Connexin mutations in X-linked Charcot-Marie-Tooth disease

X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry technique, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a gap junction protein, suggest that connexin32 plays an important role in peripheral nerve.     

Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans

Non-syndromic neurosensory autosomal recessive deafness (NSRD) is the most common form of genetic hearing loss. Previous studies defined at least 15 human NSRD loci. Recently we demonstrated that DFNB1, located on the long arm of chromosome 13, accounts for approximately 80% of cases in the Mediterranean area. Further analysis with additional markers now identifies several recombinants which narrow the candidate region to approximately 5 cM, encompassed by markers D13S141 and D13S232 and including several ESTs and candidate genes, including the connexin26 (GJB2) gene. Analysis of PCR products from our affected patients' DNA shows two frameshift mutations in the connexin26 gene. Deletion of a G within a stretch of six Gs at position 35 of the GJB2 cDNA (mutation 35delG) leads to premature chain termination and is present in 63% of NSRD chromosomes, demonstrating linkage to chromosome 13. Deletion of a T at position 167 of GJB2 (mutation 167delT), also resulting in premature chain termination, was detected in another patient. Four neutral sequence polymorphisms were also identified. These findings are in agreement with a recent study showing that mutations in the connexin26 gene are associated with genetic forms of deafness in three Pakistani families and that GJB2 is DFNB1. Connexin26 is a member of a large family of proteins involved in formation of gap junctions, which are involved in electrical synapses and the direct transfer of small molecules and ionic currents between neighboring cells. The identification of GJB2 as the DFNB1 gene should provide a better understanding of the biology of normal and abnormal hearing, help form the basis for diagnosis and may facilitate development of strategies for treatment of this common genetic disorder.     

Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3

DFNB3, a locus for nonsyndromic sensorineural recessive deafness, maps to a 3-centimorgan interval on human chromosome 17p11.2, a region that shows conserved synteny with mouse shaker-2. A human unconventional myosin gene, MYO15, was identified by combining functional and positional cloning approaches in searching for shaker-2 and DFNB3. MYO15 has at least 50 exons spanning 36 kilobases. Sequence analyses of these exons in affected individuals from three unrelated DFNB3 families revealed two missense mutations and one nonsense mutation that cosegregated with congenital recessive deafness.     

Sudden deafness

Sudden deafness is a real clinical entity. Very important advances have been achieved these last years in cochlear physiology and afford a better knowledge of the mechanisms of deafness but not the causal agent. Two major pathogenic hypotheses are formulated: viral agent and vascular cause. Two peaks of prevalence in relation with age are described: one between 30 and 40 and the second between 55 and 60. Sudden deafness is a sensorineural emergency. The treatment primarily aims at the restitution of hearing by minimizing the period of cellular ischaemia.     

Connexin43 immunoreactivity in the catfish retina

Tyrosine hydroxylase (TH) mRNA levels in the rat substantia nigra (SN), ventral tegmental area (VTA) and locus coeruleus (LC) were measured by in situ hybridization histochemistry 1, 4, 6 and 24 h after a single injection of methamphetamine (MAP, 4 mg/kg, i.p.) or an equivalent volume of saline. TH mRNA levels in LC were transiently increased (130% of control saline group, P < 0.05) at 1 h after MAP injection, and returned to basal levels within 4 h. In contrast, acute MAP administration did not significantly affect TH mRNA levels in SN and VTA. These findings are the first to demonstrate TH mRNA expression in the different responses of catecholaminergic neurons to acute MAP administration.     

Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties

The X-linked form of Charcot-Marie-Tooth disease (CMTX) is associated with mutations in the gene encoding connexin32 (Cx32), which is expressed in Schwann cells. We have compared the functional properties of 11 Cx32 mutations with those of the wild-type protein by testing their ability to form intercellular channels in the paired oocyte expression system. Although seven mutations were functionally incompetent, four others were able to generate intercellular currents of the same order of magnitude as those induced by wild-type Cx32 (Cx32wt). In homotypic oocyte pairs, CMTX mutations retaining functional activity induced the development of junctional currents that exhibited changes in the sensitivity and kinetics of voltage dependence with respect to that of Cx32wt. The four mutations were also capable of interacting in heterotypic configuration with the wild-type protein, and in one case the result was a marked rectification of junctional currents in response to voltage steps of opposite polarity. In addition, the functional CMTX mutations displayed the same selective pattern of compatibility as Cx32wt, interacting with Cx26, Cx46, and Cx50 but failing to do so with Cx40. Although the functional mutations exhibited sensitivity to cytoplasmic acidification, which induced a >/=80% decrease in junctional currents, both the rate and extent of channel closure were enhanced markedly for two of them. Together, these results indicate that the functional consequences of CMTX mutations of Cx32 are of two drastically distinct kinds. The presence of a functional group of mutations suggests that a selective deficit of Cx32 channels may be sufficient to impair the homeostasis of Schwann cells and lead to the development of CMTX.     

Pedophilia and deafness

Data from 22 cases of deaf individuals suffering from pedophilia are presented along with a tabular summary of recent articles from the deaf press, about deaf victims of pedophilia and deaf pedophiles. Results indicate a number of factors that distinguish deaf pedophiles from hearing pedophiles. First is the prevalence of Primitive Personality Disorder in the deaf group. Corollary to this, with a significant number of pedophiles, competence to stand trial is a major issue. Other significant differences include a high rate of brain damage, illiteracy, poor communication skills, and other psychiatric illnesses. Two of the 22 cases were deaf females with pedophilia. The mean performance IQ of the sample was 102.8 and the distribution of scores was bimodal. Case histories are presented and discussed, and legal issues, prevention, and punishment are addressed.     

Hypercholesteremia and hyperfibrinogenemia in sudden deafness

BACKGROUND: The pathogenesis of sudden hearing loss has not been elucidated as yet. Insufficient perfusion of the cochlea due to an increased blood viscosity, microthrombosis, or altered vasomotion are assumed. Hypercholesterolemia and hyperfibrinogenemia are frequently observed in patients with sudden sensorineural hearing loss. The aim of this study was to investigate the incidence of hypercholesterolemia and hyperfibrinogenemia in patients suffering from sudden hearing loss compared to normal controls. In an intervention study the impact of drastic lowering of plasma cholesterol and fibrinogen by a selective extracorporal apheresis was studied. METHODS: In a case-control study of 23 patients suffering from sudden hearing loss, plasma cholesterol and fibrinogen levels as well as erythrocyte aggregation and plasma viscosity were determined. Seven sudden hearing loss patients from this group were treated with H.E.L.P. apheresis, an extracorporal procedure removing fibrinogen and idl-cholesterol from plasma. RESULTS: Plasma fibrinogen and cholesterol levels were higher in sudden hearing loss patients, leading to significantly elevated values of erythrocyte aggregation and plasmaviscosity. Six out of the seven patients treated with a single H.E.L.P. apheresis immediately showed an improvement of auditory thresholds. CONCLUSIONS: We conclude that hyperfibrinogenemia and hypercholesterolemia may contribute to the clinical event of sudden hearing loss. Our study shows for the first time that acute and drastic removal of plasma fibrinogen and low density lipoproteins can be an effective clinical tool in the treatment of patients with sudden hearing loss.     

Hereditary progressive sensorineural deafness

Progressive sensorineural hearing losses found in seven members of three families are presented. Genetic transmission patterns in the study appeared to be autosomal dominant in two families and recessive in one family. The common audiological features of these cases include bilaterally symmetrical audiometric configuration and fairly good speech discrimination. The hearing losses of most of the cases appeared to begin at high frequencies progressing later to involve lower frequencies. The main histopathological changes in the temporal bones of one of the cases were degeneration of the organ of Corti and of the spiral ganglion in the lower cochlear coils and cystic degeneration of the stria vascularis in the upper coils.     

Surgical rehabilitation of deafness

The critical effects of pH on the electronic absorption and fluorescence characteristics of the siderophore, pyochelin, are investigated. A single anionic species is shown to be sufficient to explain the data obtained under alkaline conditions. In acidic solutions, several competing ground- and excited-state equilibria are present, which lead to fluorescence emissions from both the protonated form of pyochelin and its phenolate ion. From the spectroscopic data we are also able to show that pyochelin interacts with zinc ions in the ground state via its anionic form, thereby confirming that this siderophore does not bind Fe(III) ions uniquely.     

Audiometric and ophthalmological findings in rubella deafness

In an attempt to study the relevance of ophthalmological changes to the diagnosis of cochlear hearing impairment due to fetal rubella infection, a survey of the literature combined with a clinical investigation was carried out. Based on the investigation of 57 patients, 31% had congenital hearing impairment due to fetal rubella infection. Of these patients, 61% had typical rubella retinal changes. In the remaining 69%, ophthalmoscopy revealed no abnormality, except in 1 patient. As the cause of the hearing impairment in this patient was unknown, it was concluded that the mother had suffered from subclinical rubella infection in the first trimester of her pregnancy. It is concluded that rubella retinitis is found with such a high incidence in rubella children that it can be used as a tool in the diagnosis of cochlear hearing impairment due to fetal rubella infection. Patients with congenital hearing impairment ought to undergo a routine ophthalmoscopy which will detect eventual pigmentary changes.     

Hereditary deafness in Turkey. Initial results

The authors describe a study in progress to identify Turkish families with hereditary hearing loss and isolate possible responsible disease genes. Due to extreme genetic heterogeneity and limited audiological differentiation of hereditary hearing loss, it is necessary to identify large or small families from genetic isolates to locate loci responsible for hearing loss on a chromosome. To accomplish this goal, the medical records of 3800 children were examined at the ENT Clinic of Ege University between 1975 and 1994. All were suspected of having various hearing impairments. Additionally, students from two schools for the hearing impaired in Izmir and Eskisehir, Turkey were examined. To date, 16 families with syndromal deafness and 55 families with non-syndromal hereditary hearing loss involving two or more affected individuals have been identified and categorized according to the mode of inheritance. The majority (66%) of the non-syndromal families showed an autosomal recessive pattern, 29% an autosomal dominant inheritance and 5% an X-linked mode of inheritance. In the study presented there has been a predominance of affected males versus females and the consanguinity rate was 22%.     

Sudden deafness and Barlow disease

From January 1993 to December 1994 twelve patients were evaluated for sudden hearing loss. The median age was 49 years with a range of 18 to 71. All had severe or profound initial hearing loss. The incidence of bilateral disease was 25%. Total deafness occurred in five (33%) ears. Nine (75%) patients had vestibular symptoms and eight (67%) admitted experiencing tinnitus. Two-dimensional echocardiography revealed mitral prolapse in eight (67%) patients; another patient showed moderate to severe ischemic left ventricular dysfunction with apical aneurysm.