Further audiovestibular characterization of DFNB77, caused by deleterious variants in LOXHD1, and investigation into the involvement of Fuchs corneal dystrophy.

This study focuses on further characterization of the audiovestibular phenotype and on genotype-phenotype correlations of DFNB77, an autosomal recessive type of hearing impairment (HI). DFNB77 is associated with disease-causing variants in LOXHD1, and is genetically and phenotypically highly heterogeneous. Heterozygous deleterious missense variants in LOXHD1 have been associated with late-onset Fuchs corneal dystrophy (FCD). However, up to now screening for FCD of heterozygous carriers in DFNB77 families has not been reported. This study describes the genotype and audiovestibular phenotype of 9 families with DFNB77. In addition, carriers within the families were screened for FCD. Fifteen pathogenic missense and truncating variants were identified, of which 12 were novel. The hearing phenotype showed high inter- and intrafamilial variation in severity and progression. There was no evidence for involvement of the vestibular system. None of the carriers showed (pre-clinical) symptoms of FCD. Our findings expand the genotypic and phenotypic spectrum of DFNB77, but a clear correlation between the type or location of the variant and the severity or progression of HI could not be established. We hypothesize that environmental factors or genetic modifiers are responsible for phenotypic differences. No association was found between heterozygous LOXHD1 variants and the occurrence of FCD in carriers.

Clinical aspects of an autosomal dominantly inherited hearing impairment linked to the DFNA60 locus on chromosome 2q23.1-2q23.3.

A total of 64 loci for autosomal dominant non-syndromic hearing impairment have been described, and the causative genes have been identified for 24 of these. The present study reports on the clinical characteristics of an autosomal dominantly inherited hearing impairment that is linked to a region within the DFNA60 locus located on chromosome 2 in q22.1-24.1. A pedigree spanning four generations was established with 13 affected individuals. Linkage analysis demonstrated that the locus extended over a 2.96 Mb region flanked by markers D2S2335 and D2S2275. The audiograms mainly showed a distinctive U-shaped configuration. Deterioration of hearing started at a wide age range, from 12 to 40 years. Cross-sectional analysis showed rapid progression of hearing impairment from mild to severe, between the ages of 40 and 60 years, a phenomenon that is also observed in DFNA9 patients. The results of the individual longitudinal analyses were generally in line with those obtained by the cross-sectional analysis. Speech recognition scores related to the level of hearing impairment (PTA1,2,4 kHz) appeared to be fairly similar to those of presbyacusis patients. It is speculated that hearing impairment starting in mid-life, as shown by DFNA60 patients, could play a role in the development of presbyacusis. Furthermore, speech recognition did not deteriorate appreciably before the sixth decade of life. We conclude that DFNA60 should be considered in hearing impaired patients who undergo a rapid progression in middle age and are negative for DFNA9. Furthermore, cochlear implantation resulted in good rehabilitation in two DFNA60 patients.

Variable degrees of hearing impairment in a Dutch DFNX4 (DFN6) family.

OBJECTIVE: Investigation of the audiometric characteristics of a large Dutch DFNX4 family with a p.Glu72X mutation in the SMPX gene. PATIENTS AND METHODS: Sixty family members participated in this study and examination consisted of medical history, otoscopy, pure tone and speech audiometry. Linkage and mutation analysis revealed a pathogenic mutation in the SMPX gene. RESULTS: All 25 mutation carriers exhibited hearing impairment, except one woman aged 25 years. The men (n = 10) showed more severe hearing impairment than the women (n = 14) and already at a younger age. The age of onset according to history was 2-10 years (mean: 3.3 years) in men and 3-48 years (mean: 26.4 years) in women. In the men, severe threshold deterioration mainly occurred during the first two decades of life, especially at the higher frequencies. The women showed milder threshold deterioration and more pronounced across-subjects and individual inter-aural variation, especially at 2-8 kHz. Longitudinal linear regression analysis demonstrated significant progression of at least two frequencies in five individuals (3 men and 2 women). The speech recognition scores of the mutation carriers with hearing impairment were decreased at relatively young ages compared to a reference group of patients with only presbycusis, especially in men. However, all these patients tended to have better speech recognition scores than the presbycusis patients at matching PTA(1,2,4 kHz) levels. CONCLUSION: This study demonstrates the phenotypic heterogeneity in this large family with an X-linked pattern of inherited sensorineural hearing impairment. The men showed more severe hearing impairment at a younger age with more pronounced progression during the first two decades of life, while women demonstrated less severe hearing impairment with more gradual progression and a wider variation in age of onset, degree of hearing impairment and inter-aural asymmetry in thresholds.

Audiometric characteristics of a Dutch family with Muckle-Wells syndrome.

Description of the audiometric and vestibular characteristics of a Dutch family with Muckle-Wells syndrome (MWS). Examination of all family members consisted of pure tone audiometry, otoscopy and genetic analysis. In addition, a selected group underwent speech audiometry, vestibulo-ocular examination, acoustic reflex testing and tests assessing loudness scaling, gap detection, difference limen for frequency and speech perception in noise. Linear regression analyses were performed on the audiometric data. Six clinically affected family members participated in this study and all were carriers of a p.Tyr859His mutation in the NLPR3 gene. Most affected family members reported bilateral, slowly progressive hearing impairment since childhood. Hearing impairment started at the high frequencies and the low- and mid-frequency threshold values deteriorated with advancing age. Annual threshold deterioration (ATD) ranged from 1.3 to 1.9 dB/year with the highest values at the lower frequencies. Longitudinal linear regression analysis demonstrated significant progression for a number of frequencies in five individuals. Speech recognition scores were clearly affected. However, these individuals tended to have higher speech recognition scores than presbyacusis patients at similar PTA(1,2,4 kHz) levels. The loudness growth curves were steeper than those found in individuals with normal hearing, except for one family member (individual IV:6). Suprathreshold measurements, such as difference limen for frequency (DL(f)), gap detection and particularly speech perception in noise were within the normal range or at least close to data obtained in two groups of patients with a so-called conductive type of hearing loss, situated in the cochlea. Hearing impairment in MWS is variable and shows resemblance to previously described intra-cochlear conductive hearing impairment. This could be helpful in elucidating the pathogenesis of hearing impairment in MWS. Other associated symptoms of MWS were mild and nonspecific in the present family. Therefore, even without any obvious syndromic features, MWS can be the cause of sensorineural hearing impairment, especially when combined with (mild) skin rash and musculoskeletal symptoms. An early diagnosis of MWS is essential to prevent irreversible damage from amyloidosis. The effect of IL-1ß inhibitors on hearing impairment is more controversial, but an early start of treatment seems to be essential. Therefore, our results are of importance in patient care and counselling.