Genotype-Phenotype Correlation Study in a Large Series of Patients Carrying the p.Pro51Ser (p.P51S) Variant in COCH (DFNA9) Part II: A Prospective Cross-Sectional Study of the Vestibular Phenotype in 111 Carriers

Sebastien P F JanssensdeVarebeke, Julie Moyaert, Erik Fransen, Britt Bulen, Celine Neesen, Katrien Devroye, Raymond van de Berg, Ronald J E Pennings, Vedat Topsakal, Olivier Vanderveken, Guy Van Camp, Vincent Van Rompaey, Sebastien P F JanssensdeVarebeke, Julie Moyaert, Erik Fransen, Britt Bulen, Celine Neesen, Katrien Devroye, Raymond van de Berg, Ronald J E Pennings, Vedat Topsakal, Olivier Vanderveken, Guy Van Camp, Vincent Van Rompaey

Abstract

Introduction: DFNA9 is characterized by adult-onset hearing loss and evolution toward bilateral vestibulopathy (BVP). The genotype-phenotype correlation studies were conducted 15 years ago. However, their conclusions were mainly based on symptomatic carriers and the vestibular data exclusively derived from the horizontal (lateral) semicircular canal (SCC). The last decade was marked by the emergence of new clinical diagnostic tools, such as the video head impulse test (vHIT) and vestibular-evoked myogenic evoked potentials (VEMPs), expanding our evaluation to all six SCCs and the otolith organs (saccule and utricule).

Aim: The aim of this study was to comprehensively evaluate vestibular function in the largest series presymptomatic as well as symptomatic p.P51S variant carriers, to determine which labyrinthine part shows the first signs of deterioration and which SCC function declines at first and to determine the age at which p.P51S variant carriers develop caloric areflexia on VNG and vHIT vestibulo-ocular reflex (VOR)-gain dysfunction as defined by the Barany Society criteria for BVP.

Material and methods: One hundred eleven p.P51S variant carriers were included. The following vestibular function tests were applied in two different centers: ENG/VNG, vHIT, and VEMPs. The following parameters were analyzed: age (years), hearing loss (pure-tone average of 0.5-4 kHz [PTA0.5-4, dB HL]), sum of maximal peak slow-phase eye velocity obtained with bi-thermal (30°C and 44°C, water irrigation; 25°C and 44°C, air irrigation) caloric test (°/s), vHIT VOR-gain on LSCC, superior SCC and posterior SCC, C-VEMP both numerical (threshold, dB nHL) and categorical (present or absent), and O-VEMP as categorical (present or absent). The age of onset of vestibular dysfunction was determined both with categorical (onset in decades using Box & Whisker plots) and numeric approach (onset in years using regression analysis). The same method was applied for determining the age at which vestibular function declined beyond the limits of BVP, as defined by the Barany Society.

Results: With the categorical approach, otolith function was declining first (3rd decade), followed by caloric response (5th decade) and vHIT VOR-gains (5th-6th decade). Estimated age of onset showed that the deterioration began with C-VEMP activity (31 years), followed by caloric responses (water irrigation) (35 years) and ended with vHIT VOR-gains (48-57 years). Hearing deterioration started earlier than vestibular deterioration in female carriers, which is different from earlier reports. BVP was predicted at about 53 years of age on average with VNG caloric gain (water irrigation) and between 47 and 57 years of age for the three SCCs. Loss of C-VEMP response was estimated at about 46 years of age.

Conclusion: Former hypothesis of vestibular decline preceding hearing deterioration by 9 years was confirmed by the numeric approach, but this was less obvious with the categorical approach. Wide confidence intervals of the regression models may explain deviation of the fits from true relationship. There is a typical vestibular deterioration hierarchy in p.P51S variant carriers. To further refine the present findings, a prospective longitudinal study of the auditory and vestibular phenotype may help to get even better insights in this matter.

Trial registration: ClinicalTrials.gov NCT03716908.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Copyright © 2021 The Authors. Ear & Hearing is published on behalf of the American Auditory Society, by Wolters Kluwer Health, Inc.

Figures

Fig. 1.
Fig. 1.
Age-related bi-thermal maximal peak SPV (°/s) of caloric responses elicited with both water (red dots) and air (blue dots) stimulation. Note the considerable difference in amplitude and scale of the responses between water and air stimulation. The Barany Society BVP cutoff value of 6°/s is reached much earlier for the air stimulus. BVP, bilateral vestibulopathy; SPV, slow-phase velocity.
Fig. 2.
Fig. 2.
Dashed line: limit line for hyporeflexia, solid line: limit line for BVP (6°/s) as defined by the Barany Society. Caloric bi-thermal 30°C–44°C maximal peak SPV bi-thermal SPV versus age using water (A) and air (B) stimulus. Note the different ages of onset between caloric responses with air versus water irrigation. SPV, slow-phase velocity.
Fig. 3.
Fig. 3.
Dashed line: limit line for hyporeflexia, solid line: limit line for BVP (6°/s) as defined by the Barany Society. Caloric response obtained with bi-thermal 30°C–44°C sum of maximal peak SPV with water and air stimulus in 111 p.P51S variant carriers, 5-year interval. SPV, slow-phase velocity.
Fig. 4.
Fig. 4.
vHIT VOR-gains versus age (n = 111 p.P51S carriers, (A) average vHIT VOR-gains of lateral SCC, (B) vHIT VOR-gains of Posterior SCC, (C) vHIT VOR-gains of Superior SCC, and (D) vHIT VOR-gains of all three SCC/labyrinth. BVP, bilateral vestibulopathy; SCC, semicircular canal; vHIT, the video Head Impulse Test; VOR, vestibulo-ocular reflex.
Fig. 5.
Fig. 5.
vHIT VOR-gains derived from all three SCCs per labyrinth separately and averaged VOR-gains of all three SCC per labyrinth (n = 111 p.P51S carriers). Note that the “starting point” (vHIT VOR-gain

Fig. 6.

vHIT VOR-gains of the LSCC…

Fig. 6.

vHIT VOR-gains of the LSCC versus caloric bi-thermal (30°C–44°C) sum of maximal peak…

Fig. 6.
vHIT VOR-gains of the LSCC versus caloric bi-thermal (30°C–44°C) sum of maximal peak SPV (°/s) in n = 111 p.P51S variant carriers. A and B, VNG caloric stimulus = water irrigation. C and D, VNG caloric stimulus = air irrigation. LSCC, lateral semicircular canal; SPV, slow-phase velocity; VNG, videonystagmography.

Fig. 7.

C-VEMP Thresholds (dB nHL) versus…

Fig. 7.

C-VEMP Thresholds (dB nHL) versus age, n = 73 p.P51S carriers with normative…

Fig. 7.
C-VEMP Thresholds (dB nHL) versus age, n = 73 p.P51S carriers with normative values per age (decade). VEMP, vestibular-evoked myogenic evoked potentials.

Fig. 8.

Age-related typical vestibulograms (ARTV) and…

Fig. 8.

Age-related typical vestibulograms (ARTV) and age-related typical vHITs (ARTvH) with predicted values obtained…

Fig. 8.
Age-related typical vestibulograms (ARTV) and age-related typical vHITs (ARTvH) with predicted values obtained by modeling vestibular test results (C-VEMP thresholds (dBnHL), caloric bi-thermal maximal peak SPV gain and vHIT VOR-gains of the three SCCs (LSCC, SSCC, PSCC), after fitting regression models. A, ARTV. B, ARTvHI. LSCC, lateral semicircular canal; PSCC, posterior semicircular canal; SSCC, superior semicircular canal.

Fig. 9.

Age-related typical vHIT VOR-gains (ARTvH)…

Fig. 9.

Age-related typical vHIT VOR-gains (ARTvH) (means and 95% confidence intervals) n = 111…

Fig. 9.
Age-related typical vHIT VOR-gains (ARTvH) (means and 95% confidence intervals) n = 111 p.P51S variant carriers.

Fig. 10.

Age-related typical observed vestibulograms (ARTV),…

Fig. 10.

Age-related typical observed vestibulograms (ARTV), based in measurements. To obtain optimal visualization, c-VEMP…

Fig. 10.
Age-related typical observed vestibulograms (ARTV), based in measurements. To obtain optimal visualization, c-VEMP thresholds were reversed and rescaled with factor (1/30), caloric bi-thermal maximal peak SPV values were rescaled with factor (1/30) (means+95% confidence intervals). SPV, slow-phase velocity.

Fig. 11.

Decline hierarchy of both auditory…

Fig. 11.

Decline hierarchy of both auditory and vestibular dysfunction: location of end-organ versus age…

Fig. 11.
Decline hierarchy of both auditory and vestibular dysfunction: location of end-organ versus age of onset (years). Note the “_f” refers to female and “_m” refers to male for the hearing frequencies.
All figures (11)
Fig. 6.
Fig. 6.
vHIT VOR-gains of the LSCC versus caloric bi-thermal (30°C–44°C) sum of maximal peak SPV (°/s) in n = 111 p.P51S variant carriers. A and B, VNG caloric stimulus = water irrigation. C and D, VNG caloric stimulus = air irrigation. LSCC, lateral semicircular canal; SPV, slow-phase velocity; VNG, videonystagmography.
Fig. 7.
Fig. 7.
C-VEMP Thresholds (dB nHL) versus age, n = 73 p.P51S carriers with normative values per age (decade). VEMP, vestibular-evoked myogenic evoked potentials.
Fig. 8.
Fig. 8.
Age-related typical vestibulograms (ARTV) and age-related typical vHITs (ARTvH) with predicted values obtained by modeling vestibular test results (C-VEMP thresholds (dBnHL), caloric bi-thermal maximal peak SPV gain and vHIT VOR-gains of the three SCCs (LSCC, SSCC, PSCC), after fitting regression models. A, ARTV. B, ARTvHI. LSCC, lateral semicircular canal; PSCC, posterior semicircular canal; SSCC, superior semicircular canal.
Fig. 9.
Fig. 9.
Age-related typical vHIT VOR-gains (ARTvH) (means and 95% confidence intervals) n = 111 p.P51S variant carriers.
Fig. 10.
Fig. 10.
Age-related typical observed vestibulograms (ARTV), based in measurements. To obtain optimal visualization, c-VEMP thresholds were reversed and rescaled with factor (1/30), caloric bi-thermal maximal peak SPV values were rescaled with factor (1/30) (means+95% confidence intervals). SPV, slow-phase velocity.
Fig. 11.
Fig. 11.
Decline hierarchy of both auditory and vestibular dysfunction: location of end-organ versus age of onset (years). Note the “_f” refers to female and “_m” refers to male for the hearing frequencies.

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