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1.
Am J Ophthalmol ; 143(5): 847-852, 2007 May.
Article in English | MEDLINE | ID: mdl-17368553

ABSTRACT

PURPOSE: Investigation of a possible association between vertical corneal striae and mutations in the COCH gene, observed in four DFNA9 families with autosomal dominant hearing loss and vestibular dysfunction. DESIGN: Prospective case series. METHODS: Ophthalmologic examinations with photography of the cornea after instillation of fluorescein were performed in 98 family members with 61 mutation carriers of four DFNA9 families at the Radboud University Nijmegen Medical Centre. Families 1 and 2 harbor the Pro51Ser mutation, and families 3 and 4 harbor the Gly88Glu and the Gly87Trp mutation, respectively. Statistical analysis was performed to find an association between the vertical corneal striae and the COCH mutation for each family and to test whether the four families were different in this respect. RESULTS: The vertical corneal striae were exclusively visible after instillation of fluorescein. They caused minor problems, as dry eye symptoms, and were not present in the general Dutch ophthalmologic population. The striae were present from an age of 47 years in 32 individuals, of whom 27 individuals had a COCH mutation. Statistical analysis on the striae and the COCH mutations showed a significant association in families 1, 2, and 3 (P = .0006), but not in family 4 (P = .63). CONCLUSIONS: Data analysis demonstrated a significant association between vertical corneal striae and the Pro51Ser and Gly88Glu mutations in the COCH gene in DFNA9 families 1, 2, and 3 with cochleovestibular dysfunction. Our findings suggest that the vertical corneal striae and cochleovestibular dysfunction may be caused by the same COCH mutations.


Subject(s)
Corneal Diseases/genetics , Deafness/genetics , Hearing Loss, Sensorineural/genetics , Point Mutation , Proteins/genetics , Adult , Cochlear Diseases/genetics , Cornea/pathology , Corneal Diseases/diagnosis , Extracellular Matrix Proteins , Family , Female , Genes, Dominant , Haplotypes , Heterozygote , Humans , Intraocular Pressure , Male , Middle Aged , Pedigree , Prospective Studies , Vestibular Diseases/genetics , Visual Acuity
2.
Otol Neurotol ; 27(3): 323-31, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16639269

ABSTRACT

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.


Subject(s)
Dyneins/genetics , Eye/physiopathology , Family , Hearing Loss/genetics , Myosins/genetics , Vestibule, Labyrinth/physiopathology , Vision Disorders/genetics , Adult , Aged , Audiometry, Pure-Tone , Audiometry, Speech , Chromosome Disorders , Cross-Sectional Studies , DNA Mutational Analysis , Electroretinography , Eye/pathology , Female , Hearing Loss/physiopathology , Humans , Longitudinal Studies , Male , Middle Aged , Myosin VIIa , Ophthalmoscopy , Pedigree , Regression Analysis , Vision Disorders/pathology , Vision Disorders/physiopathology , Visual Fields/genetics
3.
Otol Neurotol ; 26(5): 918-25, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16151338

ABSTRACT

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.


Subject(s)
Cochlear Diseases/genetics , Deafness/genetics , Family , Mutation , Proteins/genetics , Vestibule, Labyrinth/physiopathology , Adult , Aged , Audiometry, Pure-Tone , Auditory Threshold , Chromosomes, Human, Pair 14 , Cochlear Diseases/physiopathology , Deafness/complications , Extracellular Matrix Proteins , Female , Heterozygote , Humans , Male , Middle Aged , Pedigree , Regression Analysis , Tinnitus/complications , Tinnitus/genetics
4.
Hum Genet ; 115(2): 149-56, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15221449

ABSTRACT

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.


Subject(s)
Hearing Loss/genetics , Mutation , Myosins/genetics , Amino Acid Sequence , Base Sequence , Dyneins , Genes, Dominant , Humans , Models, Molecular , Myosin VIIa , Pedigree
5.
Audiol Neurootol ; 9(1): 34-46, 2004.
Article in English | MEDLINE | ID: mdl-14676472

ABSTRACT

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.


Subject(s)
Carrier Proteins/genetics , Hearing Loss, Sensorineural/genetics , Mutation , Receptors, Estrogen , Adolescent , Adult , Aged , Alternative Splicing , Audiometry, Pure-Tone , Child , DNA Mutational Analysis , Female , Genetic Linkage , Genotype , Humans , Male , Middle Aged , Pedigree , Speech Discrimination Tests , Tomography, X-Ray Computed , Vestibular Function Tests
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