connexin 26 mutations in nonsyndromic autosomal recessive hearing loss: speech and hearing...

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  • International Journal of Pediatric Otorhinolaryngology (2004) 68, 9951005

    Connexin 26 mutations in nonsyndromicautosomal recessive hearing loss: speech andhearing rehabilitation

    Massimo Mesolella*, Gaetano Tranchino, Massimiliano Nardone,Sergio Motta, Vieri Galli

    Department of Otolaryngology, University School of Medicine Federico II, Naples, Italy

    Received 25 March 2003 ; received in revised form 18 February 2004; accepted 24 February 2004

    KEYWORDSConnexin 26;Hereditary hearing loss;Non-syndromicrecessive deafness;Speech rehabilitation

    Summary Objective: Hearing loss is the most common form of sensory impair-ment, with approximately one infant/1000 born with profound congenital deafness. Apre-lingual bilateral sensorineural hearing impairment poses a substantial problem asit negatively impacts on the subjects ability to conduct a normal social life. The aimof the study was to observe, in a group of children affected by prelingual non-sydromicautosomal recessive hearing impairment:

    (1) the role of the possible mutation of connexin 26 in the pathogenesis of thehearing loss;

    (2) the audiological and clinical aspects of the hearing impairment;(3) therapy to be adopted for the different patients.

    Methods: The study was carried out on 39 patients, 16 males and 23 females, agedbetween six and 17 years (mean 12 years), affected by non syndromic congenitaldeafness, presumably hereditary, referred to the out-patients audiology clinic for chil-dren of the Department of Otolaryngology of the Federico II University of Naples.Results: Our study conducted on 39 children with pre-lingual bilateral sensorineuralautosomal recessive deafness showed as follows:

    (I) from a molecular perspective: an incidence of 41% in the cases studied of mutations in the encoding of the

    connexin 26 gene; a prevalence in our case study of the 35delG mutation (69%).

    (II) The characteristics of the hearing impairments in the children studied were ho-mogeneous, regardless of the presence or absence of a connexin 26 mutation: the hearing impairment was pre-lingual bilateral sensorineural, the impairment often involved mainly the high frequencies, but, especially in

    the severe forms an involvement of all the frequencies was not rare; the hearing impairments were symmetrical and non progressive in time.

    *Corresponding author. Present address: Via Filangieri n. 72, 80121, Naples, Italy. Tel.: +39-081-415321; fax: +39-081-415321.E-mail address: [email protected] (M. Mesolella).

    0165-5876/$ see front matter 2004 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.ijporl.2004.02.015

  • 996 M. Mesolella et al.

    (III) the results of the application of prosthesis and thereafter rehabilitative languagetherapy are generally satisfactory but correlated of course to the severity of thehearing loss.

    Conclusion: In conclusion, we hope that further developments in the research ongenetic hearing impairments will promptly result in advances in clinical practice.

    2004 Elsevier Ireland Ltd. All rights reserved.

    1. Introduction

    In recent years there has been a marked improve-ment in diagnostic techniques used to identifyhearing impairments in children, in particular thoseinvolving objective audiometry; this has had a ma-jor clinical impact on the early identication ofhearing loss, on dening the degree and on deter-mining the site of the lesion.The results afforded with these, integrated with

    the ndings of conditioned child audiometrywhenit can reliably be performedhave made it possibleto intervene early on with the necessary rehabil-itation and prosthetic measures, with positive ef-fects on language learning and more generally onthe cognitive and psycho-affective development ofthe child with severe or profound deafness.Interesting progress has also been made in recent

    years in the etiopathogenesis of hereditary deaf-ness thanks to the research into molecular genet-ics, which has much contributed to the knowledgeof the chromosome loci connected with the hear-ing function, to their alteration and to the relativerepercussions on the physiopathology of hearing [9].The epidemiological studies show that the inci-

    dence in children of hearing impairments occurringin the pre-lingual stage is 1/1000 newborns per year,over 50% of which can be attributed to a geneticcause [7,21,22,24,25].Autosomal recessive deafness accounts for the

    majority of the latter forms (7080%), whereas theincidence is much lower for autosomal dominantforms (1525%), for those linked to chromosome X(23%) and those of a mitochondrial origin (23%)[20,32].As regards the loci responsible for disease, for

    the non syndromal forms the DFNB1 locus has beenmost extensively researched. First described in1994 by Guilford [11,12], it is epidemiologically re-sponsible for many forms of prelingual sensorineu-ral deafness, not only in different populations inthe Mediterranean [35], but also in other coun-tries such as the USA, Japan and China [3,17,19,23,37].Subsequent research [15,30] showed that a mu-

    tation in the GJB2 gene is generally responsible for

    severe or profound sensorineural deafness, whichcharacterises the rst form of autosomal recessivedeafness described (DFNB1). This gene encodes theformation of the Connexin 26 (Cx 26) protein, amember of a large family of membrane proteins(Connexins) involved in the formation of the inter-cellular channels of the plasma membranes of manycells. These channels regulate the cell metabolism[1], the differentiation [34] and the transmission ofelectric impulses between the cells [10].Cx 26, presumably, is involved in a potassium

    circulation pathway allowing potassium enter-ing the hair cells during sound mechanosensorytransduction to be removed to the stria vascularis[18], Mutations affecting Cx 26 presumably resultin aberrancies in potassium recirculation, subse-quently leading to cell death and deafness.Histochemical techniques have shown the pres-

    ence of connexin 26 in the stria vascularis,basement membrane, limbus and in the spiralprominence of the cochlea [13,14].The aim of the study was to observe, in a group of

    children affected by prelingual non-syndromic au-tosomal recessive hearing impairment:

    the role of the possible mutation of connexin 26in the pathogenesis of the hearing loss;

    the audiological and clinical aspects of the hear-ing impairment;

    therapy to be adopted for the different patients.

    2. Materials and methods

    The study was carried out on 39 patients, 16 malesand 23 females, aged between six and 17 years(mean 12 years), affected by non syndromic con-genital deafness, presumably hereditary, referredto the out-patients audiology clinic for children ofthe Department of Otolaryngology of the FedericoII University of Naples.All subjects underwent diagnostic evaluation,

    which included:

    (A) collection of anamnestic data;(B) general and otorhinolaryngoiatry examination;

  • Connexin 26 deafness 997

    (C) audiological examinations comprising pure-toneaudiometry, acoustic admittance measure-ment, auditory brainstem response (ABR) andotoacoustic emissions;

    (D) molecular gene testing;(E) C.T. of the ear;(F) The rehabilitative therapeutic options to be


    (A) personal and family anamnestic investigation:parents were questioned to ascertain the ab-sence of disorders and/or malformations ofthe ear, acquired pathologies of the ear andrisk factors (infections contracted during preg-nancy, birth weight less than 1500 g, neona-tal APGAR score

  • 998 M. Mesolella et al.

    the presence of mutations in the coding of theconnexin 26 gene.To carry out this test, 10ml of blood was

    drawn from each patient, preserved in EDTA atroom temperature and dispatched within 48 hto the genetics laboratory for molecular evalu-ation.DNA sequencing was carried out on these

    samples by polymerase chain reaction (PCR),according to the standard procedure in theliterature [33,37].On the basis of this the patients were divided

    into two groups:Group A subjects with mutations in the con-

    nexin 26 gene;Group B subjects without this mutation.

    (E) A C.T. scan of the temporal bone excluded, inall cases, any bone malformation of the middleand/or inner ear.

    (F) As regards the choice of therapy all subjectspromptly received a hearing aid, following thecriteria of dynamic prosthesization adopted atour institute [26,27], and started aggressivespeech therapy.

    Dynamic prosthesisation is used to favour ini-tially the amplication of the low frequencies so asto favour a rapid educational program of the sub-ject and over time to put to better use the residualhearing capacity by personalising the hearing aid,implementing a more suitable or better adaptedprosthesis thanks to the acquisition of new infor-mation due to the better collaboration by the childas a consequence of his/her psycho-intellectualdevelopment and to the progress made in speechtherapy [26].In cases when the prosthesis offered poor re-

    sults and the parents concurred, a multi channelcochlear implant was applied.The results of the prosthesis and language

    therapy were considered satisfactory if they af-forded:

    recovery with hearing aid of the communicativeability with word discrimination capacity of over50% (the utterances were two-syllable words andthe intensity of the signal was 65 dB SPL in ab-sence of noise);

    as regards language development, the ability toconstruct phrases in a sentences using accuratesyntax, semantics and morphology.

    After application of the prosthesis, language re-habilitation was carried out using the verbal-tonalmethod with the modications introduced at our in-stitute [26].

    For subjects who received cochlear implant,rehabilitation was carried o