Acta Oto-Laryngologica, 2006; 126: 237 /239
ORIGINAL ARTICLE
No evidence of hearing loss in pseudohypoaldosteronism type 1 patients
THEO A. PETERS1, ELENA LEVTCHENKO2, COR W. R. J. CREMERS1, JO H. A. J. CURFS1 & LEO A. H. MONNENS2 Departments of 1Otorhinolaryngology and 2Pediatric Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Abstract Conclusions. The fact that pseudohypoaldosteronism type 1 (PHA-1) patients with a defect in the a subunit of epithelial sodium channels (ENaC) in the cochlea have normal hearing suggests compensation by alternative sodium transport mechanisms. Consequently, hearing loss due to defective cochlear transmembrane serine protease TMPRSS3 activity is likely to be related to its effect on proneurotrophin cleavage, indicating an action on neurological components of hearing. The normal hearing of PHA-1 patients with affected mineralocorticoid receptors, together with experimental results in animals, indicates that the mineralocorticoid aldosterone is not the most crucial regulator of sodium transport in the cochlea. Objective. Profound hearing loss has been observed in patients with a defect in transmembrane serine protease TMPRSS3, the presumed activator of ENaCs. Renal ENaCs and their regulators, such as the mineralocorticoid receptors, are present in the cochlear structures involved in hearing. The aim of this study was to investigate whether PHA-1 patients with defects in these channels or regulators suffer from hearing impairment. Material and methods. Puretone audiometry was performed in four cases with PHA-1 due to mutations in aENaC (n /2) or mineralocorticoid receptor (n/2). Results. All examined cases had normal hearing at all tested frequencies.
Keywords: Epithelial sodium channel, hearing loss, mineralocorticoid receptor, pseudohypoaldosteronism type 1, transmembrane serine protease
Introduction The epithelial sodium channel (ENaC) is believed to be essential for maintaining a low sodium concentration in the endolymph [1]. Confirming the role of ENaC, profound hearing loss has been observed in DFNB8 as well as DFNB10 patients with a defect in the presumed activator of ENaCs, the transmembrane serine protease TMPRSS3 [2,3]. Aldosterone activates ENaC in the kidney through the mineralocorticoid receptor, which is also detected in specific cochlear cells involved in hearing [4]. Patients with the uncommon (:/100 cases have been reported so far) inherited pseudohypoaldosteronism type 1 (PHA-1) due to mutations in ENaC (autosomal recessive form) or mineralocorticoid receptor (autosomal dominant form) exhibit renal salt wasting with hyperkalemic metabolic acidosis [5]. Whether these patients suffer from hearing
impairment is unknown. Therefore we performed pure-tone audiometry in four cases with clinically and genetically proven PHA-1. Material and methods Standard clinical pure-tone (air and bone conduction) audiometry was performed in a sound-dampened room in four patients with PHA-1. The first two patients*/a sister (Case 1), present age 10 years and brother (Case 2), present age 6 years */displayed autosomal recessive inherited PHA-1 with a homozygous mutation of aENaC (aC1473T 0/ aR492stop). The clinical (at onset of disease; Table I) and genetic characteristics of these two patients have been described previously [6]. The mutations were determined with polymerase chain reaction (PCR) amplification methods using venous blood. The other two patients */a mother (Case 4), present
Correspondence: Theo A. Peters, PhD, Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: /31 24 3615168. Fax: /31 24 3540251. E-mail:
[email protected]
(Received 22 June 2005; accepted 15 September 2005) ISSN 0001-6489 print/ISSN 1651-2551 online # 2006 Taylor & Francis DOI: 10.1080/00016480500388893
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Table I. Blood characteristics of PHA-1 patients with respect to normal values. Case No. 1 2 3 4 Normal subject Normal subject
Age at testing
Mutation type
Serum Na (mM)
Serum K (mM)
7 days 10 days 3 weeks 40 years B/4 weeks Adult
aENaC aENaC MR MR Normal Normal
124 126 105 138 130 /145 135 /145
9.7 8.1 8.7 3.8 3.5 /6.0 3.5 /6.0
Plasma aldosterone (nM) 18 27 7.2 0.63 1 /3.8 0.1 /0.3
MR /mineralocorticoid receptor.
age 40 years and daughter (Case 3), present age 12 years */displayed autosomal dominant inherited PHA-1 with a heterozygous mutation of the mineralocorticoid receptor (1690delG). Case 3 presented clinically at 3 weeks of age with feeding difficulties, vomiting and dehydration. Blood examination revealed hyponatremia, hyperkalemia and elevated aldosterone levels (Table I). She was treated with NaCl and ion-exchange resin and at the time of writing is in good health. Despite the presence of the mutation Case 4 has never exhibited signs of dehydration. Laboratory tests demonstrated elevated aldosterone (Table I).
Results All four cases displayed normal audiograms for their age (Figure 1) and no signs of hearing impairment could be detected. Discussion An important role has been attributed to ENaC as a candidate for maintaining a low sodium concentration in the endolymph [1]. In the mouse cochlea, ENaC, together with TMPRSS3 (the transmembrane serine protease which is mutated in nonsyndromic autosomal recessive deafness DFNB8/
Figure 1. Pure-tone audiograms of Cases 1 /4 at their present ages. Cross/left ear; circle/right ear.
Hearing in PHA-1 patients 239 10), has been co-localized in the spiral ganglion, supporting cells of the organ of Corti and stria vascularis [2,3]. TMPRSS3 is able to activate ENaC in vitro in Xenopus laevis oocytes, while TMPRSS3 mutants fail to activate ENaC [2]. It can be hypothesized that lack of TMPRSS3 activity would lead to an increase in the sodium concentration of the endolymph, resulting in hearing impairment. However, hearing loss was absent in our two cases with a proven defect in aENaC. This indicates that other sodium transporters in the inner ear may compensate for the lack of function of ENaC. In this respect the hearing loss associated with a defect in TMPRSS3 should be explained differently. Involvement of TMPRSS3 in the proteolytic cleavage of proneurotrophins may play a role indicative of an effect on the neurological compound of hearing [2]. Nevertheless, we will continue the follow-up of these two cases, who are at present 6 and 10 years old, respectively, because the onset of hearing loss can (apart from congenital hearing loss in DFNB10) also occur later in childhood (DFNB8). The study of Erichsen et al. [4] addresses the action of the mineralocorticoid aldosterone in the mouse cochlea. The mineralocorticoid receptor was detected in the same structures as NaK-ATPase and during maturation there is a latency between the increases in this receptor and NaK-ATPase. In the cochleae of mineralocorticoid receptor-deficient mice no significant differences in NaK-ATPase content and distribution were detected when compared to wild-type mice. An influence of aldosterone on NaK-ATPase through the mineralocorticoid receptor was expected [5], but could not be confirmed. In addition, in primary cultures of semicircular canal duct epithelium of the rat vestibular system, only non-physiologically high concentrations of aldosterone were able to influence ENaCmediated sodium absorption [7]. The absence of hearing loss in our two cases with a proven mutation in mineralocorticoid receptors is thus in agreement with the observations in animals, indicating an absent or modest influence of aldo-
sterone on sodium transport in the cochlea through the mineralocorticoid receptor. Conclusions The fact that patients with PHA-1 who display defects in aENaC or mineralocorticoid receptors have normal hearing may indicate that sodium transport in the cochlea: (i) can be compensated by alternative sodium transporters; (ii) is not regulated by TMPRSS3 activity and therefore defects in this regulator must be considered to have an effect on the neurological compound of hearing; and (iii) is not or hardly dependent on aldosterone activity. In general it is thus useful to investigate human cochleae with defects in electrolyte transport mechanisms because this will facilitate interpretation of experimental data collected in animal studies and stimulate further research.
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