Progression of Low-Frequency Sensorineural Hearing Loss (DFNA6/14-WFS1)

ORIGINAL ARTICLE Progression of Low-Frequency Sensorineural Hearing Loss (DFNA6/14-WFS1)

Ronald J. E. Pennings, MD; Steven J. H. Bom, MD; Kim Cryns, MSc; Kris Flothmann; Patrick L. M. Huygen, PhD; Hannie Kremer, PhD; Guy Van Camp, PhD; Cor W. R. J. Cremers, PhD

Objective: To assess the audiometric profile and speech Results: All individuals showed low-frequency hearing recognition characteristics in affected members of 2 fami- impairment. The 2-kHz frequency was more affected in lies with DFNA6/14 harboring heterozygous mutations the Dutch III family than in the Dutch IV family. Pro- in the WFS1 gene that cause an autosomal dominant non- gressive hearing loss beyond presbycusis was found syndromic sensorineural hearing impairment trait. in the Dutch IV family and in 3 individuals in the Dutch III family. Annual threshold deterioration was Design: Family study. between 0.6 and 1 dB per year at all frequencies. The speech recognition scores in the Dutch III family Setting: Tertiary referral center. showed significantly more deterioration at increasing levels of hearing impairment compared with those in Patients: Thirteen patients from 2 recently identified the Dutch IV family. Dutch families with DFNA6/14 (Dutch III and IV). Conclusion: Both families showed an autosomal Methods: Cross-sectionalandlongitudinalanalysesofpure- dominant, progressive, low-frequency sensorineural tone thresholds at octave frequencies of 0.25 to 8 kHz were hearing impairment caused by heterozygous WFS1 performed, and speech phoneme recognition scores were mutations. assessed.Progressionwasevaluatedbylinearregressionanaly- sis with and without correction for presbycusis. Arch Otolaryngol Head Neck Surg. 2003;129:421-426

HIRTY-FOUR YEARS ago, the A recent finding is that the WFS1 gene Vanderbilt University He- harbors heterozygous mutations in DFNA6 reditary Deafness Study and DFNA14, and that DFNA6 and Group1 described a large DFNA14 represent the same locus, fur- family with low-frequency ther designated as DFNA6/14.4 Homozy- sensorineuralT hearing impairment show- gous mutations in the WFS1 gene ac- ing an autosomal dominant pattern of in- count for the autosomal recessive Wolfram heritance. Several years later, Konigsmark syndrome.5,6 To our knowledge, 3 fami- et al2 described 3 more families harboring lies with heterozygous mutations in the a dominant low-frequency hearing impair- WFS1 gene have been described: USA1 ment trait. Audiograms in all families dis- (L829P mutation4), Dutch I7 (T699M4), played upward-sloping patterns. Today, and Dutch II8 (A716T4). All families characterization of nonsyndromic forms of showed mild progression of hearing im- hereditary hearing impairment is based pairment; however, only in the Dutch II more on genetic characteristics than on family did this persist beyond correction clinical findings. The loci for nonsyn- for presbycusis.9 Brodwolf et al10 recently From the Departments of dromic autosomal dominant forms of hear- described a German family with Otorhinolaryngology, ing impairment are designated DFNA (DFN DFNA6/14 in whom linkage analysis University Medical Centre for deafness and A for autosomal domi- showed a harboring of low- to mid- St Radboud, Nijmegen, nant) and are numbered in chronological frequency hearing impairment. Young et the Netherlands (Drs Pennings, order of discovery. Forty loci are known to al11 described a Newfoundland kindred Bom, Huygen, Kremer, and cause autosomal dominant nonsyn- harboring the same WFS1 mutation Cremers), and Medical 3 Genetics, University of dromic hearing impairment. Only 2 of (A716T) as was detected in the Dutch II Antwerp, Antwerp, Belgium them, DFNA1 and DFNA6/14, are charac- family. (Ms Cryns, Mr Flothmann, terized by predominant low-frequency hear- This report describes the hearing im- and Dr Van Camp). ing impairment. pairment in 2 additional families with

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I:2 I:1 I:1 I:2 I:3 I:4

12 II:1 II:2 II:3 II:4 II:5 II:1 II:2

III:1 III:2 III:3 III:4 III:5 III:6

III:1 III:2 III:3 III:4 III:5

IV:1 IV:2 IV:3 IV:4 IV:5 IV:6 IV:7 IV:8 IV:9

IV:1 IV:2 IV:3 IV:4 IV:5 V:1 V:2 V:3 V:4 V:5

Figure 1. Pedigrees of the Dutch III and Dutch IV kindreds. Squares indicates men; circles, women; slashed symbols, deceased; crossed symbols, Duchenne-type muscular dystrophy; diamond symbol, number of unaffected siblings; and solid symbols, low-frequency hearing impairment.

DFNA6/14, Dutch III and Dutch IV, that harbor 2 mu- age correct) were derived from individual performance- tations in the WFS1 gene, G674E and G674V, respec- intensity plots. Regression analysis was performed for tively. performance-age plots (scores related to age) and performance-impairment plots (scores on means of pure-tone METHODS thresholds at 0.5, 1, and 2 kHz). Speech recognition scores were fitted by a linear regression line. The x-coordinate relat- In the Dutch III and Dutch IV families (Figure 1), the WFS1 ing to a 90% score (X90) represented the onset age (in years) gene was analyzed for mutations after audiograms of mem- for X and the onset level for pure-tone audiogram thresholds bers of both families demonstrated low-frequency hearing im- (measured in decibels hearing level) at 0.5 to 2 kHz. The 95% pairment. Four affected individuals from the Dutch III family confidence interval (CI) for X90 was obtained by nonlinear had a G674E mutation, and 9 from the Dutch IV family had a regression analysis using an alternative equation for the linear 12 G674V mutation. From the pedigree, it was concluded that regression line, Y=slope(X−X90)+90, where Y is the binaural the deceased individual III:2 in the Dutch IV family also har- mean air conduction threshold measured in decibels hearing bored the G674V mutation. level. t Tests (including Welch correction if the Bartlett test In this study, we assess the audiometric profile and speech detected unequal variances) were used to test differences in recognition performance in affected family members with X90 between the families. Slope represented the deterioration DFNA6/14 of different ages. Medical histories were taken, fo- rate relative to age and deterioration gradient for pure-tone cusing on acquired and syndromic conditions. Otoscopy was audiogram threshold. performed and previous audiologic data were retrieved, in- Analysis of covariance was used to compare slopes and including data on deceased individual III:2 in the Dutch IV fam- tercepts between regression lines pertaining to different fre- ily. Pure-tone thresholds (binaural means of air and bone con- quencies within a given family or pertaining to the families at duction) at octave frequencies of 0.25 to 8 kHz and speech a given frequency. Some slopes and intercepts were pooled where recognition scores (monaural means of maximum phoneme possible. scores) were obtained in a sound-treated room according to the Vestibulo-ocular responses were evaluated in individuals norms defined by the International Organization for Standard- IV:2 and IV:5 in the Dutch IV family using electronystagmog- ization (ISO).13,14 In individual III:3 in the Dutch IV family, data raphy with computer analysis. Saccadic, smooth pursuit, op- on the left ear were excluded because of previous ear surgery. tokinetic, and vestibular nystagmus responses were evalu- Cross-sectional linear regression analysis was performed ated. Vestibular stimulation comprised rotatory and caloric tests. on threshold-on-age data from the patients’ most recent visits, Details and normal values have been previously described.16 using commercially available software (Prism 3.02; GraphPad Software, Inc, San Diego, Calif). Progression, identified by an upward slope, was evaluated with and without correction for RESULTS presbycusis. Progression was considered significant when a significant positive slope (PϽ.03) was detected for the raw thresh- Four individuals in the Dutch III family and 9 in the Dutch old data at a sufficiently high number of different sound fre- IV family showed low-frequency hearing impairment. The quencies (PϽ.05 in the appropriate binomial distribution). Dutch IV kindred also harbored a Duchenne-type mus- Threshold data were also evaluated for progression after cor- cular dystrophy trait; according to family history, 3 af- rection for age and sex for median norms (50th percentile) of 15 fected boys (Figure 1) without hearing impairment died presbycusis, according to the ISO 7029 norms. at a young age. Age-related typical audiograms were derived from the re- Cross-sectional analysis of threshold-on-age data was sults of the cross-sectional regression analysis of the raw data. Individual longitudinal regression analysis, also including cor- performed in both families. The results are shown in rection for presbycusis, was performed for individuals III:1, IV:1, Figure 2. The scattering of threshold data points was and IV:2 in the Dutch III family. not substantially different between the 2 families. Both For cross-sectional regression analysis of speech audio- families showed significant progression. When indi- metric data, maximum phoneme recognition scores (percent- vidual frequencies were compared, analysis of raw data

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Family Dutch IV 100 Family Dutch III

120 2 kHz 4 kHz 8 kHz Threshold, dB HL

100

0 0 204060800 204060800 20406080 Age, y Age, y Age, y

Figure 2. Cross-sectional analysis of binaural means of air conduction thresholds (in decibels hearing level [db HL]) for the Dutch IV kindred (open circles) relative to age (in years). Regression lines are included. Bold lines indicate significant progress; dotted lines, age-corrected thresholds (small diamonds). Progression of thresholds was significant at all frequencies, except for those at 2 and 4 kHz and the age-corrected thresholds at 8 kHz. Threshold data for the Dutch III family (solid circles and small crosshair symbols) are included, but without the corresponding regression lines.

showed no significant differences in progression be- was 0.8% per year (95% CI, 0.5%-1.1% per year). The val- tween the families. In the Dutch IV kindred, no signifi- ues for the Dutch IV family were similar, with a mean on- cant difference in progression among the frequencies was set age of 28 years (95% CI, 18-38 years) and a mean de- found using raw data. The pooled annual threshold deterioration rate of 0.5% per year (95% CI, 0.1%-0.9% per terioration was 1.0 dB. However, after correction for pres- year). A significant performance difference between the bycusis, the Dutch IV family showed significant progres- families was found only in the level of impairment (Fig- sion, which was not the case for individuals in the Dutch ure 5B). In the Dutch III family, the mean deterioration III family. gradient was almost 2% per decibel (95% CI, 1.4%-2.6% Age-related typical audiograms for the 2 families dis- per decibel). In the Dutch IV family, it was 0.45% per deci- played ascending configurations from low-frequency bel (95% CI, 0.3%-0.6% per decibel). There was no sig- thresholds (fairly flat at 0.25-1 kHz) of about 40 to 70 nificant difference in mean onset level between the fami- dB in the Dutch III kindred and 40 to 90 dB in the Dutch lies (Dutch III, 58 dB hearing level [95% CI, 55-61 dB] IV kindred (Figure 3). A flat threshold configuration and Dutch IV, 51 dB hearing level [95% CI, 42-60 dB]). was found at 2 kHz in the Dutch III family. In younger None of the patients reported substantial vestibu- individuals, the thresholds at 4 to 8 kHz were close to lar symptoms, and the 2 individuals examined showed normal, especially in the Dutch IV family. normal ocular motor and vestibular responses. In individuals III:1, IV:1, and IV:2 in the Dutch III family, longitudinal regression analysis of pure-tone au- COMMENT diograms was performed. Significant progression was detected in all of them (Figure 4), persisting beyond cor- The Dutch III (longitudinal analyses) and Dutch IV (cross- rection for presbycusis. Age-related typical audiograms sectional analyses) families showed similar progression that derived for these analyses (plots not shown) were simi- persisted after correction for presbycusis. On evaluation of lar to those obtained for the cross-sectional analysis (Fig- speech recognition scores, the performance-impairment ure 3). plots were significantly different between the 2 kindreds, Figure 5 demonstrates results of the analyses of while the performance-age plots were similar. speech recognition scores for the Dutch III and Dutch IV Although nonsyndromic autosomal dominant hear- families. The regression lines in the performance-age plots ing impairment is a heterogeneous condition, the sub- show a slow decline in score with increasing age. The mean group of loci predominantly affecting the lower frequen- onset age for individuals in the Dutch III family was 25 cies is homogeneous to some extent. DFNA1 was the first years (95% CI, 16-34 years); the mean deterioration rate locus identified with a nonsyndromic autosomal domi-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 A –10 Dutch III (G674E)12 Dutch IV (G674V)12 0 10 00 10 20 20 20 30 30 40 40 50 40 60 70 50 60 60

80 70

100

120

7 8, 9 4 4 B –10 Dutch I (T699M)4 Dutch II (A716T) United States1 (L829P) 0 0 10 20 20 10 30 20 20 0 40 30 30

40 40 40 50 50 50 60 60 70 60 60

Threshold, dB HL80 Threshold, dB HL 70

100

120 0.25 0.5 128 4 0.25 0.5 128 4 0.25 0.5 128 4 Frequency, kHz Frequency, kHz Frequency, kHz

Figure 3. Age-related typical audiograms for 5 families with DFNA6/14 (A, present families; B, previously described families1,7,8), with corresponding WFS1 mutations4,12 dB HL indicates decibels hearing level.

120 III:1 IV:1 IV:2 Frequency 0.25 kHz 2 kHz 100 0.5 kHz 4 kHz 1 kHz 8 kHz 80

Threshold, dB HL 20

010203040 50 0510 15 20 25 0510 15 20 Age, y Age, y Age, y

Figure 4. Longitudinal analyses of raw threshold (in decibels hearing level [dB HL]) data for frequencies ranging from 0.25 to 8 kHz in individuals III:1, IV:1, and IV:2 in the Dutch III family. Bold lines indicate significant progression.

nant hearing impairment trait. It is located on chromo- report were reanalyzed in a cross-sectional analysis and some 5q31 and is characterized as a progressive low- no significant progression beyond presbycusis was found.8 frequency type of hearing impairment.17,18 Lynch et al19 In the Dutch I family, Van Camp et al21 discovered a identified this mutation in the DIAPH1 gene in a large third locus associated with low-frequency sensorineural Costa Rican family. To our knowledge, no other fami- hearing impairment on chromosome 4p16.3, close to the lies showing linkage to the DFNA1 locus have been de- DFNA6 locus but without an apparent overlap. Kunst et scribed. al7 described the audiometric presentation in this Dutch I Lesperance et al20 identified a second locus (DFNA6) family and demonstrated progression of hearing impair- for dominant low-frequency hearing impairment on chro- ment, but not beyond that attributable to presbycusis. mosome 4p16.3 in the American family in whom the cor- The Dutch II family was linked to a larger chromo- responding phenotype had been outlined by the Vander- somal region comprising DFNA6 and DFNA14. Progres- bilt University Hereditary Deafness Study Group.1 sion was mild but significant, and ranged from 0.5 dB Predominant involvement of the frequencies from 0.25 to per year at 0.25 kHz to 1.3 dB per year at 8 kHz. Signifi- 1 kHz was found. Recently, the raw data published in that cant progression persisted after correction for presbycu-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 sis.9 Recently, Brodwolf et al10 described an additional family linked to DFNA6/14 showing a nonprogressive low- Family Dutch III Family Dutch IV A B frequency hearing impairment. Young et al11 have reported 100 90 another low-frequency hearing impairment trait, desig- 80 IV nated DFNA38, in a Newfoundland family harboring the IV 60 same mutation (A716T) in the WFS1 gene as was found III III in the Dutch II family. 40 % Correct

Age-related typical audiograms for the clinically de- 20 scribed families are depicted in Figure 3; they demon- 25 28 51 58 0 strate 2 types, with (G674V and A716T) and without 0 2040600204060 80 100 120 (T699M and L829P) progression beyond presbycusis at Age, y PTA 0.5-2 kHz, dB HL low frequencies (0.25-1 kHz). The G674E mutation in the Dutch III family seems to have caused a progression Figure 5. Cross-sectional analyses shown in performance-age plot of binaural means of percentage correct phoneme recognition scores relative to that is intermediate between these 2 extremes. Cross- age (in years) (A) and the same score shown in performance-impairment sectional analysis of this family did not indicate progres- plot relative to (binaural means of) pure-tone average (PTA) at 0.5 to 2 kHz sion after presbycusis correction, but this may have been (measured in decibels hearing level) (B). Linear regression lines are shown with Roman numerals indicating the families (III, solid circles; IV, open because of a lack of sufficient number of observations. circles). Dotted lines and numbers relate to 90% correct scores. However, longitudinal analysis in 3 individuals in this family, involving more observations, demonstrated progression beyond presbycusis. This rare syndrome has a prevalence of 1 in 770000 in Speech recognition scores have also been evalu- the United Kingdom.25 Wolframin, encoded by WFS1, is ated for some individuals in the Dutch II family.9 The a transmembrane protein.5,6 It has been localized to the scores for younger individuals (Ͻ32 years) were within endoplasmic reticulum and probably plays a role in the 90% to 100% range, which is in line with the mean membrane trafficking, protein processing, and regula- onset ages of 25 and 28 years found for the Dutch III and tion of endoplasmic reticulum calcium homeostasis.26 IV families, respectively. The mean onset levels for these However, its exact location and role in the cochlea re- 2 families ranged from 50 to 60 dB hearing levels. There main obscure. Electrophysiologic, magnetic resonance was no substantial difference in pure-tone audiogram find- imaging, and neuropathological studies27-29 of this syn- ings between the Dutch III and IV families, although the drome have shown general progressive degeneration of 2-kHz threshold appeared to be more affected in the Dutch the central and peripheral nervous systems, including III family (ie, in line with a flat threshold at 0.25-2 kHz). the vestibulocochlear nerve. Ohata et al30 described an Speech performance scores relative to age were not sub- increased risk of hearing impairment and diabetes melli- stantially different. However, a significant difference in tus in heterozygous carriers. Unfortunately, no frequen- speech performance relative to the level of hearing im- cies were specified and hearing impairment was defined pairment was detected. This difference may have been as an overall threshold greater than 20 dB hearing level. related to the worse pure-tone threshold found at 2 kHz Young et al11 described an individual in the Newfound- in the Dutch III family. land family who was a homozygous carrier and who had The point mutations in these 2 families cause a mis- diabetes mellitus at a young age and other clinical fea- sense mutation of the same amino acid, G674. This gly- tures reminiscent of Wolfram syndrome. However, this cine is substituted by glutamic acid in the Dutch III fam- individual was not affected by optic atrophy. Therefore, ily and by valine in the Dutch IV family. The phenotype it seems possible that carriers of the Wolfram syndrome relating to the A716T mutation4 was similar to that in show low-frequency hearing impairment that is similar these families. to that found in DFNA6/14. Recently, it was demonstrated in 7 families that heterozygous mutations in the WFS1 gene are responsible Accepted for publication December 5, 2001. for traits linked to DFNA6/14.4 In the original family dem- The clinical study was supported by grants from the onstrating DFNA6, a key recombinant that excluded the Heinsius Houbolt Foundation, Wassenaar, the Nether- DFNA14 candidate region had actually been based on a lands, and the Nijmegen Otorhinolaryngology Research phenocopy. This led to an incorrect localization of Foundation (Dr Cremers). The genetic study was sup- DFNA6, while in fact DFNA6 and DFNA14 represent a ported by grant G.0277.01 from the Flemish Fund for Sci- single locus. entific Research, Fonds voor Wetenschappelijk Onderzoek The WFS1 gene encodes the protein wolframin and Vlaanderen, Brussels, Belgium (Dr Van Camp). Ms Cryns is homozygously mutated in Wolfram, or DIDMOAD (dia- holds a predoctoral position with the Instituut voor de aan- betes insipidus, diabetes mellitus, optic atrophy, and deaf- moediging van Innovatie door Wetenschap en Technologie ness) syndrome. The minimum features required for the in Vlaanderen, Brussels. diagnosis are type 1 diabetes mellitus and optic atrophy. We thank the 2 participating families and acknowl- However, diabetes insipidus (described in 54%-58% edge R. J. C. Admiraal, PhD, and F. P. M. Cremers, PhD, of cases) and “deafness” (described in 51%-62%) are also for referring them. common features of this syndrome.22 This autosomal re- Corresponding author: Ronald J. E. Pennings, MD, cessive syndrome seems to be associated with a high- Department of Otorhinolaryngology, University Medical frequency hearing impairment, rather than the low- Centre St Radboud, PO Box 9101, 6500 HB Nijmegen, the frequency impairment found in the present families.23,24 Netherlands (e-mail: [email protected]).

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