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Contains fulltext : 50720.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To report hearing impairment and vestibular and ocular features in a Dutch DFNA11 family and to compare these results to reported data on three other DFNA11 families. STUDY DESIGN: Family study. METHODS: Regression analysis was performed in relation to age to outline the development of hearing thresholds and speech recognition scores. Vestibular and ocular functions were examined. RESULTS: First symptoms of hearing impairment started between the ages of 4 and 43 years. Most of the audiograms were symmetric and flat or downsloping. The annual threshold deterioration increased from 0.2 to 2.6 dB per year at 0.25 to 8 kHz in the longitudinal analyses and in the cross-sectional analysis from 0.3 to 0.9 dB per year. The speech recognition score was quite good, deteriorating by 0.9% per year from a 90% score at the age of 36 years onward. Remarkably, extensive ocular examination including corrected visual acuity and refraction measurements, slit-lamp examination, ophthalmoscopy, Goldmann perimetry, electroretinography and electro-oculography revealed signs of subclinical retinal dysfunction. None of the patients showed the classic triad of retinitis pigmentosa. Pure-tone thresholds, phoneme recognition scores, and vestibular responses of the mutation carriers were fairly similar to previously described DFNA11 families. CONCLUSION: Even though the diverse mutations are located in different regions of the myosin VIIa gene, the cochleovestibular phenotype is fairly similar in all DFNA11 families. Surprisingly, only in this family was subclinical retinal dysfunction detected.

A novel DFNA5 mutation was found in a Dutch family, of which 37 members were examined. A nucleotide substitution was identified in the splice acceptor site of intron 7, leading to skipping of exon 8 in part of the transcripts. The mutation was found in 18 individuals. Sensorineural hearing impairment was non-syndromic and symmetric. In early life, presumably congenitally, hearing impairment amounted to 30 dB in the high frequencies. Progression was most pronounced at 1 kHz (1.8 dB/year). Speech recognition was relatively good with a phoneme score of about 50% at the age of 70. Onset age was 37 years, and recognition deteriorated by 1.3% per year. The recognition score deteriorated by 1.0% per decibel threshold increase from a mean pure-tone average (PTA at 1, 2 and 4 kHz) of 63 dB onwards. Vestibular function was generally normal. The second mutation identified in the DFNA5 gene results in hearing impairment, similar to that in the original DFNA5 family in terms of pure-tone thresholds, but with more favourable speech recognition.

Contains fulltext : 48221.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To analyze cochleovestibular impairment features in P51S COCH mutation carriers (n = 22) in a new, large Dutch family and to compare the results to those obtained in previously identified similar mutation carriers (n = 52). To evaluate age-related features between progressive hearing and vestibular impairment of all mutation carriers (n = 74). STUDY DESIGN: Family study. METHODS: Regression analysis was performed in relation to age to outline the development of hearing thresholds, speech recognition scores, and vestibulo-ocular reflex time constant as the key vestibular response parameter. RESULTS: Pure tone thresholds, phoneme recognition scores, and vestibular responses of the mutation carriers in the new family were essentially similar to those previously established in all other mutation carriers. Hearing started to deteriorate in all mutation carriers from 43 years of age onwards, whereas deterioration of vestibular function started from age 34. CONCLUSION: Vestibular impairment starts earlier, progresses more rapidly, and, eventually, is more complete than hearing impairment in P51S COCH mutation carriers.

Contains fulltext : 58223.pdf (Publisher’s version ) (Closed access) Myosin VIIA is an unconventional myosin that has been implicated in Usher syndrome type 1B, atypical Usher syndrome, non-syndromic autosomal recessive hearing impairment (DFNB2) and autosomal dominant hearing impairment (DFNA11). Here, we present a family with non-syndromic autosomal dominant hearing impairment that clinically resembles the previously published DFNA11 family. The affected family members show a flat audiogram at young ages and only modest progression, most clearly at the high frequencies. In addition, they suffer from minor vestibular symptoms. Linkage analysis yielded a maximum two-point lodscore of 3.43 for marker D11S937 located within 1 cM of the myosin VIIA gene. The myosin VIIA gene was sequenced and 11 nucleotide variations were found. Ten nucleotide changes represent benign intronic variants, silent exon mutations or non-pathologic amino acid substitutions. One variant, a c.1373A-->T transversion that is heterozygously present in all affected family members and absent in 300 healthy individuals, is predicted to result in an Asn458Ile amino acid substitution. Asn458 is located in a region of the myosin VIIA motor domain that is highly conserved in different classes of myosins and in myosins of different species. To evaluate whether the Asn458Ile mutation was indeed responsible for the hearing impairment, a molecular model of myosin VIIA was built based on the known structure of the myosin II heavy chain from Dictyostelium discoideum. In this model, conformational changes in the protein caused by the amino acid substitution Asn458Ile are predicted to disrupt ATP/ADP binding and impair the myosin power-stroke, which would have a severe effect on the function of the myosin VIIA protein.

A novel DFNA5 mutation was found in a Dutch family, of which 37 members were examined. A nucleotide substitution was identified in the splice acceptor site of intron 7, leading to skipping of exon 8 in part of the transcripts. The mutation was found in 18 individuals. Sensorineural hearing impairment was non-syndromic and symmetric. In early life, presumably congenitally, hearing impairment amounted to 30 dB in the high frequencies. Progression was most pronounced at 1 kHz (1.8 dB/year). Speech recognition was relatively good with a phoneme score of about 50% at the age of 70. Onset age was 37 years, and recognition deteriorated by 1.3% per year. The recognition score deteriorated by 1.0% per decibel threshold increase from a mean pure-tone average (PTA at 1, 2 and 4 kHz) of 63 dB onwards. Vestibular function was generally normal. The second mutation identified in the DFNA5 gene results in hearing impairment, similar to that in the original DFNA5 family in terms of pure-tone thresholds, but with more favourable speech recognition.