Variations in genetic assessment and recurrence risks quoted for childhood deafness: a survey of clinical geneticists.
(1/1607)
We report here the results of a questionnaire survey of consultant clinical geneticists in the United Kingdom to which we had an 81% response rate. In this questionnaire we asked about: (1) the nature of services currently offered to families with hearing impaired children, (2) what recurrence risks they quoted in isolated non-syndromic cases, and (3) what they might suggest for improving the range of genetic services available at present. We noted great variation both in these services and in the recurrence risks quoted in isolated cases. Based on the results of the questionnaire, we have proposed a protocol for the investigation of permanent childhood hearing impairment, which we believe to be both comprehensive and practical in an outpatient clinic setting. It is only by improving existing clinical and social understanding and knowledge of childhood hearing impairment that it will become possible to use recent molecular advances to develop comprehensive and consistent services for these families. (+info)
Human deafness dystonia syndrome is a mitochondrial disease.
(2/1607)
The human deafness dystonia syndrome results from the mutation of a protein (DDP) of unknown function. We show now that DDP is a mitochondrial protein and similar to five small proteins (Tim8p, Tim9p, Tim10p, Tim12p, and Tim13p) of the yeast mitochondrial intermembrane space. Tim9p, Tim10p, and Tim12p mediate the import of metabolite transporters from the cytoplasm into the mitochondrial inner membrane and interact structurally and functionally with Tim8p and Tim13p. DDP is most similar to Tim8p. Tim8p exists as a soluble 70-kDa complex with Tim13p and Tim9p, and deletion of Tim8p is synthetically lethal with a conditional mutation in Tim10p. The deafness dystonia syndrome thus is a novel type of mitochondrial disease that probably is caused by a defective mitochondrial protein-import system. (+info)
Contralateral deafness following unilateral suboccipital brain tumor surgery in a patient with large vestibular aqueduct--case report.
(3/1607)
A 68-year-old female developed contralateral deafness following extirpation of a left cerebellopontine angle epidermoid cyst. Computed tomography showed that large vestibular aqueduct was present. This unusual complication may have been caused by an abrupt pressure change after cerebrospinal fluid release, which was transmitted through the large vestibular aqueduct and resulted in cochlear damage. (+info)
Inner ear and kidney anomalies caused by IAP insertion in an intron of the Eya1 gene in a mouse model of BOR syndrome.
(4/1607)
A spontaneous mutation causing deafness and circling behavior was discovered in a C3H/HeJ colony of mice at the Jackson Laboratory. Pathological analysis of mutant mice revealed gross morphological abnormalities of the inner ear, and also dysmorphic or missing kidneys. The deafness and abnormal behavior were shown to be inherited as an autosomal recessive trait and mapped to mouse chromosome 1 near the position of the Eya1 gene. The human homolog of this gene, EYA1, has been shown to underly branchio-oto-renal (BOR) syndrome, an autosomal dominant disorder characterized by hearing loss with associated branchial and renal anomalies. Molecular analysis of the Eya1 gene in mutant mice revealed the insertion of an intracisternal A particle (IAP) element in intron 7. The presence of the IAP insertion was associated with reduced expression of the normal Eya1 message and formation of additional aberrant transcripts. The hypomorphic nature of the mutation may explain its recessive inheritance, if protein levels in homozygotes, but not heterozygotes, are below a critical threshold needed for normal developmental function. The new mouse mutation is designated Eya1(bor) to denote its similarity to human BOR syndrome, and will provide a valuable model for studying mutant gene expression and etiology. (+info)
Defective high-affinity thiamine transporter leads to cell death in thiamine-responsive megaloblastic anemia syndrome fibroblasts.
(5/1607)
We have investigated the cellular pathology of the syndrome called thiamine-responsive megaloblastic anemia (TRMA) with diabetes and deafness. Cultured diploid fibroblasts were grown in thiamine-free medium and dialyzed serum. Normal fibroblasts survived indefinitely without supplemental thiamine, whereas patient cells died in 5-14 days (mean 9.5 days), and heterozygous cells survived for more than 30 days. TRMA fibroblasts were rescued from death with 10-30 nM thiamine (in the range of normal plasma thiamine concentrations). Positive terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) staining suggested that cell death was due to apoptosis. We assessed cellular uptake of [3H]thiamine at submicromolar concentrations. Normal fibroblasts exhibited saturable, high-affinity thiamine uptake (Km 400-550 nM; Vmax 11 pmol/min/10(6) cells) in addition to a low-affinity unsaturable component. Mutant cells lacked detectable high-affinity uptake. At 30 nM thiamine, the rate of uptake of thiamine by TRMA fibroblasts was 10-fold less than that of wild-type, and cells from obligate heterozygotes had an intermediate phenotype. Transfection of TRMA fibroblasts with the yeast thiamine transporter gene THI10 prevented cell death when cells were grown in the absence of supplemental thiamine. We therefore propose that the primary abnormality in TRMA is absence of a high-affinity thiamine transporter and that low intracellular thiamine concentrations in the mutant cells cause biochemical abnormalities that lead to apoptotic cell death. (+info)
Allele specific oligonucleotide analysis of the common deafness mutation 35delG in the connexin 26 (GJB2) gene.
(6/1607)
Despite the large number of genes that are expected to be involved in non-syndromal, recessive deafness, only a few have been cloned. One of these genes is GJB2, which encodes connexin 26. A frameshift mutation in this gene has been reported to be common in several populations and a carrier frequency of about 1 in 30 people has been detected in Italy and Spain. Mutation 35delG is difficult to detect because it lies within a stretch of six guanines flanked by thymines, so the deletion of one G does not create or destroy a restriction site and mutagenesis primers are not useful for this mutation. We have generated an allele specific oligonucleotide method that uses 12-mer oligonucleotides and easily discriminates between the normal and 35delG alleles. The method should permit a rapid analysis of this mutation in congenital cases (recessive or sporadic), including diagnosis and carrier detection of 35delG in the population. (+info)
A comparison of language achievement in children with cochlear implants and children using hearing aids.
(7/1607)
English language achievement of 29 prelingually deaf children with 3 or more years of cochlear implant (CI) experience was compared to the achievement levels of prelingually deaf children who did not have such CI experience. Language achievement was measured by the Rhode Island Test of Language Structure (RITLS), a measure of signed and spoken sentence comprehension, and the Index of Productive Syntax (IPSyn), a measure of expressive (signed and spoken) English grammar. When the CI users were compared with their deaf age mates who contributed to the norms of the RITLS, it was found that CI users achieved significantly better scores. Likewise, we found that CI users performed better than 29 deaf children who used hearing aids (HAs) with respect to English grammar achievement as indexed by the IPSyn. Additionally, we found that chronological age highly correlated with IPSyn levels only among the non-CI users, whereas length of CI experience was significantly correlated with IPSyn scores for CI users. Finally, clear differences between those with and without CI experience were found by 2 years of post-implant experience. These data provide evidence that children who receive CIs benefit in the form of improved English language comprehension and production. (+info)
Can routine information systems be used to monitor serious disability?
(8/1607)
OBJECTIVE: To determine whether reliable birth cohort prevalence rates of disabling conditions in early childhood can be obtained from child health information systems. DESIGN: Comparison of two sources of information on motor and sensory disabilities: from child health information systems held by health authorities, and a population register that uses multiple sources of ascertainment. SETTING: The counties of Oxfordshire, Buckinghamshire, and Northamptonshire. PARTICIPANTS: Children born to residents of the three counties between 1984 and 1989. RESULTS: Eight hundred and twenty children (6.0/1000 live births) were identified from the child health system as having one or more of the conditions, and 580 (4.2/1000 live births) were identified from the population register; however, only 284 children were identified by both sources. CONCLUSIONS: It is currently impossible to monitor trends in the prevalence rate of disabling disorders in childhood using the child health information systems. Agreement about ways of collecting, recording, and collating information on disability would be a useful step towards realising the full potential of these systems. (+info)