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.
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12 February 2018
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Acknowledgements
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.
Funding
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.
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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).
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Christian Hamel died during the processing of the manuscript.
A correction to this article is available online at https://doi.org/10.1007/s00439-018-1870-7.
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Fig. S1.
Representative sequence chromatograms for the ATP1A3 missense mutation c.2452G > A; p.Glu818Lys compared to a normal control. The arrow indicates the nucleotide change of the heterozygous missense mutation. Nomenclature of mutation refers to the ATP1A3 RefSeq NM_152296.4, (Gene ID: NG_008015.1) with nucleotide number +1 being A of the start codon ATG. (PDF 301 kb)
Fig. S2.
A, Preserved OAEs at age 13 in case 3, with noticeable high amplitudes. B, ABR (calibrated in dB peSPL) from left and right ear in case 3 without reproducible responses (PDF 346 kb)
Fig. S3.
Case 12 at age 19 years. A Air conduction thresholds for right (red symbols) and left (blue symbols) ear. B. ABR with click stimulus in rarefaction and condensation mode, right and left ear. Phase-reversed cochlear microphonics at 80 dB nHL and higher intensities in combination with no stimulus artefact. C. Transtympanic electrocochleography with alternating click (right ear). A large summation potential is seen with threshold at 50 dB nHL pointing to preserved inner hair cell function. (PDF 634 kb)
Fig. S4.
Case 14 A, Pure tone audiograms at age 29 years (pale lines) and at 32 years (dark lines) showing some progression in the right ear (red) and possibly in the left ear (blue). B, TEOAE and DPOAE are present in both ears. TEOAE Stimulus 83.7 and 85.8 dBpe, reject level = 48.0dBspl; DPOAE Stimulus = 70/70 dB; 8 pts/octave; F2/F1 – 1.22; reject level = 49.5 dBspl, Otodyamics Ltd ILOv6 C, Click ABR shows no repeatable response at 100 dB nHL in either ear. (PDF 2640 kb)
Fig. S5.
Case 15 A, Pure tone audiogram at age 11 years showing moderate hearing loss. B, TEOAE and DPOAE are present. TEOAE Stimulus 85.8 and 86.9 dBpe, reject level = 49.5 dBspl; DPOAE, Stimulus = 65/55 dB; 3 pts/octave; F2/F1 – 1.22; reject level = 49.5 dBspl, Otodyamics Ltd ILOv6 C, Tone pip ABR shows no repeatable response at 80dBnHL at 4 kHz. D, Click ABR showing cochlear microphonics are present in both ears, more marked on the right. Note that primary low frequencies are affected. (PDF 2889 kb)
Fig. S6.
Case 16 A, Pure tone audiograms at age 8 years (pale lines) and 9 years (dark lines) showing severe low- and high-frequency hearing impairment on the right and profound low and moderate hearing loss on the left ear. There has been progression at 500 Hz in the left ear. B, TEOAE and DPOAE are present in both ears at age 7 years. TEOAE Stimulus 83.7 and 83.7 dBpe, reject level = 54.0 and 50.9 dBspl; DPOAE Stimulus = 65/55 dB; 3 pts/octave; F2/F1 – 1.22; reject level = 49.5 dBspl, Otodyamics Ltd ILOv6 C, Click ABR shows no repeatable response at 90 dB nHL in either ear. D, Click ABR shows cochlear microphonics are present in both ears. (PDF 1094 kb)
Fig. S7.
Optical Coherence Tomography (OCT) measuring the retinal nerve fibre thickness profile (RNFL) from case13. A) Retinal nerve fibre (RNFL) thickness profile (black curve) in case 13 at age 13 years shows a reduced RNFL thickness in all quadrants, temporal (TMP), superior (SUP), inferior (INF) and nasal (NAS) sides, in both eyes. OD, right eye; OS, left eye. The green area defines the 5th to 95th (normal thickness), the yellow area the 1st to 5th (border-line thickness) and the red area below the first percentiles (abnormal thickness). Colour scale of the thickness profile is indicated in the colour bar at the bottom of the figure. On the right, RNFL thickness in individual sectors and clock hours demonstrates decreased RNFL thickness in the superior (S), inferior (I), nasal (N) and temporal (T) quadrants of right and left eyes. RNFL measurements in corresponding quadrants are noted in μm. The table represents key parameters of optic nerve head and RNFL analysis. There is severe decreased average RNFL thickness with an average RNFL thickness of 45.22 μm in the right eye and 47.22 μm in the left eye. B) Eye fundus picture of affected case13 shows pale, almost white optic nerve of the left eye at age 26 years. In unaffected people the optic nerve appears pink. (PDF 239 kb)
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Tranebjærg, L., Strenzke, N., Lindholm, S. et al. The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management. Hum Genet 137, 111–127 (2018). https://doi.org/10.1007/s00439-017-1862-z
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DOI: https://doi.org/10.1007/s00439-017-1862-z