Учебники / Genetic Hearing Loss Willems 2004

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under sympathic stimulation under stress such as swimming, scolding, and high sounds.

The clinically overlapping autosomal dominant RWS, named after the initial reports in 1963 and 1964 by Romano and Ward (4,5), and the delineation of the genetic predisposing factors behind the two conditions with apparently di erent modes of inheritance, have since become the focus of much scientific attention. Another early observation by Levine and Wordsworth in 1949 was not reported until 1958 because they waited for others to make the same observation of the rare association of profound hearing impairment and syncopal attacks (6). It was implied that the availability of electrocardiography in the 1950s paved the way for proper documentation of the cardiac abnormality in the syndrome (1). Fraser predicted in 1964 that the similarity between ECGs in the apparently different clinical entities might reflect a genetic relationship in causation (7). He specifically suggested the possibility that JLNS and isolated cardiac arrhythmia were due to either homozygosity or heterozygosity of mutations in the same gene(s).

This prediction has indeed been supported by several reports of autosomal dominant LQTS and autosomal recessive JLNS due to di erent mutations in the genes: KCNQ1 and KCNE1. In addition, isolated autosomal recessive LQTS has been described in cases of mutations in KCNQ1 without audiological a ection, whereas no instances of isolated hearing impairment due to heterozygosity for a KCNQ1 or KCNE1 mutation have been identified so far. The mechanisms at the tissue level to explain this are still largely unknown.

The focus in reviews has often been on LQTS because of its higher frequency (8–10).

III.PREVALENCE ESTIMATES

The estimates of prevalence rely on reports with and without molecular confirmation, which makes it hard to estimate true figures.

Fraser et al. estimated prevalence rates of 1.6–6 per million (minimum and maximum estimates in 4–15-year-olds in England, Wales, and Ireland) inhabitants in England, Wales, and Ireland (7). Other studies lacking molecular investigation gave frequencies of 0.3% (2/154), 3.8% (5/132), and 6% (6/196) in Japan, Turkey, and the United States, respectively (11– 14). The JLNS cases were identified either through the demonstration of elongated Q-T interval in populations of deaf children (11–13) or as congenital deafness associated with LQTS (14), and no molecular investigations

were presented. Slightly variable diagnostic criteria were applied. The Turkish reports pinpointed the influence of consanguinity on the frequency (12,13). No molecular screening of populations of the deaf have been published. Estimates from Norway based on nationwide identification of all JLNS cases over several years may indicate a frequency of 1:200.000 (24/4.3 million) in the general population. Regional variation was found due to a founder mutation (15).

The syndome has been reported from Norway (1,15–17), England (7,16–18), Turkey (12,13,19,20), Sweden (Tranebjærg, unpublished data), Finland (21), Lebanon (22), Morocco (19), Kabylia (19), Haiti (23), ‘‘Caucasian American family’’ (23), Saudi-Arabia (24), the Amish (25), and France (26–28). See also Table 1.

IV. DIAGNOSTIC CRITERIA

In the ECG, the P wave represents atrial repolarization, the QRS complex represents ventricular depolarisation, and the T wave represents ventricular repolarization. A normal QTc is f400 ms. QTc prolongation results from abnormal cardiac repolarization The diagnostic criteria for LQTS were described by Schwartz et al. (29) and modified by Priori et al. (30). LQTS is characterized by a QTc >440 ms in males and >460 ms in females associated with at least one of the following abnormalities: stress-related episodes of syncope, documented torsades de pointes, and a family history of early (under age 35) sudden cardiac death. Minor criteria include congenital deafness, episodes of T-wave alternans, low heart rate (in children), and abnormal ventricular repolarization. Diagnostic criteria for JLNS are congenital profound hearing impairment combined with a long Q-T. Syncopal attacks are most often associated with exercise, exertion or motion (‘‘fear, flight, or fright’’) (29,30).

The hearing impairment in JLNS has without exception been congenital, profound, and stable. There has been no evidence for hearing impairment in heterozygous carriers of KCNE1 or KCNQ1 mutations (15; Kontula, personal communication).

V.OTHER CLINICAL ASPECTS

Older reports indicated an association with iron-deficient anemia in several instances (3,31), but we could not confirm this association to be an invariable part of the JLNS in our recent study (15). A likely explanation is anemia due to insu cient dietary iron intake.

A report from Turkish JLNS patients did not identify associated neurological abnormalities (20). Seizures in severely hearing-impaired individuals must always be considered to represent syncopal attacks due to unrecognized cardiac abnormalities as in JLNS, but otherwise no increased occurrence of epilepsy has been found (20). Numerous instances of misdiagnosed epilepsy and subsequent medical treatment are known (15).

Because of several reports of sudden unexpected childhood deaths in JLNS cases, it has been suggested that LQTS and JLNS might explain a recognizable fraction of sudden infant death syndrome (SIDS). Schwartz et al. provided clinical and electrocardiographic evidence for the possibility of unrecognized sudden infant death syndrome to be among cases with prolonged Q-T interval (32). A subsequent report confirmed a known LQTSrelated KCNQ1 mutation, C350T, in a SIDS patient (33).

In one Finnish family, a case of SIDS, identified by a questionnaire survey, was examined molecularly and identified to be a heterozygous carrier of the KCNQ1 R589D mutation (21). In the published and wellcharacterized Norwegian JLNS families we found no cases of SIDS among relatives (15). The well-characterized spectrum of four identified KCNQ1 mutations underlying JLNS in Norway makes this an excellent country to systematically screen a large number of SIDS cases for unrecognized JLNS mutations. An ongoing study has, so far, not identified any positive cases (Torleiv Rognum, 2002, personal communication). In summary, there is no evidence that a major fraction of SIDS cases are due to undiagnosed LQTS/JLNS.

VI. MOLECULAR GENETICS

All the genes identified so far in congenital LQTS encode ion channels responsible for the proper electrical activity of the cardiac cells. Among the estimated more than 70 human potassium genes, four out of five KCNQ genes have been associated with some channelopathy: cardiac arrhythmias, deafness, or epilepsy (34). Since 1995, six genes associated with cardiac arrhythmia susceptibility have been discovered: KCNQ1 (formerly KvLQT1),

KCNH2 (formerly HERG), SCN5A, KCNE1 (formerly MinK), KCNE2

(formerly MiRP1), and RyR2 (10). A seventh locus, LQT4, has been located to chromosome 4q25-27, but the gene awaits identification (35). Further genetic heterogeneity is predicted, since some LQTS families do not fit with linkage to either of the known loci or genes (10). Mutations in the sodium channel gene, SCN5A, and the ryanodine receptor gene, RyR2, also cause Brugada syndrome (right-bundle-branch block, ST segment elevation in leads V1–V3, and sudden death) and ventricular tachycardia (10).

The KCNQ1 gene, found to be mutated in LQT cases, encodes for the (pore-forming) a-subunit of the voltage-gated K+ channel protein that interacts with the (regulatory) h-subunit encoded by the KCNE1 gene, and this gene immediately became an attractive candidate gene for mutation search in cases of normal KCNQ1 sequence and LQT. Exclusion of the KCNQ1 gene in some JLNS families was provided independently by two groups, reporting unrelated families with evidence against linkage to the KCNQ1 locus on chromosome 11p15.5 (22,36), and soon after mutations were identified in the KCNE1 gene (22). Individuals with JLNS have two mutations in either KCNQ1 or KCNE1 and therefore have no functional IKs channels. The hearing impairment segregates in a recessive fashion and the prolonged Q-T interval and cardiac arrhythmia in a semidominant way. So far, other loci or genes have not been implied as involved in JLNS although there are reports of clinically ascertained JLNS patients with one or no mutations detected (15,23,37).

KCNQ1 and KCNE1 interact to form the slow-activating delayed rectifying potassium channel (IKs) current and KCNH2 interact with KCNE2 to form the rapid delayed rectifying potassium current (IKr). This potassium channel repolarizes cardiac action potentials, and provides a pathway for the transepithelial potassium secretion in the inner ear (19,38) and is involved in keeping the potassium concentration high in the endolymph, which surrounds the organ of Corti. Mutations in the KCNQ1 or KCNE1 gene results in delayed repolarization and the inadequate endolymph production leads to degeneration of the organ of Corti (38). The molecular basis of the delayed rectifier current IKs in the heart was recently extensively reviewed (39).

Mutation in another KCNQ potassium channel gene, KCNQ4, is associated with autosomal dominant hearing impairment, but no cardiac abnormality (40). So far, no cases have been reported with impaired hearing associated with heterozygosity for mutations in KCNQ1, KCNH1, KCNE1,

KCNE2, or SCN5A.

VII. SPECTRUM OF MUTATIONS

A compilation of the correct total number of patients and of all diseasecausing mutations in KCNQ1 and KCNE1 genes is complicated by the fact that there are several cases with only one or no mutations reported in clinically diagnosed cases (13,23,37,48), and several examples of duplicate reports of identical patients. With that reservation, a total of at least 19 di erent KCNQ1 mutations have been reported in JLNS patients (Table 1). They include seven missense and 12 frameshift/stop/splice mutations. At

least seven other KCNQ1 mutations are associated with autosomal recessive LQTS of ‘‘forme fruste’’ (49,50), which migh also cause JLNS. Table 1 summarizes all published JLNS mutations in the KCNQ1 and the KCNE1 genes. From Finland, two di erent mutations were identified and one of them, G589D, was found in heterozygosity in LQTS patients and in compound heterozygosity in a JLNS family. This mutation accounted for 30% of all LQTS mutations in Finland (21).

VIII. GENETIC EPIDEMIOLOGY—THE SCANDINAVIAN PANORAMA

Our review from 1999 showed that 46% (11/24) of all disease alleles in diagnosed case of JLNS in Norway shared a new 5-bp KCNQ1 mutation, and that the seven families all originated from mid-Norway (15). Three other mutations were also described. No other country but Norway has been implied to have a frequency of the condition as high as our estimate of 1:200,000 (24/4.3 million) nationwide (15).

Interestingly, the Finnish founder mutation, G589D, was associated with LQTS in the heterozygous state and with JLNS in the homozygous state (21). Only about one quarter of identified carriers of the mutation were symptomatic (LQTS).

A KCNQ1 missense mutation, R518X, occurred in 5/24 disease alleles (four families) in Norway and has been identified in various countries in both LQTS and JLNS families (9,15–17,42). The mutation may be associated with autosomal dominant LQTS in heterozygosity and recessive LQTS or JLNS in homozygosity/compound heterozygosity form, making clinical prediction extremely di cult on the basis of heterozygosity for this mutation. Except for these examples no predominant mutations have been found.

IX. HISTOPATHOLOGICAL AND FUNCTIONAL ASPECTS

To gain a deeper understanding of the pathogenesis of JLNS, it is of interest to compare older histological temporal bone investigations with more recent expression studies of the responsible genes. In three unrelated patients (11-year-old girl, 3-year-old boy, 12-year-old girl) (7,31,51,52) temporal bones demonstrated abnormal deposits of PAS-positive material in stria vascularis, as well as degeneration of the organ of Corti (52), whereas initial indications of spiral ganglion neuronal cell death (51) could not be confirmed later (52).