CAOS—Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss

Abstract

We describe the molecular basis of a distinctive syndrome characterized by infantile stress-induced episodic weakness, ataxia, and sensorineural hearing loss, with permanent areflexia and optic nerve pallor. Whole exome sequencing identified a deleterious heterozygous c.2452 G>A, p.(E818K) variant in the ATP1A3 gene and structural analysis predicted its protein-destabilizing effect. This variant has not been reported in context with rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood, the 2 main diseases associated with ATP1A3. The clinical presentation in the family described here differs categorically from these diseases in age of onset, clinical course, cerebellar over extrapyramidal movement disorder predominance, and peripheral nervous system involvement. While this paper was in review, a highly resembling phenotype was reported in additional patients carrying the same c.2452 G>A variant. Our findings substantiate this variant as the cause of a unique inherited autosomal dominant neurologic syndrome that constitutes a third allelic disease of the ATP1A3 gene.

Research conference summary from the 2014 International Task Force on ATP1A3 -Related Disorders

“…21 Of note, only 5 of 18 identified patients exhibit pes cavus, and a full spectrum of manifestations is likely broader. 7,21–23 …”

Familial childhood-onset progressive cerebellar syndrome associated with the ATP1A3 mutation

“…3 Our proband has flat feet, and she and her daughter have scoliosis, extending the musculoskeletal phenotype of ATP1A3 -spectrum syndromes. The age at onset in this family fits with CAPOS/CAOS and AHC, and the development of pyramidal signs and an extrapyramidal disorder observed is more in keeping with nonparoxysmal AHC/RDP features.…”

“…1–3 Intermediate RDP-AHC phenotypes are emerging. Positional mutations 274, 583, 867, and 923 lead to both RDP and AHC, suggesting different pathomechanisms.…”

Unmet Needs in Dystonia: Genetics and Molecular Biology—How Many Dystonias?

“…The disease is inherited in an autosomal dominant manner with reduced penetrance. Heterozygous missense and de novo mutations in the Na+/K+-ATPase alpha3 subunit ( ATP1A3 ) can cause either rapid-onset dystonia-parkinsonism (DYT12) (44), or alternating hemiplegia of childhood (AHC), a severe neurodevelopmental syndrome characterized by hemiplegic episodes and neurological complaints (45), respectively. Notably, no DYT12 mutations were reported to cause AHC, whereas in two cases the same amino acid was affected.…”

“…Both DYT12 and AHC mutations lead to reduced ATPase activity, whereas AHC mutations did not affect the protein expression level that was observed for DYT12 . Recently, a third allelic disorder for ATP1A3 was identified, episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss (CAOS) by exome sequencing (45). How different mutations in ATP1A3 can lead to three disorders with distinct neurological manifestations is not yet known and needs further functional investigations but highlights the complexity and challenges of current genetics research.…”