Martijn H. Kemperman

A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26).

Linkage analysis in a multigenerational family with autosomal dominant hearing loss yielded a chromosomal localisation of the underlying genetic defect in the DFNA20/26 locus at 17q25-qter. The 6-cM critical region harboured the γ-1-actin (ACTG1) gene, which was considered an attractive candidate gene because actins are important structural elements of the inner ear hair cells. In this study, a Thr278Ile mutation was identified in helix 9 of the modelled protein structure. The alteration of residue Thr278 is predicted to have a small but significant effect on the γ 1 actin structure owing to its close proximity to a methionine residue at position 313 in helix 11. Met313 has no space in the structure to move away. Moreover, the Thr278 residue is highly conserved throughout eukaryotic evolution. Using a known actin structure the mutation could be predicted to impair actin polymerisation. These findings strongly suggest that the Thr278Ile mutation in ACTG1 represents the first disease causing germline mutation in a cytoplasmic actin isoform.

Progressive cochleovestibular impairment caused by a point mutation in the COCH gene at DFNA9.

Objectives: Analysis of phenotype‐genotype correlation.

Audiometric, vestibular, and genetic aspects of a DFNA9 family with a G88E COCH mutation.

Objectives: To perform genetic analysis and to analyze cochleovestibular impairment features in a newly identified Dutch family with nonsyndromic autosomal dominant hearing impairment (DFNA9). Study Design: Genetic analysis was performed using microsatellite markers and single nucleotide polymorphisms. Audiometric data were collected and analyzed longitudinally. Results were compared with those obtained in previously identified P51S COCH mutation carriers (n = 74). Special attention was also given to a comparison of age-related features such as progressive hearing loss and vestibular impairment. Setting: Tertiary referral center. Patients: G88E COCH mutation carriers from a Dutch family. Main Outcome Measures: The study of clinical features of a DFNA9 family carrying a G88E COCH mutation and to compare this to the symptoms of those carrying a P51S/COCH mutation. Results: Pure-tone thresholds, phoneme recognition scores, and vestibular responses of the G88E mutation carriers were essentially similar to those previously established in the P51S mutation carriers. Hearing started to deteriorate in G88E mutation carriers from age 46 to 49 years and onward, whereas deterioration of vestibular function started from approximately age 46 years. In the P51S mutation carriers, vestibular impairment started earlier, at approximately age 34 years. However, the difference in age of onset with the G88E mutation carriers was not significant. Remarkably, the proportion of patients who developed complete vestibular areflexia within the age range of 40 to 56 years was significantly lower for the G88E mutation carriers than for the P51S mutation carriers. Conclusion: Apart from a significantly lower frequency of vestibular areflexia between the ages of 40 and 56 years, there are no phenotypic differences between carriers of the G88E and P51S mutations in the COCH gene.

Vestibular deterioration precedes hearing deterioration in the P51S COCH mutation (DFNA9): an analysis in 74 mutation carriers.

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.

Progressive fluctuant hearing loss, enlarged vestibular aqueduct, and cochlear hypoplasia in branchio-oto-renal syndrome.

Objective To study the results of petrosal bone imaging and audiometric long-term follow-up of two patients with branchio-oto-renal (BOR) syndrome and relate them to the clinical features, including caloric responses. Study Design Longitudinal case study. Setting Tertiary referral center. Patients A father and son with the BOR syndrome. Main Outcome Measures Both patients underwent imaging studies to detect and evaluate inner ear anomalies. Longitudinal audiometric analysis of the hearing threshold data over the previous 23 years was performed. Caloric tests were performed at various ages. Results The son had a short, wide internal acoustic canal, a hypoplastic cochlea, a plump vestibule, and a wide vestibular aqueduct on both sides; the semicircular canals and endolymphatic sac were of normal size. He showed progressive fluctuant sensorineural hearing loss. Caloric tests disclosed hyporeflexia on the left side. The father had a plump internal acoustic canal and hypoplastic cochlea on both sides. The left vestibule was hypoplastic, and the left vestibular aqueduct was marginally enlarged. He showed severe hearing impairment, without substantial progression or fluctuation, and caloric areflexia on the left side. Conclusion These findings suggest a correlation between progressive fluctuant sensorineural hearing loss with caloric hypofunction and the presence of an enlarged vestibular aqueduct in the BOR syndrome. Additional longitudinal case studies are needed to further evaluate such a correlation.