Causes of hearing impairment in the Norwegian paediatric cochlear implant program.

Severe to profound hearing impairment (HI) is estimated to affect around 1/2000 young children. Advances in genetics have made it possible to identify several genes related to HI. This information can cast light upon prognostic factors regarding the outcome in cochlear implantation, and provide information both for scientific and genetic counselling purposes. From 1992 to 2005, 273 children from 254 families (probands) were offered cochlear implants in Norway. An evaluation of the causes of HI, especially regarding the genes GJB2, GJB6, SLC26A4, KCNQ1, KCNE1, and the mutation A1555G in mitochondrial DNA was performed in 85% of the families. The number of probands with unknown cause of HI was thus reduced from 120 to 68 (43% reduction). Ninety-eight (46%) of the probands had an identified genetic etiology of their HI. A relatively high prevalence of Jervell and Lange-Nielsen syndrome was found. The main causes of severe and profound HI were similar to those found in other European countries. GJB2 mutations are a common cause of prelingual HI in Norwegian cochlear implanted children.

A novel missense mutation in ACTG1 causes dominant deafness in a Norwegian DFNA20/26 family, but ACTG1 mutations are not frequent among families with hereditary hearing impairment.

The gamma-actin gene (ACTG1) encodes a major cytoskeletal protein of the sensory hair cells of the cochlea. Recently, mutations in ACTG1 were found to cause autosomal dominant, progressive, sensorineural hearing impairment linked to the DFNA20/26 locus on chromosome 17q25.3 in four American families and in one Dutch family. We report here the linkage of autosomal dominant, progressive, sensorineural hearing impairment in a large Norwegian family to the DFNA20/26 locus. Sequencing of ACTG1 identified a novel missense mutation (c.1109T>C; p.V370A) segregating with the hearing loss. Functional analysis in yeast showed that the p.V370A mutation restricts cell growth at elevated temperature or under hyperosmolar stress. Molecular modelling suggested that the p.V370A mutation modestly alters a site for protein-protein interaction in gamma-actin and thereby modestly alters gamma-actin-based cytoskeletal structures. Nineteen Norwegian and Danish families with autosomal, dominant hearing impairment were analyzed for mutations in ACTG1 by sequencing, but no disease-associated mutations were identified. Finally, a long-term follow-up of the hearing loss progression associated with the p.V370A mutation in ACTG1 is provided. The present study expands our understanding of the genotype-phenotype relationship of this deafness gene and provides a sensitive and simple functional assay for missense mutations in this gene, which may assist future molecular diagnosis of autosomal-dominant hearing impairment. Finally, the present results do not indicate that mutations in ACTG1 are a frequent cause of autosomal-dominant postlingual sensorineural hearing impairment in Norway nor Denmark.

Jervell and Lange-Nielsen syndrome in Norwegian children: aspects around cochlear implantation, hearing, and balance.

OBJECTIVES: Jervell and Lange-Nielsen syndrome (JLNS) is a rare cause of autosomal recessive inherited deafness. JLNS patients are candidates for cochlear implantation, and represent a group that needs special attention and precautions. The aim of this article is to draw some guidelines for dealing with these patients, and to emphasize the importance of electrocardiography (ECG) screening of congenitally deaf patients. A probable vestibular dysfunction is also discussed. DESIGN: Eight of 273 implanted children (2.9%) at Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway have been diagnosed with JLNS. All the children were evaluated with ECG, six of them before cochlear implantation. Auditory perception was evaluated with the littlEARS Auditory Questionnaire, or with a test battery developed at Rikshospitalet-Radiumhospitalet Medical Center. DNA sequencing was used to screen for mutations in the genes KCNQ1 and KCNE1. The cases are presented and discussed in a retrospective case review. RESULTS: Two of the children are dead. The corrected QT (QTc) interval in the ECG was markedly prolonged in all the children (median QTc, 0.59 sec; range, 0.53-0.65). Six children have more than 1 yr experience with their cochlear implant. Four of them are performing average or above compared with the other implanted children. All the children have mutations in the KCNQ1 gene. Six of our patients have delayed gross motor development, and the remaining two are markedly delayed compared with their older siblings. CONCLUSIONS: Cochlear implantation can be performed safely and with good results in children with JLNS, but requires knowledge of the diagnosis and necessary precautions have to be taken. ECG should be taken for all children with congenital deafness, preferably before exposure to strong sound stimuli. Vestibular dysfunction seems to be a part of JLNS, but this needs further investigation.