Increased variation in mtDNA in patients with familial sensorineural hearing impairment

Analyses of mitochondrial DNA (mtDNA) sequences have revealed non-neutral patterns, suggesting that many amino acid mutations in animal mtDNA may be mildly deleterious, but this has not been verified in human clinical series. Since sensorineural hearing impairment (SNHI) is a common manifestation in many of the syndromes caused by mutations in mtDNA, this may be regarded as the phenotype of choice in attempts to detect mutations that may have a mildly deleterious effect on mitochondrial function. We selected 32 subjects from among 117 unrelated SNHI patients with SNHI in maternal relatives by means of family history, determined the entire coding region sequence of mtDNA and compared the sequence variation with that in 32 haplogroup-matched controls taken at random from 192 Finnish sequences. The 32 control sequences differed from the remaining 160 sequences by 36±9 substitutions (mean ± SD), while the difference for the 32 patients was 58±4 substitutions (P=0.005 for difference; Wilcoxon signed rank test). Differences were also found in the number of new haplotypes and new non-synonymous mutations or mutations in tRNA or rRNA genes. A total of 12 rare mtDNA variants were detected in the patients, and only 3 of these were considered to be neutral in effect. It is proposed that increased sequence variation in mtDNA may be a genetic risk factor for SNHI, and the increased frequency of rare haplotypes in these patients points to the presence of mildly deleterious mutations in mtDNA.     

Progressive hearing loss,and recurrent sudden sensorineural hearing loss associated with GJB2 mutations--phenotypic spectrum and frequencies of GJB2 mutations in Austria

Mutations of GJB2 (encoding connexin 26) are the most common cause of hearing loss (HL) in different populations, and a broad spectrum of GJB2 mutations has been identified. We screened 204 consecutive patients with non-syndromic sensorineural hearing loss for GJB2 mutations. Causative GJB2mutations were identified in 31 (15.2%) patients, and two common mutations, c.35delG and L90P (c.269T>C), accounted for 72.1% and 9.8% of GJB2 disease alleles. In four additional patients (2.0%) only one recessive GJB2 mutation was identified, making genetic counselling difficult. No genotype-phenotype correlation was established. We found, however, that homozygotes for truncating mutations were more likely to have a more severe degree of HL compared with other genotypes. Moreover, we showed by co-segregation studies that L90P is a GJB2 disease allele, and that compound heterozygotes for L90P and any recessive mutation share a mild to moderate phenotype. GJB2-associated HL was linked with progressive HL or with recurrent sudden sensorineural hearing loss (SSNHL) in three of 15 cases being analysed retrospectively. We extended the phenotypic spectrum of GJB2-related disease and recommend GJB2 mutation screening also in cases of progressive HL, and recurrent SSNHL. In addition, a carrier frequency of 1/110 (0.9%) for the most common Caucasian mutation in this gene, c.35delG, was determined in 1,212 blood donors from West-Austria, supporting the prevailing hypothesis of a Mediterranean founder mutation. Based on population and patient data, an overall GJB2 mutation carrier frequency of 1.3% was estimated for West-Austria.     

Genetic characteristics of recessive sensorineural hearing loss

Genetic characteristics of recessive sensorineural hearing impairment mediated by 5 recessive genes were studied. One of these is responsible for early progressive hearing loss, others causing congenital deafness. The incidence of early progressive recessive hearing loss in a population is 1:20,000, gene frequency being 0.007; the incidence of heterozygotes for this gene is 1.4%. The incidence of each of 4 forms of recessive congenital hearing loss in a population is 1.125:10,000, the frequency of these genes being 0.0106; the incidence of heterozygotes for each of these genes is 2.1%. The total frequency of all recessive genes for sensorineural hearing impairment is 0.0494 and the incidence of heterozygotes for all genes is 9.9%. The frequency of different genotypes for recessive genes specifying sensorineural hearing loss was established, based on the data obtained.     

MTHFR 677T is a strong determinant of the degree of hearing loss among Polish males with postlingual sensorineural hearing impairment

Hearing impairment (HI) is the most common sensory handicap. Congenital HI often has a genetic basis, whereas the etiology of nonsyndromic postlingual HI (npHI) usually remains unidentified. Our purpose was to test whether the MTHFR C677T (rs1801133) polymorphism affecting folate metabolism is associated with the occurrence or severity of npHI. We studied rs1801133 genotypes in 647 npHI patients (age <40, sudden sensorineural loss excluded, HI characterized as mean of better ear hearing thresholds for 0.5-8 kHz) and 3273 adult controls from the background population. Genotype distribution among patients and controls was similar, but among male cases (n = 302) we found a dose-dependent correlation of MTHFR 677T with the degree of HI (mean thresholds in dB: 38.8, 44.9, and 53.3, for CC, CT, and TT genotypes, respectively; p = 0.0013, p(cor.) = 0.017). Among male patients rs1801133 TT significantly increased the risk of severe/profound HI (odds ratio = 4.88, p = 0.001). Among controls the known effect of MTHFR 677T on plasma total homocysteine was more pronounced in men than in women (p<0.00004 for genotype-sex interaction) suggesting that in Poland folate deficiency is more prevalent in males. In conclusion, we report a novel strong effect of MTHFR 677T among males with npHI. The functional significance of rs1801133 suggests that these patients may benefit from folate supplementation-an intervention which is simple, cheap, and devoid of side effects.     

The A1555G mitochondrial DNA mutation in Greek patients with non-syndromic, sensorineural hearing loss

Mitochondrial DNA mutations are undoubtedly a factor that contributes to sensorineural, non-syndromic deafness. One specific mutation, the A1555G, is associated with both aminoglycoside-induced and non-syndromic hearing impairment. The mutation is considered to be the most common of all mitochondrial DNA deafness-causing mutations but its frequency varies between different populations. Here we report on the first large screening of the A1555G mitochondrial DNA mutation in the Greek population. The aim of this study was to determine the frequency of the A1555G mutation in Greek sensorineural, non-syndromic deafness patients, with childhood onset. We screened 478 unrelated Greek patients with hearing loss of any degree and found two individuals harboring the A1555G mutation (0.42%). Both cases had been subjected to aminoglycosides. They were prelingual, familial and homoplasmic for the A1555G mutation. One of the cases was also found heterozygous for the frequent GJB2 35delG mutation, while the other case was negative. The A1555G mutation seems to be less common than in other European populations.     

Drug-induced aseptic meningitis, sensorineural hearing loss and vestibulopaty

We report clinically rare and serious adverse reactions that occurred after the co-administration of ranitidine, ibuprofen and ciprofloxacin: completely reversible aseptic meningitis and irreversible bilateral sensorineural hearing loss, tinnitus, and vestibulopathy. Recurrent urinary inflammations treated with antibacterials, classic familial migraine, and allergy to trimethoprim-sulfamethoxazole and chromium were favourable predisposing factors for the adverse event in this patient. A close chronological relation between administration of drugs (especially ibuprofen) and adverse reactions was noted. No evidence of infection and/or autoimmune disease was found. The mechanism of these serious events may be explained as a hypersensitive reaction affecting the meninges and, partially, cochlea.     

Manganese in toenails is associated with hearing loss at high frequencies in humans

Purpose: Elevated hearing thresholds from high frequencies are known to be one of the hallmarks of age-related hearing loss. Our recent study showed accumulation of manganese (Mn) in inner ears resulting in acceleration of age-related hearing loss in mice orally exposed to Mn. However, there is no evidence showing an association between Mn in non-invasive biological samples and hearing loss in humans evaluated by pure tone audiometry (PTA). In this study, we evaluated Mn in non-invasive biological samples as a possible biomarker for hearing loss in humans.

Materials and methods: We determined hearing levels by PTA and Mn levels in toenails, hair and urine with an inductively coupled plasma mass spectrometer (ICP-MS) in 145 healthy subjects in Bangladesh.

Results: Multivariable analyses showed that Mn levels in toenails, but not in hair and urine samples, were significantly associated with hearing loss at 8?kHz and 12?kHz. Moreover, our experimental study showed a significant correlation between Mn levels in inner ears and nails, but not hair, in mice orally exposed to Mn.

Conclusions: The results provide novel evidence that Mn in toenails is a possible biomarker for hearing loss at high frequencies in humans.     

X-linked recessive inheritance of sensorineural hearing loss expressed during adolescence.

Eight males in 4 generations with hearing impairment were observed in a kindred; family transmission suggested X-linked recessive inheritance. In previously reported cases of X-linked sensorineural hearing loss, hearing impairment was usually severe to profound and was either present at birth or manifested by 5 years of age.In the present cases, rapid onset of a bilateral sensorineural hearing loss occurred during adolescence and did not generally progress beyond moderate impairment. Significant deterioration in seech production did not usually result.     

Genome wide analysis in a family with sensorineural hearing loss,autism and mental retardation

Hearing loss is a common congenital anomaly with an incidence of 1 in 1000 live births. It has been described together with several other clinical features as fortuitous association or commune genetic syndrome. In this study, we investigated a consanguineous Tunisian family with moderate to profound congenital hearing loss, mental retardation and autistic behaviors. We performed a genome wide microarray analysis study using approximately 300,000 SNPs in a common set of 7 invidious of this family. We identified regions of suggestive linkage with hearing loss on chromosomes 6p12 and 7q34. In addition, we identified a deletion on chromosome 8p in the two autistic individuals. This report presents an illustration of how consanguinity could increase familial clustering of multiple hereditary diseases within the same family. The application of next generation sequencing for this family seems to be a good strategy for further analysis leading to the identification of candidate genes.     

Hereditary gingival fibromatosis and sensorineural hearing loss in a 42-year-old man with Jones syndrome

Hereditary gingival fibromatosis and sensorineural hearing loss in a 42-year-old man with Jones syndrome: Gingival fibromatosis is a rare disease, which can be seen as an isolated condition or associated with some uncommon syndromes. This case report describes the evaluation and treatment of a 42-year-old male patient with hereditary gingival fibromatosis, sensorineural hearing loss, undescended testis and maxillary odontogenic cyst (Jones Syndrome). Six years follow up of the index patient after the surgery revealed no recurrence of the gingival fibromatosis. This report also describes the anamnestic data of the patient's family that showed progressive deafness and gingival enlargement in three generations.     

Prevalence of GJB2 (CX26) gene mutations in south Iranian patients with autosomal recessive nonsyndromic sensorineural hearing loss

Hereditary hearing loss is a genetically heterogeneous disorder. Mutations in connexin 26 (CX26), are a major cause in many countries and are largely dependent on ethnic groups. The purpose of our study was to evaluate the prevalence of GJB2 mutations among affected individuals from south of Iran. Fifty patients presenting with autosomal recessive non-syndromic hearing loss from Fars, province in south of Iran, were studied for mutations in GJB2 gene and screened by direct sequencing. Mutations were detected in 15 out of 50 patients (30?%). Eight different mutations were identified; six of them were previously identified (35delG, V27I M34V, V153I, A149T, V198M). The remaining two alleles, L28I and N169T, were novel variants. The most common mutations were 35delG followed by V153I with an allele frequency of 7 and 6?%, respectively. In this study, 30?% of our subjects were found to have the causative variants or polymorphisms in GJB2 and the c.35delG mutation was the most common cause in our patients. However, more study with larger sample size as well as in vitro functional study for these new variants in Xenopus oocytes is required.     

Increased frequencies of micronuclei in T8 lymphocytes of smokers

Micronucleus frequencies and mitotic indices were analyzed in B, T4, and T8 lymphocytes from 40 smokers and 42 non-smoking referents. The highest level of micronuclei was found in T4 cells followed by T8 and B cells. These differences were statistically significant. There were statistically significant linear correlations between the micronucleus frequencies of all three subsets. There was a statistically significant effect of smoking only in the T8 cells. Smoking also increased the number of neutrophilic granulocytes and lymphocytes in the peripheral blood. There was a statistically significant effect of age on the micronucleus frequencies in T4 and T8 lymphocytes. The mitotic indices did not have any effect on the micronucleus frequencies and they were not influenced by smoking, age or sex.     

干细胞治疗感音神经性耳聋

治疗内耳疾病的主要困难之一是找到耳蜗毛细胞或者螺旋神经元丢失所导致的听力损失的治疗方法。本文讨论使用干细胞替代感觉细胞丢失为目的的几个治疗策略。作者最近在成年内耳中发现了可以分化为毛细胞的干细胞,发现了胚胎干细胞可在体外转化为毛细胞并表达毛细胞标记物。在动物模型中,成年内耳干细胞、神经干细胞和胚胎干细胞来源的前体细胞可分化成为毛细胞和神经细胞。本文将讨论使用干细胞再生损伤毛细胞的不同方法,介绍几种可行的动物模型,并讨论发展基于干细胞的细胞替代疗法治疗内耳损伤中存在的困难。