Hearing impairment in genotyped Wolfram syndrome patients.

OBJECTIVES: Wolfram syndrome is a progressive neurodegenerative syndrome characterized by the features "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). We sought to study the audiometric data of genotyped Wolfram syndrome patients with sensorineural hearing impairment. METHODS: Pure tone threshold data of 23 Wolfram syndrome patients were used for cross-sectional analysis in subgroups (age less than 16 years or between 19 and 25 years, gender, and origin). RESULTS: All subgroups, with 1 exception, showed a fairly similar type of hearing impairment with, on average, thresholds of about 25 dB (range, 0 to 65 dB) at 0.25 to 1 kHz, gently sloping downward to about 60 dB (range, 25 to 95 dB) at 8 kHz. The subgroup of Dutch women, which was excluded from the calculations of the average hearing thresholds, showed a higher degree of hearing impairment. Only the latter subgroup showed progression; however, contrary to the previous longitudinal analysis, progression was not significant in the present cross-sectional analysis, presumably because of the high degree of cross-subject variability. CONCLUSIONS: This unique collection of audiometric data from genotyped Wolfram syndrome patients shows no substantial progression in sensorineural hearing impairment with advancing age, no relation to the types of WFS1 mutations identified, and, with exclusion of the subgroup of Dutch female patients, no significant sex-related differences.

Mid-frequency DFNA8/12 hearing loss caused by a synonymous TECTA mutation that affects an exonic splice enhancer.

Autosomal dominant hearing loss is highly heterogeneous. Hearing impairment mainly involves the mid-frequencies (500-2000 Hz) in only a low percentage of the cases. In a Dutch family with autosomal dominant mid-frequency/flat hearing loss, genome-wide SNP analysis combined with fine mapping using microsatellite markers mapped the defect to the DFNA8/12 locus, with a maximum two-point LOD score of 3.52. All exons and intron-exon boundaries of the TECTA gene, of which mutations are causative for DFNA8/12, were sequenced. Only one heterozygous synonymous change in exon 16 (c.5331G>A; p.L1777L) was found to segregate with the hearing loss. This change was predicted to cause the loss of an exonic splice enhancer (ESE). RT-PCR using primers flanking exon 16 revealed, besides the expected PCR product from the wild-type allele, a smaller fragment only in the affected individual, representing part of an aberrant TECTA transcript lacking exon 16. The aberrant splicing is predicted to result in a deletion of 37 amino acids (p.S1758Y/G1759_N1795del) in alpha-tectorin. Subsequently, the same mutation was detected in two out of 36 individuals with a comparable phenotype. Owing to the position of the protein deletion just N-terminal of the zona pellucida (ZP) domain of alpha-tectorin, it is likely that the deletion of 37 amino acids may affect the proteolytic processing, structure and/or function of this domain, which results in a clinical phenotype comparable to that of missense mutations in the ZP domain. In addition, this is the first report of a synonymous mutation that affects an ESE and causes hereditary hearing loss.

Audiological evaluation of affected members from a Dutch DFNA8/12 (TECTA) family.

In DFNA8/12, an autosomal dominantly inherited type of nonsyndromic hearing impairment, the TECTA gene mutation causes a defect in the structure of the tectorial membrane in the inner ear. Because DFNA8/12 affects the tectorial membrane, patients with DFNA8/12 may show specific audiometric characteristics. In this study, five selected members of a Dutch DFNA8/12 family with a TECTA sensorineural hearing impairment were evaluated with pure-tone audiometry, loudness scaling, speech perception in quiet and noise, difference limen for frequency, acoustic reflexes, otoacoustic emissions, and gap detection. Four out of five subjects showed an elevation of pure-tone thresholds, acoustic reflex thresholds, and loudness discomfort levels. Loudness growth curves are parallel to those found in normal-hearing individuals. Suprathreshold measures such as difference limen for frequency modulated pure tones, gap detection, and particularly speech perception in noise are within the normal range. Distortion otoacoustic emissions are present at the higher stimulus level. These results are similar to those previously obtained from a Dutch DFNA13 family with midfrequency sensorineural hearing impairment. It seems that a defect in the tectorial membrane results primarily in an attenuation of sound, whereas suprathreshold measures, such as otoacoustic emissions and speech perception in noise, are preserved rather well. The main effect of the defects is a shift in the operation point of the outer hair cells with near intact functioning at high levels. As most test results reflect those found in middle-ear conductive loss in both families, the sensorineural hearing impairment may be characterized as a cochlear conductive hearing impairment.

A novel TECTA mutation in a Dutch DFNA8/12 family confirms genotype-phenotype correlation.

A novel TECTA mutation, p.R1890C, was found in a Dutch family with nonsyndromic autosomal dominant sensorineural hearing impairment. In early life, presumably congenital, hearing impairment occurred in the midfrequency range, amounting to about 40 dB at 1 kHz. Speech recognition was good with all phoneme recognition scores exceeding 90%. An intact horizontal vestibuloocular reflex was found in four tested patients. The missense mutation is located in the zona pellucida (ZP) domain of alpha-tectorin. Mutations affecting the ZP domain of alpha-tectorin are significantly associated with midfrequency hearing impairment. Substitutions affecting other amino acid residues than cysteines show a significant association with hearing impairment without progression. Indeed, in the present family progression seemed to be absent. In addition, the presently identified mutation affecting the ZP domain resulted in a substantially lesser degree of hearing impairment than was previously reported for DFNA8/12 traits with mutations affecting the ZP domain of alpha-tectorin.

Visual impairment in Finnish Usher syndrome type III.

PURPOSE: To evaluate visual impairment in Finnish Usher syndrome type 3 (USH3) and compare this with visual impairment in Usher syndrome types 1b (USH1b) and 2a (USH2a). METHODS: We carried out a retrospective study of 28 Finnish USH3 patients, 24 Dutch USH2a patients and 17 Dutch USH1b patients. Cross-sectional regression analyses of the functional acuity score (FAS), functional field score (FFS*) and functional vision score (FVS*) related to age were performed for all patients. The FFS* and FVS* were calculated using the isoptre V-4 test target instead of the usual III-4 target. Statistical tests relating to regression lines and Student's t-test were used to compare between USH3 patients and the other genetic subtypes of Usher syndrome. RESULTS: Cross-sectional analyses revealed significant deterioration in the FAS (1.3% per year), FFS* (1.4% per year) and FVS* (1.8% per year) with advancing age in the USH3 patient group. At a given age the USH3 patients showed significantly poorer visual field function than the USH2a patients. CONCLUSIONS: The rate of deterioration in visual function in Finnish USH3 patients was fairly similar to that in Dutch USH1b or USH2a patients. At a given age, visual field impairment in USH3 patients was similar to that in USH1b patients but poorer than in USH2a patients.

Prenatal diagnosis of the fetus with hypoplastic left heart syndrome management and outcome.

OBJECTIVES: To review our 13-year experience with prenatally detected hypoplastic left heart syndrome (HLHS) of which management remains controversial. MATERIAL AND METHODS: Retrospective study of the management and outcome in all cases of HLHS diagnosed prenatally in a tertiary referral center for pediatric cardiology and cardiac surgery between January 1988 and July 2001. RESULTS: The diagnosis of HLHS was made in 32 fetuses. One mother had two pregnancies associated with HLHS. In 16 cases parents opted for termination of pregnancy and in five for compassionate care. Four fetuses died in utero, and seven patients received a palliative reconstructive Norwood procedure. In seven fetuses, associated anomalies were detected: three chromosomal and structural and four only structural. In six fetuses, other associated intracardiac anomalies were detected. Of seven infants operated, six had no associated anomalies and only one is alive at an age of 17 months. CONCLUSION: The low percentage of intention to treat among patients in our center (34%) is in accordance with the percentage found in another study from the UK (36.2%), but differs significantly from reported series across the Atlantic (67%). Prenatal diagnosis of the HLHS provides opportunities not only for getting patients in optimal preoperative condition when surgery is offered, but also for in-depth counseling of the parents on this severe malformation. A minority of parents faced with the difficult decision of possible termination of pregnancy, compassionate care or the Norwood strategy, choose surgical treatment which might be based on socioreligious differences and the interpretation of the long-term quality of life.