The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management
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.
We thank all of the families for their participation. Thanks to Dr. Deirdre Lucas and Dr. Rudrapathy Palaniappan for clinical expertise and data collection in one of the British cases, to Clara van Karnebeek for genetic testing of cases 15 and 16, to Dr. Anne Läßig for phoniatrics in case 18, and to the Swedish expert team of deafblindness. Lone Sandbjerg Hindbæk, Kennedy Center, is thanked for excellent technical help. We thank Hans Ulrik Møller, Department of Ophthalmology, Viborg Hospital for long standing continuous efforts to make a diagnosis in the Danish families, and raising suspicion about mitochondrial aetiology during these efforts. We thank Dr. Marcus Dittrich and Dr. Tobias Müller Müller from the Department of Bioinformatics, the University of Würzburg, Germany, for pipeline development and bioinformatics support in case 18. We would like to thank Arnold Starr, MD, Professor Emeritus Recalled, Neurology and Neurobiology, University California Irvine for critical reading and valuable comments to the manuscript.
All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. TM is supported by the German Research Foundation through the Leibniz Program.
Compliance with ethical standards
This is a retrospective study performed in accordance with Helsinki declaration. All patients have given informed consent to publish. For case 18, the study has been approved by the Ethics Committee of the University of Würzburg (approval number: 46/15).
Conflict of interest
The authors declare that they have no conflict of interest.
- Heimer G, Sadaka Y, Israelian L, Feiglin A, Ruggieri A, Marshall CR, Scherer SW, Ganelin-Cohen E, Marek-Yagel D, TzadokM Nissenkorn A, Anikster Y, Minassian BA, Zeev BB (2015) CAOS-episodic cerebellar ataxia, areflexia, optic atrophy, and sensorineural hearing loss: a third allelic disorder of the ATP1A3 gene. J Child Neurol 30:1749–1756CrossRefPubMedGoogle Scholar
- Heinzen EL, Arzimanoglou A, Brashear A, Clapcote SJ, Gurrieri F, Goldstein DB, Jóhannesson SH, Mikati MA, Neville B, Nicole S, Ozelius LJ, Poulsen H, Schyns T, Sweadner KJ, van den Maagdenberg A, Vilsen B, ATP1A3 Working Group (2014) Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol 13(5):503–514CrossRefPubMedPubMedCentralGoogle Scholar
- Jespersen T, Grunnet M, Angelo K, Klaerke DA, Olesen SP (2002) Dual-function vector for protein expression in both mammalian cells and Xenopus laevis oocytes. BioTechniques 32:536–538, and 540Google Scholar
- Kampfhaus RW (ed) (2005) Clinical assessment of child and adolescent intelligence, 2nd edn. Springer, New York (ISBN-10:0–387-26299-7 and ISBN-13:978–0387262994) Google Scholar
- Morth JP, Pedersen BP, Toustrup-Jensen MS, Sørensen TL-M, Petersen J, Andersen JP, Vilsen B, Nissen P (2017) Crystal structure of the sodium-potassium pump. Nature 450. https://doi.org/10.1038/nature06419
- Panagiotakaki E, Grandis ED, Stagnaro M, Heinzenb EL, Fons C, Sisodiya S, de Vries B, Goubau C, Weckhuysen S, Kemlink D, Scheffer I, Lesca G, Rabilloud M, Klich A, Ramirez-Camacho A, Ulate-Campos A, Campistol J, Gianotta M, Moutard M-L, Doummar D, Hubsch-Bonneaud C, Jaffer F, Cross H, Gurrieri F, Tiziano D, Nevsimalova S, Neville B, van den Maagdenberg AMJM, Mikati M, Goldstein DB, Vavassori R, Arzimanoglou A, The Italian IBAHC Consortium, The French AHC consortium and the International AHC Consortium (2015) Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood—a study of 155 patients. Orphanet J Rare Dis 10:123CrossRefPubMedPubMedCentralGoogle Scholar
- Rodriguez-Ballesteros M, del Castillo F, Martin Y, Moreno-Pelayo MA, Morera C, Prieto F, Marco J, Morant A, Gallo-Teran J, Morales-Angulo C, Navas C, Trinidad G, Cruz Tapia M, Moreno F, del Castillo I (2003) Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF). Hum Mutat 22:451–456CrossRefPubMedGoogle Scholar
- Santarelli R, Rossi R, Scimemi P, Cama E, Valentino ML, La Morgia C, Caporali L, Liguori R, Magnavita V, Monteleone A, Biscaro A, Arslan E, Carelli V (2015) OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation. Brain 138:563–576CrossRefPubMedPubMedCentralGoogle Scholar
- Viollet L, Glusman G, Murphy KJ, Newcomb TM, Reyna SP, Sweney M, Nelson B, Andermann F, Andermann E, Acsadi G, Barbano RL, Brown C, Brunkow ME, Chugani HT, Cheyette SR, Collins A, DeBrosse SD, Galas D, Friedman J, Hood L, Huff C, Jorde LB, King MD, LaSalle B, Leventer RJ, Leweit AJ, Massart MB, Mérida MR II, Ptáček LJ, Roach JC, Rust RS, Renault F, Sanger TD, de Menezes MAS, Tennyson R, Uldall P, Zhang Y, Zupanc M, Xin W, Silver K, Swoboda KJ (2015) Alternating hemiplegia of childhood: retrospective genetic study and genotype–phenotype correlations in 187 subjects from the US AHCF Registry. PLoS One 10(5):e0127045. https://doi.org/10.1371/journal.pone.0127045 [Erratum in PLoS One 2015;10(8):e0137370] CrossRefPubMedPubMedCentralGoogle Scholar