undertook genetic analysis of three affected families to identify the cause of dominantly-inherited CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss) syndrome.MethodsWe used whole-exome sequencing to analyze two families affected with CAPOS syndrome, including the original family reported in 1996, and Sanger sequencing to assess familial segregation of rare variants identified in the probands and in a third, apparently unrelated family with CAPOS syndrome.ResultsWe found an identical heterozygous missense mutation, c.2452G > A (p.(Glu818Lys)), in the Na+/K+ ATPase α3(ATP1A3) gene in the proband and his affected sister and mother, but not in either unaffected maternal grandparent, in the first family. The same mutation was also identified in the proband and three other affected members of the second family and in all three affected members of the third family. This mutation was not found in more than 3600 chromosomes from unaffected individuals.ConclusionOther mutations in ATP1A3 have previously been demonstrated to cause rapid-onset dystonia-parkinsonism (also called dystonia-12) or alternating hemiplegia of childhood. This study shows that an allelic mutation in ATP1A3 produces CAPOS syndrome.

The Expanding Spectrum of Neurological Phenotypes in Children With ATP1A3 Mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and Beyond

“…14 In all three families, onset of symptoms was associated with a febrile illness. 13,14 Age of onset varied between 6 months and 5 years of age.…”

“…14 In all three families, onset of symptoms was associated with a febrile illness. 13,14 Age of onset varied between 6 months and 5 years of age. 13,14 All affected individuals had cerebellar ataxia, areflexia, optic atrophy, and sensorineural hearing loss at the most recent examination.…”

“…Additionally, all patients had varying degrees of areflexia and pes cavus deformity, ultimately leading to the acronym of CAPOS. More recently, Demos et al 14 reported on additional families with similar syndromic features, during which a novel mutation in ATP1A3 was identified. Additional clinical features were described in this limited series of patients and are reviewed in more detail in later sections.…”

“…13,14 Age of onset varied between 6 months and 5 years of age. 13,14 All affected individuals had cerebellar ataxia, areflexia, optic atrophy, and sensorineural hearing loss at the most recent examination. 14 Three of ten individuals had pes cavus at the most recent examination.…”

“…Recently, three additional families were described with a single, identical ATP1A3 missense mutation. 14 …”