0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

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

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
[+] Author Affiliations

From the Departments of Otorhinolaryngology, University Medical Centre St Radboud, Nijmegen, the Netherlands (Drs Pennings, Bom, Huygen, Kremer, and Cremers), and Medical Genetics, University of Antwerp, Antwerp, Belgium (Ms Cryns, Mr Flothmann, and Dr Van Camp).


Arch Otolaryngol Head Neck Surg. 2003;129(4):421-426. doi:10.1001/archotol.129.4.421.
Text Size: A A A
Published online

Objective  To assess the audiometric profile and speech recognition characteristics in affected members of 2 families with DFNA6/14 harboring heterozygous mutations in the WFS1 gene that cause an autosomal dominant nonsyndromic sensorineural hearing impairment trait.

Design  Family study.

Setting  Tertiary referral center.

Patients  Thirteen patients from 2 recently identified Dutch families with DFNA6/14 (Dutch III and IV).

Methods  Cross-sectional and longitudinal analyses of pure-tone thresholds at octave frequencies of 0.25 to 8 kHz were performed, and speech phoneme recognition scores were assessed. Progression was evaluated by linear regression analysis with and without correction for presbycusis.

Results  All individuals showed low-frequency hearing impairment. The 2-kHz frequency was more affected in the Dutch III family than in the Dutch IV family. Progressive hearing loss beyond presbycusis was found in the Dutch IV family and in 3 individuals in the Dutch III family. Annual threshold deterioration was between 0.6 and 1 dB per year at all frequencies. The speech recognition scores in the Dutch III family showed significantly more deterioration at increasing levels of hearing impairment compared with those in the Dutch IV family.

Conclusion  Both families showed an autosomal dominant, progressive, low-frequency sensorineural hearing impairment caused by heterozygous WFS1 mutations.

Figures in this Article

THIRTY-FOUR YEARS ago, the Vanderbilt University Hereditary Deafness Study Group1 described a large family with low-frequency sensorineural hearing impairment showing an autosomal dominant pattern of inheritance. Several years later, Konigsmark et al2 described 3 more families harboring a dominant low-frequency hearing impairment trait. Audiograms in all families displayed upward-sloping patterns. Today, characterization of nonsyndromic forms of hereditary hearing impairment is based more on genetic characteristics than on clinical findings. The loci for nonsyndromic autosomal dominant forms of hearing impairment are designated DFNA (DFN for deafness and A for autosomal dominant) and are numbered in chronological order of discovery. Forty loci are known to cause autosomal dominant nonsyndromic hearing impairment.3 Only 2 of them, DFNA1 and DFNA6/14, are characterized by predominant low-frequency hearing impairment.

A recent finding is that the WFS1 gene harbors heterozygous mutations in DFNA6 and DFNA14, and that DFNA6 and DFNA14 represent the same locus, further designated as DFNA6/14.4 Homozygous mutations in the WFS1 gene account for the autosomal recessive Wolfram syndrome.5,6 To our knowledge, 3 families with heterozygous mutations in the WFS1 gene have been described: USA1 (L829P mutation4), Dutch I7 (T699M4), and Dutch II8 (A716T4). All families showed mild progression of hearing impairment; however, only in the Dutch II family did this persist beyond correction for presbycusis.9 Brodwolf et al10 recently described a German family with DFNA6/14 in whom linkage analysis showed a harboring of low- to mid-frequency hearing impairment. Young et al11 described a Newfoundland kindred harboring the same WFS1 mutation (A716T) as was detected in the Dutch II family.

This report describes the hearing impairment in 2 additional families with DFNA6/14, Dutch III and Dutch IV, that harbor 2 mutations in the WFS1 gene, G674E and G674V, respectively.

In the Dutch III and Dutch IV families (Figure 1), the WFS1 gene was analyzed for mutations after audiograms of members of both families demonstrated low-frequency hearing impairment. Four affected individuals from the Dutch III family had a G674E mutation, and 9 from the Dutch IV family had a G674V mutation.12 From the pedigree, it was concluded that the deceased individual III:2 in the Dutch IV family also harbored the G674V mutation.

Place holder to copy figure label and caption
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.

Graphic Jump Location

In this study, we assess the audiometric profile and speech recognition performance in affected family members with DFNA6/14 of different ages. Medical histories were taken, focusing on acquired and syndromic conditions. Otoscopy was performed and previous audiologic data were retrieved, including data on deceased individual III:2 in the Dutch IV family. Pure-tone thresholds (binaural means of air and bone conduction) at octave frequencies of 0.25 to 8 kHz and speech recognition scores (monaural means of maximum phoneme scores) were obtained in a sound-treated room according to the norms defined by the International Organization for Standardization (ISO).13,14 In individual III:3 in the Dutch IV family, data on the left ear were excluded because of previous ear surgery.

Cross-sectional linear regression analysis was performed on threshold-on-age data from the patients' most recent visits, 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 presbycusis. Progression was considered significant when a significant positive slope (P<.03) was detected for the raw threshold data at a sufficiently high number of different sound frequencies (P<.05 in the appropriate binomial distribution). Threshold data were also evaluated for progression after correction for age and sex for median norms (50th percentile) of presbycusis, according to the ISO 7029 norms.15

Age-related typical audiograms were derived from the results of the cross-sectional regression analysis of the raw data. Individual longitudinal regression analysis, also including correction for presbycusis, was performed for individuals III:1, IV:1, and IV:2 in the Dutch III family.

For cross-sectional regression analysis of speech audiometric data, maximum phoneme recognition scores (percentage correct) were derived from individual performance-intensity plots. Regression analysis was performed for performance-age plots (scores related to age) and performance-impairment plots (scores on means of pure-tone thresholds at 0.5, 1, and 2 kHz). Speech recognition scores were fitted by a linear regression line. The x-coordinate relating to a 90% score (X90) represented the onset age (in years) for X and the onset level for pure-tone audiogram thresholds (measured in decibels hearing level) at 0.5 to 2 kHz. The 95% confidence interval (CI) for X90 was obtained by nonlinear regression analysis using an alternative equation for the linear regression line, Y = slope(XX90) + 90, where Y is the binaural mean air conduction threshold measured in decibels hearing level. t Tests (including Welch correction if the Bartlett test detected unequal variances) were used to test differences in X90 between the families. Slope represented the deterioration rate relative to age and deterioration gradient for pure-tone audiogram threshold.

Analysis of covariance was used to compare slopes and intercepts between regression lines pertaining to different frequencies within a given family or pertaining to the families at a given frequency. Some slopes and intercepts were pooled where possible.

Vestibulo-ocular responses were evaluated in individuals IV:2 and IV:5 in the Dutch IV family using electronystagmography with computer analysis. Saccadic, smooth pursuit, optokinetic, and vestibular nystagmus responses were evaluated. Vestibular stimulation comprised rotatory and caloric tests. Details and normal values have been previously described.16

Four individuals in the Dutch III family and 9 in the Dutch IV family showed low-frequency hearing impairment. The Dutch IV kindred also harbored a Duchenne-type muscular dystrophy trait; according to family history, 3 affected boys (Figure 1) without hearing impairment died at a young age.

Cross-sectional analysis of threshold-on-age data was performed in both families. The results are shown in Figure 2. The scattering of threshold data points was not substantially different between the 2 families. Both families showed significant progression. When individual frequencies were compared, analysis of raw data showed no significant differences in progression between the families. In the Dutch IV kindred, no significant difference in progression among the frequencies was found using raw data. The pooled annual threshold deterioration was 1.0 dB. However, after correction for presbycusis, the Dutch IV family showed significant progression, which was not the case for individuals in the Dutch III family.

Place holder to copy figure label and caption

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.

Graphic Jump Location

Age-related typical audiograms for the 2 families displayed ascending configurations from low-frequency thresholds (fairly flat at 0.25-1 kHz) of about 40 to 70 dB in the Dutch III kindred and 40 to 90 dB in the Dutch IV kindred (Figure 3). A flat threshold configuration was found at 2 kHz in the Dutch III family. In younger individuals, the thresholds at 4 to 8 kHz were close to normal, especially in the Dutch IV family.

Place holder to copy figure label and caption
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.

Graphic Jump Location

In individuals III:1, IV:1, and IV:2 in the Dutch III family, longitudinal regression analysis of pure-tone audiograms was performed. Significant progression was detected in all of them (Figure 4), persisting beyond correction for presbycusis. Age-related typical audiograms derived for these analyses (plots not shown) were similar to those obtained for the cross-sectional analysis (Figure 3).

Place holder to copy figure label and caption
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.

Graphic Jump Location

Figure 5 demonstrates results of the analyses of speech recognition scores for the Dutch III and Dutch IV families. The regression lines in the performance-age plots show a slow decline in score with increasing age. The mean onset age for individuals in the Dutch III family was 25 years (95% CI, 16-34 years); the mean deterioration rate was 0.8% per year (95% CI, 0.5%-1.1% per year). The values for the Dutch IV family were similar, with a mean onset age of 28 years (95% CI, 18-38 years) and a mean deterioration rate of 0.5% per year (95% CI, 0.1%-0.9% per year). A significant performance difference between the families was found only in the level of impairment (Figure 5B). In the Dutch III family, the mean deterioration gradient was almost 2% per decibel (95% CI, 1.4%-2.6% per decibel). In the Dutch IV family, it was 0.45% per decibel (95% CI, 0.3%-0.6% per decibel). There was no significant difference in mean onset level between the families (Dutch III, 58 dB hearing level [95% CI, 55-61 dB] and Dutch IV, 51 dB hearing level [95% CI, 42-60 dB]).

Place holder to copy figure label and caption
Figure 5.

Cross-sectional analyses shown in performance-age plot of binaural means of percentage correct phoneme recognition scores relative to age (in years) (A) and the same score shown in performance-impairment plot relative to (binaural means of) pure-tone average (PTA) at 0.5 to 2 kHz (measured in decibels hearing level) (B). Linear regression lines are shown with Roman numerals indicating the families (III, solid circles; IV, open circles). Dotted lines and numbers relate to 90% correct scores.

Graphic Jump Location

None of the patients reported substantial vestibular symptoms, and the 2 individuals examined showed normal ocular motor and vestibular responses.

The Dutch III (longitudinal analyses) and Dutch IV (cross-sectional analyses) families showed similar progression that persisted after correction for presbycusis. On evaluation of speech recognition scores, the performance-impairment plots were significantly different between the 2 kindreds, while the performance-age plots were similar.

Although nonsyndromic autosomal dominant hearing impairment is a heterogeneous condition, the subgroup of loci predominantly affecting the lower frequencies is homogeneous to some extent. DFNA1 was the first locus identified with a nonsyndromic autosomal dominant hearing impairment trait. It is located on chromosome 5q31 and is characterized as a progressive low-frequency type of hearing impairment.17,18 Lynch et al19 identified this mutation in the DIAPH1 gene in a large Costa Rican family. To our knowledge, no other families showing linkage to the DFNA1 locus have been described.

Lesperance et al20 identified a second locus (DFNA6) for dominant low-frequency hearing impairment on chromosome 4p16.3 in the American family in whom the corresponding phenotype had been outlined by the Vanderbilt University Hereditary Deafness Study Group.1 Predominant involvement of the frequencies from 0.25 to 1 kHz was found. Recently, the raw data published in that report were reanalyzed in a cross-sectional analysis and no significant progression beyond presbycusis was found.8

In the Dutch I family, Van Camp et al21 discovered a third locus associated with low-frequency sensorineural hearing impairment on chromosome 4p16.3, close to the DFNA6 locus but without an apparent overlap. Kunst et al7 described the audiometric presentation in this Dutch I family and demonstrated progression of hearing impairment, but not beyond that attributable to presbycusis.

The Dutch II family was linked to a larger chromosomal region comprising DFNA6 and DFNA14. Progression was mild but significant, and ranged from 0.5 dB per year at 0.25 kHz to 1.3 dB per year at 8 kHz. Significant progression persisted after correction for presbycusis.9 Recently, Brodwolf et al10 described an additional family linked to DFNA6/14 showing a nonprogressive low-frequency hearing impairment. Young et al11 have reported another low-frequency hearing impairment trait, designated DFNA38, in a Newfoundland family harboring the same mutation (A716T) in the WFS1 gene as was found in the Dutch II family.

Age-related typical audiograms for the clinically described families are depicted in Figure 3; they demonstrate 2 types, with (G674V and A716T) and without (T699M and L829P) progression beyond presbycusis at low frequencies (0.25-1 kHz). The G674E mutation in the Dutch III family seems to have caused a progression that is intermediate between these 2 extremes. Cross-sectional analysis of this family did not indicate progression after presbycusis correction, but this may have been because of a lack of sufficient number of observations. However, longitudinal analysis in 3 individuals in this family, involving more observations, demonstrated progression beyond presbycusis.

Speech recognition scores have also been evaluated for some individuals in the Dutch II family.9 The scores for younger individuals (<32 years) were within the 90% to 100% range, which is in line with the mean onset ages of 25 and 28 years found for the Dutch III and IV families, respectively. The mean onset levels for these 2 families ranged from 50 to 60 dB hearing levels. There was no substantial difference in pure-tone audiogram findings between the Dutch III and IV families, although the 2-kHz threshold appeared to be more affected in the Dutch III family (ie, in line with a flat threshold at 0.25-2 kHz). Speech performance scores relative to age were not substantially different. However, a significant difference in speech performance relative to the level of hearing impairment was detected. This difference may have been related to the worse pure-tone threshold found at 2 kHz in the Dutch III family.

The point mutations in these 2 families cause a missense mutation of the same amino acid, G674. This glycine is substituted by glutamic acid in the Dutch III family and by valine in the Dutch IV family. The phenotype relating to the A716T mutation4 was similar to that in these families.

Recently, it was demonstrated in 7 families that heterozygous mutations in the WFS1 gene are responsible for traits linked to DFNA6/14.4 In the original family demonstrating DFNA6, a key recombinant that excluded the DFNA14 candidate region had actually been based on a phenocopy. This led to an incorrect localization of DFNA6, while in fact DFNA6 and DFNA14 represent a single locus.

The WFS1 gene encodes the protein wolframin and is homozygously mutated in Wolfram, or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome. The minimum features required for the diagnosis are type 1 diabetes mellitus and optic atrophy. However, diabetes insipidus (described in 54%-58% of cases) and "deafness" (described in 51%-62%) are also common features of this syndrome.22 This autosomal recessive syndrome seems to be associated with a high-frequency hearing impairment, rather than the low-frequency impairment found in the present families.23,24 This rare syndrome has a prevalence of 1 in 770 000 in the United Kingdom.25 Wolframin, encoded by WFS1, is a transmembrane protein.5,6 It has been localized to the endoplasmic reticulum and probably plays a role in membrane trafficking, protein processing, and regulation of endoplasmic reticulum calcium homeostasis.26 However, its exact location and role in the cochlea remain obscure. Electrophysiologic, magnetic resonance imaging, and neuropathological studies2729 of this syndrome have shown general progressive degeneration of the central and peripheral nervous systems, including the vestibulocochlear nerve. Ohata et al30 described an increased risk of hearing impairment and diabetes mellitus in heterozygous carriers. Unfortunately, no frequencies were specified and hearing impairment was defined as an overall threshold greater than 20 dB hearing level. Young et al11 described an individual in the Newfoundland family who was a homozygous carrier and who had diabetes mellitus at a young age and other clinical features reminiscent of Wolfram syndrome. However, this individual was not affected by optic atrophy. Therefore, it seems possible that carriers of the Wolfram syndrome show low-frequency hearing impairment that is similar to that found in DFNA6/14.

Corresponding author: Ronald J. E. Pennings, MD, Department of Otorhinolaryngology, University Medical Centre St Radboud, PO Box 9101, 6500 HB Nijmegen, the Netherlands (e-mail: r.pennings@kno.azn.nl).

Accepted for publication December 5, 2001.

The clinical study was supported by grants from the Heinsius Houbolt Foundation, Wassenaar, the Netherlands, and the Nijmegen Otorhinolaryngology Research Foundation (Dr Cremers). The genetic study was supported by grant G.0277.01 from the Flemish Fund for Scientific Research, Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Brussels, Belgium (Dr Van Camp). Ms Cryns holds a predoctoral position with the Instituut voor de aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen, Brussels.

We thank the 2 participating families and acknowledge R. J. C. Admiraal, PhD, and F. P. M. Cremers, PhD, for referring them.

Vanderbilt University Hereditary Deafness Study Group Dominantly inherited low-frequency hearing loss. Arch Otolaryngol.1968;88:242-250.
Konigsmark  BWMengel  MBerlinn  CI Familial low frequency hearing loss. Laryngoscope.1971;81:759-771.
Van Camp  GSmith  RJH Hereditary Hearing Loss Homepage.  Available at: http://www.uia.ac.be/dnalab/hhh/. Accessed September 15, 2001.
Bespalova  INVan Camp  GBom  SJH  et al Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Hum Mol Genet.2001;10:2501-2508.
Strom  TMHörtnagel  KHofmann  S  et al Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. Hum Mol Genet.1998;7:2021-2028.
Inoue  HTanizawa  YWasson  J  et al A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet.1998;20:143-148.
Kunst  HPMMarres  HAMHuygen  PLMVan Camp  GJoosten  FCremers  CWRJ Autosomal dominant non-syndromal low-frequency sensorineural hearing impairment linked to chromosome 4p16 (DFNA14): statistical analysis of hearing threshold in relation to age and evaluation of vestibulo-ocular functions. Audiology.1999;38:165-173.
Huygen  PLMBom  SJHVan Camp  GCremers  CWRJ The clinical presentation of the DFNA loci where causative genes have not yet been cloned: DFNA4, DFNA6/14, DFNA7, DFNA16, DFNA20 and DFNA21.  In: Cremers  CWRJ, Smith  RJH, eds. Advances in Otorhinolaryngology. Vol 61. Basel, Switzerland: Karger. In press.
Bom  SJHVan Camp  GCaethoven  GAdmiraal  RJCHuygen  PLMCremers  CWRJ Autosomal dominant low-frequency hearing impairment (DFNA6/14): a clinical and genetic family study. Otol Neurotol. In press.
Brodwolf  SBöddeker  IRZiegler  ARausch  PKunz  J Further evidence for linkage of low-mid frequency hearing impairment to the candidate region on chromosome 4p16.3. Clin Genet.2001;60:155-160.
Young  T-LIves  ELynch  E  et al Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1Hum Mol Genet.2001;10:2509-2514.
Cryns  KPfister  MPennings  RJE  et al Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations. Hum Genet.2002;110:389-394.
Not Available ISO 389: Acoustics: Standard Reference Zero for the Calibration of Pure Tone Air Conduction Audiometers.  Geneva, Switzerland: International Organization for Standardization; 1985.
Not Available ISO 8253-1: Acoustics: Audiometric Test Methods, I: Basic Pure Tone Air and Bone Conduction Threshold Audiometry.  Geneva, Switzerland: International Organization for Standardization; 1989.
Not Available ISO 7029: Acoustics: Threshold of Hearing by Air Conduction as a Function of Age and Sex for Otologically Normal Persons.  Geneva, Switzerland: International Organization for Standardization; 1984.
Kunst  HPMHuybrechts  CMarres  HAMHuygen  PLMVan Camp  GCremers  CWRJ The phenotype of DFNA13, COL11A2: nonsyndromic autosomal dominant mid-frequency and high-frequency sensorineural hearing impairment. Am J Otol.2000;21:181-187.
León  PERavents  HLynch  EDMorrow  JEKing  MC The gene for an inherited form of deafness maps to chromosome 5q31. Proc Natl Acad Sci U S A.1992;89:5181-5184.
Lalwani  AKJackler  RKSweetow  RW  et al Further characterization of the DFNA1 audiovestibular phenotype. Arch Otolaryngol Head Neck Surg.1998;124:699-702.
Lynch  EDLee  MKMorrow  JEWelcsh  PLLeón  PEKing  MC Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Science.1997;278:1315-1318.
Lesperance  MMHall  JWBess  FH  et al A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3. Hum Mol Genet.1995;4:1967-1972.
Van Camp  GKunst  HPMFlothmann  K  et al A gene for autosomal dominant hearing impairment (DFNA14) maps to a region on chromosome 4p16.3 that does not overlap the DFNA6 locus. J Med Genet.1999;36:532-536.
Fuqua  JS Wolfram syndrome: clinical and genetic aspects. Endocrinologist.2000;10:51-59.
Higashi  K Otologic findings of DIDMOAD syndrome. Am J Otol.1991;12:57-60.
Cremers  CWRJWijdeveld  PGABPinckers  AJLG Juvenile diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, atonia of the urinary tract and the bladder, and other abnormalities (Wolfram syndrome): a review of 88 cases from the literature with personal observations on 3 new patients. Acta Paediatr Scand Suppl.1977;264:1-16.
Barrett  TBundey  SMacleod  A Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet.1995;346:1458-1463.
Takeda  KInoue  HTanizawa  Y  et al WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum Mol Genet.2001;10:477-484.
Blasi  CPierelli  FRispoli  ESaponara  MVingolo  EAndreani  D Wolfram's syndrome: a clinical, diagnostic and interpretative contribution. Diabetes Care.1986;9:521-528.
Rando  TAHorton  JCLayzer  RB Wolfram syndrome: evidence of a diffuse neurodegenerative disease by magnetic resonance imaging. Neurology.1992;42:1220-1224.
Génis  DDávalos  AMolins  AFerrer  I Wolfram syndrome: a neuropathological study. Acta Neuropathol.1997;93:426-429.
Ohata  TKoizumi  AKayo  T  et al Evidence of an increased risk of hearing loss in heterozygous carriers in a Wolfram syndrome family. Hum Genet.1998;103:470-474.

Figures

Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption

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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Cross-sectional analyses shown in performance-age plot of binaural means of percentage correct phoneme recognition scores relative to age (in years) (A) and the same score shown in performance-impairment plot relative to (binaural means of) pure-tone average (PTA) at 0.5 to 2 kHz (measured in decibels hearing level) (B). Linear regression lines are shown with Roman numerals indicating the families (III, solid circles; IV, open circles). Dotted lines and numbers relate to 90% correct scores.

Graphic Jump Location

Tables

References

Vanderbilt University Hereditary Deafness Study Group Dominantly inherited low-frequency hearing loss. Arch Otolaryngol.1968;88:242-250.
Konigsmark  BWMengel  MBerlinn  CI Familial low frequency hearing loss. Laryngoscope.1971;81:759-771.
Van Camp  GSmith  RJH Hereditary Hearing Loss Homepage.  Available at: http://www.uia.ac.be/dnalab/hhh/. Accessed September 15, 2001.
Bespalova  INVan Camp  GBom  SJH  et al Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Hum Mol Genet.2001;10:2501-2508.
Strom  TMHörtnagel  KHofmann  S  et al Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. Hum Mol Genet.1998;7:2021-2028.
Inoue  HTanizawa  YWasson  J  et al A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet.1998;20:143-148.
Kunst  HPMMarres  HAMHuygen  PLMVan Camp  GJoosten  FCremers  CWRJ Autosomal dominant non-syndromal low-frequency sensorineural hearing impairment linked to chromosome 4p16 (DFNA14): statistical analysis of hearing threshold in relation to age and evaluation of vestibulo-ocular functions. Audiology.1999;38:165-173.
Huygen  PLMBom  SJHVan Camp  GCremers  CWRJ The clinical presentation of the DFNA loci where causative genes have not yet been cloned: DFNA4, DFNA6/14, DFNA7, DFNA16, DFNA20 and DFNA21.  In: Cremers  CWRJ, Smith  RJH, eds. Advances in Otorhinolaryngology. Vol 61. Basel, Switzerland: Karger. In press.
Bom  SJHVan Camp  GCaethoven  GAdmiraal  RJCHuygen  PLMCremers  CWRJ Autosomal dominant low-frequency hearing impairment (DFNA6/14): a clinical and genetic family study. Otol Neurotol. In press.
Brodwolf  SBöddeker  IRZiegler  ARausch  PKunz  J Further evidence for linkage of low-mid frequency hearing impairment to the candidate region on chromosome 4p16.3. Clin Genet.2001;60:155-160.
Young  T-LIves  ELynch  E  et al Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1Hum Mol Genet.2001;10:2509-2514.
Cryns  KPfister  MPennings  RJE  et al Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations. Hum Genet.2002;110:389-394.
Not Available ISO 389: Acoustics: Standard Reference Zero for the Calibration of Pure Tone Air Conduction Audiometers.  Geneva, Switzerland: International Organization for Standardization; 1985.
Not Available ISO 8253-1: Acoustics: Audiometric Test Methods, I: Basic Pure Tone Air and Bone Conduction Threshold Audiometry.  Geneva, Switzerland: International Organization for Standardization; 1989.
Not Available ISO 7029: Acoustics: Threshold of Hearing by Air Conduction as a Function of Age and Sex for Otologically Normal Persons.  Geneva, Switzerland: International Organization for Standardization; 1984.
Kunst  HPMHuybrechts  CMarres  HAMHuygen  PLMVan Camp  GCremers  CWRJ The phenotype of DFNA13, COL11A2: nonsyndromic autosomal dominant mid-frequency and high-frequency sensorineural hearing impairment. Am J Otol.2000;21:181-187.
León  PERavents  HLynch  EDMorrow  JEKing  MC The gene for an inherited form of deafness maps to chromosome 5q31. Proc Natl Acad Sci U S A.1992;89:5181-5184.
Lalwani  AKJackler  RKSweetow  RW  et al Further characterization of the DFNA1 audiovestibular phenotype. Arch Otolaryngol Head Neck Surg.1998;124:699-702.
Lynch  EDLee  MKMorrow  JEWelcsh  PLLeón  PEKing  MC Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Science.1997;278:1315-1318.
Lesperance  MMHall  JWBess  FH  et al A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3. Hum Mol Genet.1995;4:1967-1972.
Van Camp  GKunst  HPMFlothmann  K  et al A gene for autosomal dominant hearing impairment (DFNA14) maps to a region on chromosome 4p16.3 that does not overlap the DFNA6 locus. J Med Genet.1999;36:532-536.
Fuqua  JS Wolfram syndrome: clinical and genetic aspects. Endocrinologist.2000;10:51-59.
Higashi  K Otologic findings of DIDMOAD syndrome. Am J Otol.1991;12:57-60.
Cremers  CWRJWijdeveld  PGABPinckers  AJLG Juvenile diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, atonia of the urinary tract and the bladder, and other abnormalities (Wolfram syndrome): a review of 88 cases from the literature with personal observations on 3 new patients. Acta Paediatr Scand Suppl.1977;264:1-16.
Barrett  TBundey  SMacleod  A Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet.1995;346:1458-1463.
Takeda  KInoue  HTanizawa  Y  et al WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum Mol Genet.2001;10:477-484.
Blasi  CPierelli  FRispoli  ESaponara  MVingolo  EAndreani  D Wolfram's syndrome: a clinical, diagnostic and interpretative contribution. Diabetes Care.1986;9:521-528.
Rando  TAHorton  JCLayzer  RB Wolfram syndrome: evidence of a diffuse neurodegenerative disease by magnetic resonance imaging. Neurology.1992;42:1220-1224.
Génis  DDávalos  AMolins  AFerrer  I Wolfram syndrome: a neuropathological study. Acta Neuropathol.1997;93:426-429.
Ohata  TKoizumi  AKayo  T  et al Evidence of an increased risk of hearing loss in heterozygous carriers in a Wolfram syndrome family. Hum Genet.1998;103:470-474.

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 18

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

The Rational Clinical Examination: Evidence-Based Clinical Diagnosis
Quick Reference

The Rational Clinical Examination: Evidence-Based Clinical Diagnosis
Sensorineural Hearing Impairment