The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management

Abstract

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.

Functional consequences of the CAPOS mutation E818K of Na+,K+-ATPase

“…A recent electrophysiological study reported an accelerated release of Na ϩ toward the extracellular side in the CAPOS mutant (17), which is in good agreement with the present electrophysiological findings and is further underscored by our finding of an increased E 2 P/E 1 P ratio in the biochemical experiments ( Fig. 9).…”

“…The reduced affinity for cytoplasmic Na ϩ , the weaker voltage dependence, and the stronger K ϩ inhibition of the CAPOS mutant compared with WT, on the other hand, provide important clues to the pathophysiology of the mutant, as explained above. The previous study (17) moreover pointed to an observed increase of the inward proton leak through the CAPOS mutant as a probable disease-causing mechanism. The leak current is also increased by ␣2 Na ϩ ,K ϩ -ATPase C-terminal mutations causing familial hemiplegic migraine (36), as well as by C-terminal deletions (37,38), and certain mutations causing aldosterone producing adenomas (39).…”

Auditory Neuropathy Spectrum Disorders: From Diagnosis to Treatment: Literature Review and Case Reports

“…Individuals with mutated variants of the ATP1A3 gene present a syndromic phenotype including cerebellar ataxia, areflexia, pes cavus, optic atrophy and SNHL, summarized in the acronym CAPOS syndrome [90]. In the ten families where CAPOS syndrome has been described to date, only the specific heterozygous mutation c.2452G > A in exon 4 has been consistently reported [91][92][93][94][95][96][97][98].…”

Cochlear Implantation in a Case of Auditory Neuropathy Spectrum Disorder with CAPOS Syndrome

“…It generally starts with the sudden onset of cerebellar ataxia and febrile illness. Recurrent episodes have also been reported 11 . Hearing loss is a common symptom in patients with CAPOS syndrome, however the nature and prognosis of the disease can vary.…”