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.
Highlights
We undertook genetic analysis of three affected families to identify the cause of dominantly-inherited CAPOS syndrome
Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (OMIM 601338) is a rare neurological disorder, which to date has only been reported in a single family
Ethical review and approval according to the Finding Of Rare disease GEnes (FORGE) Canada Consortium and University of British Columbia were obtained
Summary
We 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. Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (OMIM 601338) is a rare neurological disorder, which to date has only been reported in a single family. Other features included progressive optic atrophy and sensorineural hearing loss, generalized hypotonia, areflexia and pes cavus without evidence of a peripheral neuropathy on neurophysiological studies. We have identified two additional families with CAPOS syndrome and reassessed the original family. We here describe the clinical features and natural history of this disorder and report a novel heterozygous missense mutation of the ATP1A3 gene that causes CAPOS syndrome in all ten affected members of these three apparently unrelated families
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