KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness.
Potassium channels regulate electrical signaling and the ionic composition of biological fluids. Mutations in the three known genes of the KCNQ branch of the K+ channel gene family underlie inherited cardiac arrhythmias (in some cases associated with deafness) and neonatal epilepsy. We have now cloned KCNQ4, a novel member of this branch. It maps to the DFNA2 locus for a form of nonsyndromic dominant deafness. In the cochlea, it is expressed in sensory outer hair cells. A mutation in this gene in a DFNA2 pedigree changes a residue in the KCNQ4 pore region. It abolishes the potassium currents of wild-type KCNQ4 on which it exerts a strong dominant-negative effect. Whereas mutations in KCNQ1 cause deafness by affecting endolymph secretion, the mechanism leading to KCNQ4-related hearing loss is intrinsic to outer hair cells. (+info)
3D MRI of the membranous labyrinth. An age related comparison of MR findings in patients with labyrinthine fibrosis and in persons without inner ear symptoms.
PURPOSE: We compared MRI of the membranous labyrinth in patients with chronic non-neoplastic inner ear disease and MR signs of labyrinthine fibrosis and controls depending on their age, in order to establish whether there were any MR differences regarding patient age groups, control age groups and between the patients and controls themselves. MATERIALS AND METHODS: Clinical ENT examinations as well as a T2* weighted 3D CISS (Constructive Interference in Steady State) sequence with a slice thickness of 0.7 mm were performed. Our collective was subdivided as follows: 0-19 years (10 controls, 3 patients with chronic non-neoplastic inner ear disease), 20-49 years (55 controls, 8 patients), 50 years and older (40 controls, 22 patients). Detectability of labyrinthine structures (e.g. cochlea, vestibule, semicircular canals) and filling defects were evaluated. RESULTS: In the 3 age-groups of the control collective no significant differences were observed in the membranous labyrinth. However differences concerning labyrinthine detectability emerged between controls and patients in both the 20-49 years and 50 years and older age groups. In the patient collective the 3 age groups showed no significant discrepancy in the mean number of lesions. CONCLUSION: Filling defects of the membranous labyrinth on 3D CISS MR images are pathological even in older persons. We would therefore recommend high resolution T2* weighted MRI in the case of suspected labyrinthine fibrosis. (+info)
Townes-Brocks syndrome (TBS) is an autosomal dominant disorder with multiple malformations and variable expression. Major findings include external ear anomalies, hearing loss, preaxial polydactyly and triphalangeal thumbs, imperforate anus, and renal malformations. Most patients with Townes-Brocks syndrome have normal intelligence, although mental retardation has been noted in a few. (+info)
Homozygosity mapping to the USH2A locus in two isolated populations.
Usher syndrome is a group of autosomal recessive disorders characterised by progressive visual loss from retinitis pigmentosa and moderate to severe sensorineural hearing loss. Usher syndrome is estimated to account for 6-10% of all congenital sensorineural hearing loss. A gene locus in Usher type II (USH2) families has been assigned to a small region on chromosome 1q41 called the UHS2A locus. We have investigated two families with Usher syndrome from different isolated populations. One family is a Norwegian Saami family and the second family is from the Cayman Islands. They both come from relatively isolated populations and are inbred families suitable for linkage analysis. A lod score of 3.09 and 7.65 at zero recombination was reached respectively in the two families with two point linkage analysis to the USH2A locus on 1q41. Additional homozygosity mapping of the affected subjects concluded with a candidate region of 6.1 Mb. This region spans the previously published candidate region in USH2A. Our study emphasises that the mapped gene for USH2 is also involved in patients from other populations and will have implications for future mutation analysis once the USH2A gene is cloned. (+info)
Retinitis pigmentosa and progressive sensorineural hearing loss caused by a C12258A mutation in the mitochondrial MTTS2 gene.
Family ZMK is a large Irish kindred that segregates progressive sensorineural hearing loss and retinitis pigmentosa. The symptoms in the family are almost identical to those observed in Usher syndrome type III. Unlike that in Usher syndrome type III, the inheritance pattern in this family is compatible with dominant, X-linked dominant, or maternal inheritance. Prior linkage studies had resulted in exclusion of most candidate loci and >90% of the genome. A tentative location for a causative nuclear gene had been established on 9q; however, it is notable that no markers were found at zero recombination with respect to the disease gene. The marked variability in symptoms, together with the observation of subclinical muscle abnormalities in a single muscle biopsy, stimulated sequencing of the entire mtDNA in affected and unaffected individuals. This revealed a number of previously reported polymorphisms and/or silent substitutions. However, a C-->A transversion at position 12258 in the gene encoding the second mitochondrial serine tRNA, MTTS2, was heteroplasmic and was found in family members only. This sequence change was not present in 270 normal individuals from the same ethnic background. The consensus C at this position is highly conserved and is present in species as divergent from Homo sapiens as vulture and platypus. The mutation probably disrupts the amino acid-acceptor stem of the tRNA molecule, affecting aminoacylation of the tRNA and thereby reducing the efficiency and accuracy of mitochondrial translation. In summary, the data presented provide substantial evidence that the C12258A mtDNA mutation is causative of the disease phenotype in family ZMK. (+info)
Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNASer(UCN) gene.
We studied a large Dutch family with maternally inherited, progressive, sensorineural hearing loss in 27 patients. Only in a single family member was the hearing loss accompanied by neurological symptoms including ataxia and dysarthria. DNA analysis of the mitochondrial genome revealed the insertion of a C at nucleotide position 7472 in the tRNASer(UCN) gene (7472insC mutation). We determined the percentage of mutant DNA (heteroplasmy) in blood from all family members, and found no correlation between hearing loss and leucocyte heteroplasmy. The 7472insC mutation was previously identified in a smaller family from Sicily with sensorineural hearing loss in 9 family members, six of them also presenting neurologically with ataxia and myoclonus. The presence of the 7472insC mutation in two different pedigrees strongly supports its pathogenicity. However, the interfamilial difference in penetrance of the neurologic abnormalities is most likely to be strongly influenced by secondary factors different from the 7472insC mutation, as heteroplasmy or age of the patients were similar in both families. This mutation should therefore be analysed in families with maternally inherited hearing loss, irrespective of whether the hearing loss is non-syndromic or accompanied by neurologic abnormalities. (+info)
CT and MR findings of Michel anomaly: inner ear aplasia.
In 1863, Michel described a condition characterized by a total absence of differentiated inner ear structures associated with other skull base anomalies, including an abnormal course of the facial nerve and jugular veins. Michel aplasia clearly differs from Michel dysplasia, in which arrest of embryologic development occurs later. Recently, the role of otic capsule formation on mesenchymal differentiation was reported as well as the impact of the genetic deletion of the homeobox gene on the development of the ear, cranial nerves, and hindbrain. We report two patients with a total absence of inner ear structures bilaterally, illustrating the characteristic appearance of Michel aplasia and associated skull base anomalies. (+info)
Managing meningitis in children: audit of notifications, rifampicin chemoprophylaxis, and audiological referrals.
Important aspects of the management of meningitis in children include notification to local officers for control of communicable diseases; chemoprophylaxis for index cases and close contacts in cases of meningococcal or Haemophilus influenzae meningitis; and a formal hearing assessment for all survivors. A retrospective audit of these aspects of management was carried out for children admitted with meningitis in 12 months from 1 September 1990 to 31 August 1991 at the Royal Belfast Hospital for Sick Children. Only 20 of 36(56%) cases were notified by medical staff. Chemoprophylaxis was arranged for all close family contacts but to only five of the 23(22%) index cases for whom it was indicated. Appointments for audiological testing were arranged for only 19 of the 32(59%) survivors. Subsequently all doctors, including each intake of junior doctors, were given written information on the importance of notification and locally agreed guidelines for chemoprophylaxis and hearing assessments for survivors before discharge. Guidelines were also displayed prominently in each ward. A repeat audit from January 1992 to December 1992 showed significant improvement in these aspects of care. Twenty eight of 32 cases (88%) were notified, chemoprophylaxis was given to 20 of 22(91%) index cases for whom it was indicated, and 25 of 29(86%) survivors had hearing assessments arranged before discharge. Correct management of some aspects of care cannot be assumed, even if statutory (notification), nationally agreed (chemoprophylaxis), or generally agreed good practice (hearing assessments). These aspects of care improved after the first audit but the authors conclude that the notification rate remains below 100% and a repeat audit is necessary. (+info)