Clinical follow-up and histopathology of the temporal bones in Nathalie syndrome.

The Nathalie syndrome (OMIM 255990) comprises a combination of features that do not resemble any other known syndrome and is as such an independent, rare entity. It is characterized by sensorineural hearing impairment, juvenile cataract, spinal muscular atrophy, skeletal abnormalities, retardation of growth, underdeveloped secondary gender characteristics and cardiomyopathy. Worldwide, only one family with this syndrome is known. An update of the clinical follow-up in this family and the results of autopsy are given. Audiometry showed a downsloping configuration that corresponded to the findings at histopathological examination of the cochlea: a diffuse atrophy of the organ of Corti, severe and diffuse atrophy of the stria vascularis and moderate loss of cochlear neurons in all turns. Another new striking feature is that individuals with the Nathalie syndrome have a shortened life expectancy with a risk of sudden death or death from heart failure resulting from (dilated) cardiomyopathy.

Audioprofile-directed successful mutation analysis in a DFNA2/KCNQ4 (p.Leu274His) family.

OBJECTIVES: We undertook to show that in a family with nonsyndromic autosomal dominant sensorineural hearing loss, genetic analysis can be successful when there is a match with a specific DFNA audioprofile. We also provide an update of relevant DFNA2/KCNQ4 audioprofiles and report the results of automatic audioprofile analysis using the Internet program AudioGene. METHODS: Audiometric data and blood samples were obtained from the family W08-0384. Based on the audiograms of the affected participants, mutation analysis of KCNQ4 was started. Original audiometric threshold data were collected for all identified KCNQ4-related DFNA2 families. The Internet computer program AudioGene, recently developed for automatic audioprofile analysis, was accessed. RESULTS: The family's audioprofile and the program AudioGene predicted the DFNA2/KCNQ4 locus. Mutation analysis of KCNQ4 revealed a c.821T>A (p.Leu274His) mutation of the KCNQ4 gene. This mutation has been previously identified in a Dutch family. Genetic analysis revealed a common haplotype in these two families over a region including the KCNQ4 gene. CONCLUSIONS: Familiarity with the audioprofiles of DFNA traits may lead to successful mutation analysis of the gene involved, even in a small family in which genetic linkage analysis is not an option. Alternatively, the specially developed program AudioGene can be accessed on the Internet to perform automatic audioprofile analysis of a family's (audiological) phenotype.

Progressive sensorineural hearing loss and normal vestibular function in a Dutch DFNB7/11 family with a novel mutation in TMC1.

In a Dutch family with autosomal recessive hearing loss, genome-wide single-nucleotide polymorphism analysis mapped the genetic defect to the DFNB7/11 locus. A novel homozygous A-to-G change in the TMC1 gene was detected near the splice donor site of intron 19 (c.1763+3A→G) segregating with the hearing loss in this family. One of the 6 transmembrane domains and the actual TMC channel domain are predicted to be absent in the mutant protein. The sensorineural hearing impairment in this DFNB7/11 family has a postlingual onset. Audiometric analysis initially showed a steeply downward-sloping threshold configuration. The progressive phenotype in this family resembles the phenotype previously described for families with dominant TMC1 mutations (DFNA36) rather than that of families with recessive TMC1 mutations (DFNB7/11) which invariably cause severe-to-profound prelingual hearing impairment.

Audiometric and vestibular features in a second Dutch DFNA20/26 family with a novel mutation in ACTG1.

OBJECTIVES: We analyzed the phenotype in a 5-generation DFNA20/26 family with a novel missense mutation in the ACTG1 gene (c.151G>A) and compared the findings to previous reports on DFNA20/26 families. METHODS: Audiometric data were collected from the family members of a Dutch kindred with the novel ACTG1 mutation. Cross-sectional and/or longitudinal analyses were performed on pure tone and speech audiometry data of the mutation carriers. Age-related typical audiograms were constructed. Vestibular examination was performed in all mutation carriers. RESULTS: Overall, high-frequency hearing impairment, most prominent at ages over 30 years, was observed with a progression rate of 1.1 to 2.1 dB/y, increasing with frequency. It ultimately resulted in residual hearing. Speech recognition scores remained good at given pure tone average (1, 2, and 4 kHz) levels, but were slightly poorer than those at similar levels in a group of patients with presbycusis. Vestibular examination did not reveal any consistent, statistically significant abnormalities. CONCLUSIONS: The audiometric phenotype of the Dutch DFNA20/26 family with a novel mutation in ACTG1 was largely consistent with previous reports on DFNA20/26. Considerable variations were found in audiogram configurations within the family. This is the first known DFNA20/26 family that has experienced tinnitus.

Mild and variable audiometric and vestibular features in a third DFNA15 family with a novel mutation in POU4F3.

OBJECTIVES: Cochleovestibular characteristics were investigated in a Dutch DFNA15 family with a novel POU4F3 mutation, L223P. METHODS: A 4-generation pedigree was constructed of the Dutch family with the novel L223P POU4F3 mutation. Pure tone audiometric data were collected and analyzed cross-sectionally in mutation carriers. Age-related typical audiograms were derived. Vestibular examination was performed in most of the mutation carriers. The results were compared to those obtained from previously identified 884de18 and L289F POU4F3 mutation carriers. RESULTS: A novel mutation (L223P) in POU4F3 segregated with hearing impairment in the present family. Audiometric analysis generally showed an early-adult to midlife onset of hearing impairment. High-frequency hearing impairment was observed most frequently. Age-related typical audiograms showed a down-sloping configuration at ages of more than 30 years, with the fastest rate of progression at the high frequencies. Vestibular function tests revealed hypofunction of the vestibular labyrinth in 2 mutation carriers (not statistically significant). CONCLUSIONS: The clinical features in the present family with a POU4F3 mutation were fairly similar to those in the 2 previously described DFNA15 families, but the level of hearing impairment was milder, and there was no substantial vestibular dysfunction.

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.