Maternally inherited deafness associated with a T1095C mutation in the mDNA.
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Hearing loss is a relatively frequent defect in children with a genetic or predisposition basis in about 50% of cases. Mitochondrial DNA (mtDNA)-associated disorder often present with sensorineural hearing loss (SNHL) either in isolation or as a part of a multisystem disorder in adults but the frequency in pediatric cases is unknown. We analysed deafness-related mtDNA mutations in 80 deaf children to assess the relative frequency of alterations in childhood-onset SNHL. In 16 patients in whom maternal inheritance was possible, we screened for new mutations likely to affect mitochondrial protein synthesis. In one child we detected a novel mutation (T1095C) in the 12S rRNA gene. This mutation fulfils the suggested criteria for definition of a disease-related nucleotide variant. No mutations were found in other patients. Although we cannot exclude the presence of still undefined new mtDNA mutations, our data suggest that mtDNA defect are not common in childhood-onset SNHL. (+info)
Sensorineural hearing loss and the incidence of Cx26 mutations in Austria.
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A clinical evaluation and Cx26 mutation analysis was performed in 92 consecutive patients with sensorineural hearing loss in order to delineate the spectrum of genetically caused hearing loss. Among patients of Austrian origin, 53% were classified with hereditary hearing loss. Cx26 mutations were found in 26% of NSHL patients (40% of familial vs 18% of sporadic cases). The mutation 35delG accounted for 52.8% of all presumed GJB2 disease alleles. The second most frequent mutation was L90P (16.7%) having been reported with a prevalence of 0.7-3.5% in other populations. Three novel mutations were found. The novel mutation, R143Q, was associated with dominant high-frequency hearing loss. Pseudodominant transmission of NSHL was seen in four families with Cx26 mutations. A mutation 35delG carrier rate of 0.9% was observed among 672 controls from West-Austria. Cx26 mutations were found associated with mild to profound, and with asymmetric hearing impairment. (+info)
Open trial of methotrexate as treatment for autoimmune hearing loss.
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OBJECTIVE: To assess the efficacy of low-dose methotrexate (MTX) administered for the treatment of autoimmune hearing loss. METHODS: This was a prospective, 12-month, open-label study of 17 patients with refractory autoimmune hearing loss. All patients had ongoing episodic worsening of hearing in one or both ears prior to enrollment despite traditional medical therapy. The MTX dose was 7.5-25 mg/week. Hearing loss and vertigo were evaluated at baseline and at completion of the study. Hearing improvement was defined as an improvement in pure tone threshold (PT) average of >10 dB or an increase in speech discrimination (SD) of >15%; worsening was defined as a decrease of >10 dB in PT or a decrease of >15% in SD in at least one ear. RESULTS: MTX was well tolerated. Among patients with Meniere's disease, 5 of 9 had improvement or resolution of vertigo. Equilibrium improved in all 3 patients with Cogan's syndrome and improved in 2 out of 3 patients with idiopathic hearing loss and this symptom. According to the parameters defined above, hearing improved in 11 patients (65%), was unchanged in 4 patients (23%), and worsened in 2 patients (12%). CONCLUSION: Long-term low-dose MTX therapy may be a useful therapy for at least some patients who have hearing loss with a presumptively autoimmune-mediated component that is refractory to traditional therapies. (+info)
Clinical and molecular analysis of three Mexican families with Pendred's syndrome.
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BACKGROUND: The autosomal recessive Pendred's syndrome is defined by congenital sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the Pendred's syndrome (PDS) gene that encodes pendrin, a chloride/iodide transporter expressed in the thyroid, the inner ear, and the kidney. OBJECTIVE: To perform a detailed clinical and molecular analysis of patients with Pendred's syndrome from four patients from three unrelated Mexican families. METHODS: Thyroid function tests, perchlorate test, thyroid scintigraphy, audiometry, computer tomography and magnetic resonance imaging were performed in all affected individuals. Haplotype analyses were performed using microsatellite markers flanking the PDS locus, and the PDS gene was submitted to direct sequence analysis. RESULTS: All patients presented with sensorineural deafness, Mondini malformations of the cochlea, an enlarged vestibular aqueduct, goiter, and a positive perchlorate test. Two patients were hypothyroid, two individuals were euthyroid. Sequence analysis revealed a complex homozygous deletion/insertion mutation at the end of exon 4 in the index patient of family 1 resulting in a premature stop codon at position 138. In family 2, the affected individuals were compound heterozygous for a splice acceptor mutation (IVS2 -1G>A) and a 1231G>C transversion substituting alanine 411 by proline (A411P). In family 3, the index patient was found to be homozygous for a transversion 412G>T in exon 4 replacing valine 138 by phenylalanine (V138F). CONCLUSIONS: All patients included in this study presented with the classic Pendred syndrome triad and molecular analysis revealed pendrin mutations as the underlying cause. The identification of three novel mutations, one of them of complex structure, expands the spectrum of mutations in the PDS gene and emphasizes that they display marked allelic heterogeneity. (+info)
Multiple origins of the mtDNA 7472insC mutation associated with hearing loss and neurological dysfunction.
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Several mtDNA mutations have been reported in families with both syndromic and non-syndromic hearing loss. One such mutation is the heteroplasmic 7472insC in the tRNA(Ser(UCN)) gene which has been found in six families, all from Western Europe. However, it was not clear if this distribution was due to a common founder effect or chance sampling of several unrelated families, the 7472insC mutation having occurred multiple times. Haplotype analysis of all six families supports the latter notion. This confirms the pathogenicity of the 7472insC mutation and suggests it may exist in other populations where it may prove to be a small but significant cause of hearing loss, particularly when neurological symptoms are also present. (+info)
GATA3 abnormalities and the phenotypic spectrum of HDR syndrome.
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We report on GATA3 analysis and the phenotypic spectrum in nine Japanese families with the HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal dysplasia) (MIM 146255). Fluorescence in situ hybridisation and microsatellite analyses showed heterozygous gross deletions including GATA3 in four families. Sequence analysis showed heterozygous novel mutations in three families: a missense mutation within the first zinc finger domain at exon 4 (T823A, W275R), an unusual mutation at exon 4 (900insAA plus 901insCCT or C901AACCCT) resulting in a premature stop at codon 357 with loss of the second zinc finger domain, and a nonsense mutation at exon 6 (C1099T, R367X). No GATA3 abnormalities were identified in the remaining two families. The triad of HDR syndrome was variably manifested by patients with GATA3 abnormalities. The results suggest that HDR syndrome is primarily caused by GATA3 haploinsufficiency and is associated with a wide phenotypic spectrum. (+info)
Renal diagnosis without renal biopsy. Nephritis and sensorineural deafness.
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Two examples of hereditary nephropathy within the context of clinical syndromes are described. Emphasis is put on the ability to make a renal diagnosis without renal biopsy and the benefits of screening relatives once a diagnosis is achieved. A variant of Alport's syndrome with associated macrothrombocytic thrombocytopenia, known as Epstein's syndrome, is reported. In addition siblings with Alstrom's syndrome characterized by pigmentary retinal degeneration (causing blindness in early childhood), progressive sensorineural hearing loss, and progressive renal failure are reported. Both cases had previously presented for non-renal pathology in advance of the onset of symptomatic renal failure and may have benefited from appropriate screening. (+info)
Tracheobronchial stenosis in Keutel syndrome.
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In 1971 Keutel et al. described a new syndrome in two siblings presenting with peripheral pulmonary stenoses, brachytelephalangism, neural hearing loss and abnormal cartilage calcification. Recent investigations provided evidence that mutations in the gene encoding the human matrix GLA protein cause Keutel syndrome. With these new insights in the disease the symptomatology of Keutel syndrome was reassessed. The follow-up of the two siblings was studied by clinical and post mortem examination. As a new feature of Keutel syndrome tracheobronchial stenosis and concentric calcification of pulmonary, coronary, hepatic, renal, meningeal and cerebral arteries were described. Complementary to the results in molecular genetics the symptomatology of Keutel syndrome could be revised by clinical and post mortem examination. (+info)