Учебники / Genetic Hearing Loss Willems 2004

Despite a widespread expression of KCNQ1 in human kidney, placenta, lung, and placenta (53), the strongest expression was found in heart tissue and the pattern of expression as determined by in situ hybridation was restricted to the marginal cells of stria vascularis in mouse cochlea (19). Immunohistochemical and electrophysiological studies show that the Isk protein localizes to the endolymphatic surface of stria vascularis in rat (54) and guinea pig (55), in perfect agreement with the histopathological findings in JLNS subjects (54,55).

Immunocytochemical and ultrastructural studies of wild-type and kcne / (knockout) mice demonstrated colocalization of the KCNE1 and KCNQ1 proteins at the apical surface of vestibular dark cells already from gestational day 17 (56). The vestibular cells are normal at birth in kcne1 / mice, but degenerative changes of the epithelial cells develop postnatally (56). Interestingly, the mice did not develop cardiac arrhythmia.

X.CLINICAL IMPLICATIONS OF KCNQ1 AND KCNE1 MUTATIONS

The clinical presentation as either LQTS or JLNS in carriers of KCNQ1 or KCNE1 mutation(s) depends on the nature of the underlying mutation(s) and the consequent functional impairment of the potassium channel (57). The term ‘‘lack of function’’ applies to a situation where a mutated gene does not lead to the synthesis of a full-length protein, either because of a deletion of parts of or the entire gene, or a frameshift mutation secondarily leading to a truncated peptide. This is thought to be the mechanism in those mutations presenting as recessive, in the sense that heterozygous carriers have no a ection and homozygosity for the same of two di erent mutations leads to clinically JLNS. The majority of mutations in KCNQ1 reported in JLNS patients belong to this type of disruption of the encoding gene. A few examples of splice site mutations also have been shown (Table 1). The term ‘‘dominant negative e ect’’ refers to a situation where the normal protein functions in a structure consisting of several subunits, a multimere, and where the presence of a full-length, yet abnormally changed, peptide unit interfere with the assembly between the individual subunits. This is the usual mechanism for the large majority of missense mutations reported in instances of autosomal dominant LQTS, without hearing impairment associated. Yet, identical mutations in KCNQ1 have been implicated in both JLNS and LQTS (9,15), indicating the complexity in trying to establish any genotype-phenotype correlation.

Recent electrophysiological studies of KCNE1 and KCNQ1 mutations involved in JLNS showed a spectrum of e ects from simple loss of function

to prominent dominant negative behavior (28,44). Why some individuals with such mutations, like E261D and R518X, in KCNQ1 do not develop cardiac arrhythmia may rely on some myocardial depolarization reserve, and on genetically variable susceptibility in di erent individuals (44). This explanation would also be consistent with the reduced penetrance of clinical a ection in some LQTS mutation carriers.

From the present compiled experience of a very low risk of cardiac a ection in obligate mutation carriers of KCNQ1 (15) or KCNE1 mutations in JLNS cases, it seems that a certain reduction in the current of IKs is tolerated without adverse clinical manifestation. Apparently, there must be a complete absence of K+ influx into the endolymph for hearing loss to be present (8,44).

The observations of families with autosomal recessive LQTS or ‘‘forme fruste’’ of LQTS (9,50) support the notion that C-terminal mutations in KCNQ1 a ect the function of the protein to a much lesser degree and further compromised function (by the presence of yet another mutation on the homolog chromosome) is necessary to develop overt LQTS.

The overall picture of missense mutations having a dominant negative e ect and being associated with autosomal dominant LQTS and stop/frameshift mutations leading to lack of function and being associated with autosomal recessive JLNS is disturbed by several exceptions illustrating that it is not straightforward to predict a phenotype from a given genotype. Two KCNQ1 mutations, R518X and R594Q, illustrate this complexity well. The R518X mutation was found in autosomal recessive LQTS and some heterozygous carriers had elongated Q-T interval but without fulfilling the criteria for overt LQTS. It was found in compound heterozygosity with another missense mutation, A525T (42). The same mutation was detected in four Norwegian JLNS families with either homozygosity or compound heterozygosity for this mutation. None of the carrier relatives were clinically a ected (15,16).

The R518X mutation was present in compound heterozygosity with another missense mutation in a Scottish JLNS patient (15,17), and LQTS patients without further details about the inheritance pattern or a ection status of relative given (9). Huang et al. found 1/45 carriers of the R518X clinically a ected (45). An American JLNS patient had R518X in heterozygous form and a presumed (but not identified) second mutation (23).

Heterozygosity was associated with elongated Q-T interval, but no overt LQTS or impaired hearing (17,42). The mutation is in the C-terminal end of KCNQ1, and the mutation induced a weak dominant negative e ect electrophysiologically when coinjected in a 3:1 ratio with wild-type cRNA (three times more mutant than wt cRNA), but not when injected in a 1:1 ratio (45). The KCNQ1 mutation R594Q was also found in both LQTS and

JLNS patients, and with similar variable electrophysiological e ects under di erent experimental conditions (9,17,45). The mutations Q530X and G589D show similar behavior (Table 1).

Seemingly, there are no instances of heterozygosity for KCNE1 or KCNQ1 mutations associated with isolated hearing impairment, and an invariable co-occurrence of hearing impairment and LQTS in patients with two KCNQ1 mutations, except for R518X. Splawski et al. (9) do not specify if LQTS in patients with the mutations Q530X and R594Q was autosomal recessive or dominant. There were no instances of autosomal recessive inheritance in the Finnish group with the G589D mutation (Kontula, personal communication).

It could be expected about some of the KCNQ1 mutations associated with ‘‘forme fruste’’/recessive LQTS that hearing impairment might develop in some patients. Genetic counseling in such cases must be aware of the possible risk of hearing impairment.

XI. CLINICAL MANAGEMENT AND GENETIC COUNSELING

All severely hearing impaired children should have ECG taken to diagnose the elongated Q-T interval in JLNS. The recommended medical treatment of the cardiac component of JLNS follows the same guidelines as for LQTS. The current recommendations have changed over time and were recently comprehensively summarized by Chiang and Roden (58). Basically, betablockers are the first-choice drug, then cardiac pacemaker, left cardiac sympathetic denervation, and implantable cardioverter-defibrillator, if the combination of beta-blockers, denervation, and/or pacemaker fails to prevent the cardiac syncopes (58). It is still intensively discussed if asymptomatic carriers of a mutation should receive medical treatment.

After the clinical diagnosis of JLNS has been made, e orts should be made to identify the mutations in KCNQ1or KCNE1. In Norway, which has a high prevalence of JLNS and a limited spectrum of mutations in KCNQ1, all hearing-impaired persons who are referred for genetic evaluation and all instances of newly diagnosed LQTS patients are routinely investigated for the KCNQ1 mutations: 572del5, R518X, Q530X, and E261D, and new families have been identified since our survey in 1999 (15; Tranebjærg, unpublished data). Our limited experience (15) strongly encouraged us to o er all identified carriers of LQTS mutations genetic counseling, cardiological examination, and written information about medication to be avoided, as well as being considered for prophylactic beta-blocker treatment.

The accumulated experience published so far indicates quite variable risk between di erent mutations in the KCNQ1 gene. The individual JLNS

families are often small and experience about the cardiac risk associated with being a carrier has been collected across the nuclear families sharing the same mutations. Only one obligate carrier out of 45 with KCNQ1 R518X mutation had symptoms (45). Among 26 individuals identified to be carriers of the KCNQ1 572-576del mutation and deriving from seven di erent families, only one person had clinically symptomatic LQTS (15). In the Finnish study of KCNQ1 G589D mutation carriers, 34 probands were identified and 316 heterozygous carriers were identified among 705 relatives, of whom only 83 (26%) were symptomatic. There was a slight overrepresentation of females among those with clinical a ection. In the close relatives of the three JLNS probands, no symptomatic cases were found. This study is particularly interesting because of the demonstration of a founder background of this Finnish mutation, and the opportunity to compare the genotype and subsequent phenotype in such a large series of subjects on a fairly homogeneous population background (21).

The existing experience about most KCNQ1 mutations associated with autosomal recessive LQTS is usually based on quite a few patients and the mutations demonstrated might be at risk for causing JLNS, similar to the existing experience with R518X. Genetic counseling should therefore include such aspects as well as all existing information about each mutation, including in vitro electrophysiological e ects. The anxiety aroused in the extended family of a JLNS case must be taken into account by o ering genetic counseling to relatives before a molecular carrier diagnosis is initiated. Clinical evaluation by means of ECG is not su ciently sensitive nor specific to make a risk-stratification-based approach. We therefore recommend specific mutation analysis to assess the carrier status and risk of cardiac arrhythmia, and institute proper medical treatment.

Recently, a compilation of experience with a large number of JLNS patients showed a disappointing low e cacy of beta-blockers with a 51% rate of syncopal events and a 24% risk of lethal outcome despite treatment. In this abstract, no details of identified mutations nor assumed compliance were given (59). The overall message was that JLNS remains a malignant form of LQTS with a high risk of lethal outcome despite medical treatment. The main triggers were emotions and exercise (59).

The rapidly increasing use of cochlea implant as a treatment of severely hearing-impaired infants accentuates the recommendation of establishing a diagnosis of cardiac arrhythmia, to avoid lethal complications during surgery. So far, only one such case was published and the outcome was advantageous (48). Special precautions were taken before and during the surgery, with close cardiac monitoring and beta-blocker treatment, and after 11 months of follow-up, the situation was stable. One event of cardiac syncope led to the placement of an automatic pacemaker and defibrillator.

Special attention toward monitoring the cochlea implant is well justified considering the auditory stimuli eliciting severe syncopal attacks in many reports.

The increasing implementation of universal neonatal hearing screening in many countries also facilitates early diagnosis of JLNS, and timely institution of medical prophylaxis. Especially in a country like Norway with the described genetic epidemiology, molecular screening for the existing KCNQ1 mutations could easily be incorporated as part of the panel of genetic tests o ered to all newly diagnosed infants with severely impaired hearing capacity.

ACKNOWLEDGMENTS

The author wants to thank the Oticon Foundation for financial support and Prof. Torleiv Rognum and Prof. Kontula Kimmo for sharing unpublished findings.

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