British Medical Bulletin

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British Medical Bulletin 63:73-94 (2002)
© 2002 The British Council

Hereditary deafness and phenotyping in humans

Maria Bitner-Glindzicz

Unit of Clinical and Molecular Genetics, Institute of Child Health, London, UK

	Abstract

Top Abstract Introduction Epidemiology of hearing... Autosomal recessive deafness Autosomal dominant non-syndromic... Maternally inherited hearing... Conclusions Key points for clinical... References

 
Hereditary deafness has proved to be extremely heterogeneous genetically with more than 40 genes mapped or cloned for non-syndromic dominant deafness and 30 for autosomal recessive non-syndromic deafness. In spite of significant advances in the understanding of the molecular basis of hearing loss, identifying the precise genetic cause in an individual remains difficult. Consequently, it is important to exclude syndromic causes of deafness by clinical and special investigation and to use all available phenotypic clues for diagnosis. A clinical approach to the aetiological investigation of individuals with hearing loss is suggested, which includes ophthalmology review, renal ultrasound scan and neuro-imaging of petrous temporal bone. Molecular screening of the GJB2 (Connexin 26) gene should be undertaken in all cases of non-syndromic deafness where the cause cannot be identified, since it is a common cause of recessive hearing impairment, the screening is straightforward, and the phenotype unremarkable. By the same token, mitochondrial inheritance of hearing loss should be considered in all multigeneration families, particularly if there is a history of exposure to aminoglycoside antibiotics, since genetic testing of specific mitochondrial genes is technically feasible.

Most forms of non-syndromic autosomal recessive hearing impairment cause a prelingual hearing loss, which is generally severe to profound and not associated with abnormal radiology. Exceptions to this include DFNB2 (MYO7A), DFNB8/10 (TMPRSS3) and DFNB16 (STRC) where age of onset may sometimes be later on in childhood, DFNB4 (SLC26A4) where there may be dilated vestibular aqueducts and endolymphatic sacs, and DFNB9 (OTOF) where there may also be an associated auditory neuropathy. Unusual phenotypes in autosomal dominant forms of deafness, include low frequency hearing loss in DFNA1 (HDIA1) and DFNA6/14/38 (WFS1), mid-frequency hearing loss in DFNA8/12 (TECTA), DFNA13 (COL11A2) and vestibular symptoms and signs in DFNA9 (COCH) and sometimes in DFNA11 (MYO7A). Continued clinical evaluation of types and course of hearing loss and correlation with genotype is important for the intelligent application of molecular testing in the next few years.

	Introduction

Top Abstract Introduction Epidemiology of hearing... Autosomal recessive deafness Autosomal dominant non-syndromic... Maternally inherited hearing... Conclusions Key points for clinical... References

 
Hearing impairment is the most common sensory disorder world-wide. When present in an infant, it may have dramatic effects on language acquisition and educational progress. Hearing loss which becomes apparent in later childhood or in adult life may have profound effects upon the social and working lives of those affected.

Causes of hearing impairment are numerous (Table 1) and, in a particular population, the relative contribution of genetic and environmental causes may be determined by social factors such as population structure and consanguinity, infection control and immunisation, and provision of neonatal and postnatal medical care¹. Thus, in non-industrialised countries, environmental causes of hearing loss may outnumber those that are genetically determined whereas in industrialised countries the importance of the genetic contribution to hearing loss has become more apparent.

View this table: [in this window] [in a new window]   Table 1 Causes of hearing impairment

 
Epidemiological surveys of the deaf have consistently shown that about 50% of childhood deafness can be attributed to genetic causes, but all of the surveys have pointed out that the cause cannot be determined in a considerable proportion of individuals¹. Recent molecular work has demonstrated that in this group of ‘cause unknown’ deafness, genetic causes are common and extremely heterogeneous. Many deaf individuals and their families want to know the cause of their deafness and particularly whether it is genetic. Proven genetic diagnosis may allow for accurate genetic counselling and family planning, carrier testing for relatives, and may provide essential information about environmental risk factors (e.g. aminoglycoside antibiotics in those with the A1555G mtDNA mutation, or risk of progression of hearing loss in those with dilated vestibular aqueducts). In addition, precise molecular diagnosis may be important for planning and assessing success of therapies such as cochlear implant² or future gene therapy.

The increasing knowledge of the molecular basis of hearing impairment will raise expectations among deaf people and their families that the exact cause of their hearing impairment may be determined and understood by genetic analysis. While this may be possible for some families with common causes of genetic hearing impairment or extensive family histories, the complexity of hearing, demonstrated by the underlying molecular heterogeneity, poses considerable problems in aetiological diagnosis in the majority. The aim of this chapter is not to provide an exhaustive description of genes implicated in hereditary deafness, but to describe a clinical approach to diagnosis and genetic testing, with the interested non-specialist in mind.

	Epidemiology of hearing impairment

Top Abstract Introduction Epidemiology of hearing... Autosomal recessive deafness Autosomal dominant non-syndromic... Maternally inherited hearing... Conclusions Key points for clinical... References

 
About 1 per 1000 children in the UK is born with a permanent hearing impairment and a similar number develop this during early childhood³. As age increases so too does the prevalence of hearing impairment; by the age of 40–50 years, 2.3% of the population experience a hearing loss of greater than 40 dB, and nearly 30% of those over 70 years are similarly affected⁴. Genetic factors are likely to be important in all of these age groups.

About 30% of those with a genetic form of hearing loss present with other clinical features in addition to hearing impairment, as part of a syndrome. It is important to make a syndrome diagnosis because: (i) it is important to monitor the individual and family for known complications and associations of the syndrome, such as renal or eye disease; (ii) inheritance may be clearly defined for many syndromic causes of deafness even if the gene is unknown; and (iii) molecular testing, which may confirm the diagnosis and aid genetic counselling, may be available for many of the commoner syndromes.

Although some syndromes may present in an obvious manner to the clinician, others require specialised investigation and a high index of suspicion in order to make the diagnosis. For these reasons, it is important to examine fully every individual with hearing impairment. Special attention should be paid to facial appearance, including the eyes, appearance of the external ears and neck, the skin (its pigmentation and its quality), and examination of the hands for unusual creases, extra or missing fingers and appearance of the digits. Those organs which cannot be easily seen, such as the eye and the kidney, with which syndromic associations are common, require additional investigations. Table 2 outlines the suggested clinical investigation of patients presenting with hearing impairment. The aim of this is to diagnose syndromic hearing loss, to exclude environmental causes and to build a picture of the phenotype of the hearing loss which may be valuable for directing molecular analysis. Table 3 gives examples of the genes underlying syndromic forms of hearing impairment.

View this table: [in this window] [in a new window]   Table 2 Aetiological investigation of hearing impairment

 

View this table: [in this window] [in a new window]   Table 3 Some of the genes underlying syndromic forms of hearing impairment

 
In the remaining 70% of cases, hearing loss is not associated with additional clinical features and is termed ‘non-syndromic'. Studies of marriages between the deaf have long indicated that a large number of genes are likely to be involved in human hearing impairment, and estimates have varied considerably¹. More recent molecular analysis has borne out some of the higher estimates and indeed, to date, more than 40 genes for autosomal dominant deafness and more than 30 for autosomal recessive deafness mapped or cloned, although in some cases the same gene may be responsible for both dominant and recessive deafness⁵. Unsurprisingly, a wide variety of molecules has now been implicated in the causation of human hearing impairment, including transcription factors and activators, motor molecules, extracellular matrix components, cytoskeletal proteins, components of ion channels and gap junctions. These are summarized in Table 4.

View this table: [in this window] [in a new window]   Table 4 Cloned genes involved in non-syndromic hearing impairment

 
For many years, this extreme heterogeneity hampered genetic studies because many different genetic forms of hearing loss give rise to similar clinical phenotypes, preventing the pooling of families in genetic linkage studies. Mapping strategies circumvented these problems by using single, large, dominant families, large consanguineous families and population isolates, where genetic homogeneity is far more likely. Although these approaches have been highly successful in mapping and identifying genes, they give no indication of molecular epidemiology of genetic deafness, i.e. how much a particular gene contributes to deafness world-wide or in a particular ethnically mixed country. Indeed, preliminary studies indicate that most recessively acting genes, with the exception of GJB2 (Connexin 26), which encodes for the protein Connexin 26, are small contributors to hereditary deafness as a whole⁶. This means that genetic heterogeneity coupled with relative clinical homogeneity in presentation, require the clinician to use all available phenotypic clues in order to direct molecular testing and determine aetiology.

	Autosomal recessive deafness

Top Abstract Introduction Epidemiology of hearing... Autosomal recessive deafness Autosomal dominant non-syndromic... Maternally inherited hearing... Conclusions Key points for clinical... References

 
It is estimated that up to 75–80% of those with non-syndromic genetic hearing impairment have an autosomal recessive cause, 10–15% have an autosomal dominant cause, with the remainder being X-linked, mitochondrial or chromosomal. Autosomal dominant deafness loci are designated DFNA, autosomal recessive loci designated DFNB and X-linked loci, DFN. The loci are numbered according to the order in which they were mapped, DFNA1 being the first autosomal gene mapped in 1992⁵.

Most of the recessively inherited forms of hearing impairment cause a phenotypically identical severe to profound, prelingual hearing loss⁵, but mutations at a few loci – DFNB2 (MYO7A)⁷, DFNB8/10 (TMPRSS3)⁸ and DFNB16 (STRC)⁹ – cause a delayed, childhood-onset hearing impairment. Also of note is that hearing loss caused by mutations at DFNB4 (SLC26A4) may be associated with dilated vestibular aqueducts and endolymphatic sacs¹⁰, and there may be an associated auditory neuropathy with mutations in DFNB9 (OTOF)¹¹. In addition, vestibular symptoms have been noted in DFNB2 (MYO7A), DFNB4 (SLC26A4) and DFNB12 (CDH23).

Hearing impairment caused by mutation in GJB2 (DFNB1) – a common cause of non-syndromic recessive and sporadic deafness

Epidemiological surveys of the deaf suggested that non-syndromic hearing loss was genetically heterogeneous, and that there was unlikely to be a single major gene involved. The discovery of GJB2 and the subsequent realisation that it is a common cause of hearing impairment in many populations^12–18 was largely unexpected, although there was some previously published evidence of this in haplotype analysis of small families with non-syndromic deafness^19,20. The gene GJB2 encodes a gap junction protein known as Connexin 26. There is now good evidence that up to 50% of recessive non-syndromic hearing loss may be accounted for by mutations in this gene in Caucasian and European populations^12,13. In European, North American and Mediterranean populations, the most common mutation is a deletion of a single guanine nucleotide in a series of six guanines known as 35delG^18,20. This mutation may account for 70% of mutant alleles of GJB2 and the carrier frequency of this mutation alone is estimated at around 1 in 51 overall in Europe, but is considerably higher in some populations^12,13,21. Originally, this mutation was thought to be a deletion hot-spot, but more recent evidence has suggested that it may be due to a founder effect, i.e. an ancient mutation which has become wide-spread possibly due to some undefined heterozygote advantage²².

Study of other ethnic groups has shown that different mutations may be more common. For example, the 167delT mutation is the most prevalent mutation found in the Ashkenazi Jewish population with a probable carrier frequency of 3–4%, again possibly due to a founder effect^16,23. In East Asian populations, the 235delC mutation is the most common mutation¹⁷ and three mutations, W24X, W77X and Q124X, have been found commonly in families from different parts of the Indian subcontinent²⁴.

Not only is mutation in GJB2 a common cause of non-syndromic recessive deafness, but mutations have been also been found in a significant number of sporadic cases – consistent with autosomal recessive inheritance^14,15. Estimates vary, but between 10–30% of individuals with severe-to-profound non-syndromic hearing impairment of unknown cause have been shown to harbour mutations in this gene. Molecular analysis of GJB2 in hearing-impaired individuals is simplified by the fact that this is a small gene consisting of two exons, only one of which codes for the protein, Connexin 26. Therefore, analysis of the gene in the diagnostic setting is relatively straightforward. This is a powerful argument for offering GJB2 screening as part of the routine aetiological work-up in the diagnosis of all cases of non-syndromic deafness of unknown cause (Table 5). A further argument for offering GJB2 testing on a wide-spread basis is the observation that the phenotype of hearing impairment caused by mutations in this gene is rather unremarkable, implying that one cannot select patients for analysis based on clinical phenotype²⁵. There are no associated vestibular abnormalities or abnormality on the CT scan of the temporal bone. The deafness caused by mutations in GJB2 is frequently severe or profound, but there can be considerable variation in severity even within families^23,26–28. Deafness is usually stable, but progression has been reported^25,29. Onset is nearly always pre-lingual, but not necessarily congenital, and it is possible that hearing may be normal at birth and progress rapidly during the first few months of life³⁰. This implies that some babies with mutations in GJB2 may pass new-born hearing screening but become profoundly deaf during infancy.

View this table: [in this window] [in a new window]   Table 5 Rationale of routine GJB2 (Connexin 26) mutation screening in all cases of non-syndromic hearing impairment where cause is unknown

 
GJB2 may also be a rare cause of autosomal dominant deafness, both syndromic and non-syndromic (DFNA3)³¹. Phenotypes described include mild-to-profound hearing impairment, which is commonly progressive in nature, and may be associated with varying skin phenotypes including palmoplantar keratoderma (caused by the missense mutations G59A, R75W and DE42), Vohwinkel syndrome (associated with D66H), and keratitis-ichthyosis-deafness (KID, associated with D50N, G12R and S17F mutations)^32–36. It would, therefore, seem sensible to screen the gene in individuals with deafness associated with epidermal defects. Interestingly, the R75W mutation appears to cause a variable skin phenotype since in some families it is reported to cause deafness with palmoplantar keratoderma, but in others the skin symptoms may be very mild or absent^33,37. However, the missense mutations, W44C and C202F, definitely appear to cause non-syndromic deafness at the DFNA3 locus^5,31. The role of the M34T allele in hearing loss is contentious since experimental studies show that there is a functional effect on the Connexin 26 molecule^38,39, but genetic studies now cast doubt on whether this is clinically significant^40,41.

Once GJB2 analysis has been completed in the individual whose hearing loss is of unknown cause, there are very few further avenues for molecular investigation in small families or isolated cases at the present time. Recent data suggest that other recessive genes, with the exception of SLC26A4, contribute fairly equally to non-syndromic recessive deafness at least in Caucasian sibling pairs⁶.

Hearing impairment caused by SLC26A4 (DFNB4/Pendred syndrome) – a significant cause of familial dilated vestibular aqueducts

Pendred syndrome describes the association of congenital deafness and goitre inherited in an autosomal recessive manner. Decades ago, Fraser estimated that mutations in this gene, giving rise to classical Pendred syndrome, may account for 5–10% of those with prelingual hearing impairment⁴². More recently, it has become apparent that the clinical presentation of individuals with mutations in this gene is highly variable. Features may range from those with classical Pendred syndrome presenting with goitre and prelingual profound sensorineural hearing loss, to those with absence of goitre, normal biochemical thyroid function and normal organification of iodine as demonstrated on a perchlorate discharge test, in whom the hearing impairment presents as non-syndromic. The most frequent presentation of the hearing loss is sensorineural, profound and prelingual but there may be a history of fluctuating progressive hearing loss that affects mainly the high frequencies⁴³. Vestibular dysfunction has been demonstrated in a high proportion of individuals although not all are symptomatic. The major clue to diagnosis in an individual without overt goitre is, however, neuro-imaging. Enlargement of the vestibular aqueduct is the commonest abnormality which may be present in up to 80% of those with the disorder and in some cases there may also be a Mondini cochlea (1.5 cochlear turns instead of the normal 2.5)^44,45. Dilatation or enlargement of the vestibular aqueducts is by no means diagnostic of Pendred syndrome, since these have been demonstrated in other genetic forms of hearing impairment including branchio-oto-renal syndrome and renal tubular acidosis with deafness^46,47. However, in the absence of these syndromes where dilatation of the vestibular aqueduct and deafness is familial, there is a high chance of finding a mutation in the SLC26A4 gene but a rather lower mutation pick-up rate in isolated cases⁴⁴.

PDS, the protein product of SLC26A4, is an anion transporter^48–50, expressed in the endolymphatic duct and sac from embryonic day 13 onwards and in non-sensory parts of the utricle, saccule and cochlea where it may be involved regulation and resorption of endolymph^51,52. This is an attractive hypothesis since a protein involved in inner-ear fluid homeostasis might account for fluctuating hearing loss observed in individuals with mutations in the gene and for enlargement of the vestibular aqueduct and endolymphatic duct contained within it.

Many mutations have been described throughout the coding region of the gene including some which appear to be common^53,54. Initial reports described a genotype–phenotype correlation based on functional study of chloride and iodide uptake by PDS transfected Xenopus oocytes^49,55. Data suggested that mutations associated with full-blown Pendred syndrome cause a complete loss of transport whereas variants reported in those with non-syndromic deafness showed residual transport function. However, more recent assays of iodide efflux using transiently transfected mammalian cells, failed to show any correlation of mutation type with transport function and phenotype⁵⁶. This is in keeping with the situation seen in human families in which there maybe clear phenotypic variation between siblings with the same mutation.

	Autosomal dominant non-syndromic deafness

Top Abstract Introduction Epidemiology of hearing... Autosomal recessive deafness Autosomal dominant non-syndromic... Maternally inherited hearing... Conclusions Key points for clinical... References

 
Most forms of autosomal dominant non-syndromic deafness are difficult to distinguish phenotypically. The majority of autosomal dominant genes are associated with hearing impairment that is post-lingual in onset, often beginning before the age of 20 years. Some forms, however, notably DFNA4, DNFA9 and DFNA10 are associated with hearing impairment starting somewhat later during the third and fourth decades. Mutations at the DFNA6/14/38 locus as well as those associated with the DFNA9 locus tend to have distinguishable clinical phenotypes, and DFNA12, DFNA13 and DFNA21 are characterised by mid-frequency hearing impairment.

WFS1 gene mutations (DFNA6/14/38) – a common cause of familial low frequency hearing loss

Mutations at only two loci are known to cause low-frequency sensorineural hearing loss; individuals from a single large Costa-Rican family with mutations at the DFNA1 locus have a rapidly progressive, fully penetrant form of hearing impairment in which affected individuals become profoundly deaf across all frequencies by the fourth decade of life⁵⁷.

In contrast to the DFNA1 phenotype, mutations at DFNA6/14/38 (caused by mutations in the gene WFS1) show overall mild progression consistent with presbyacusis^58–60. Affected individuals show fully penetrant, early-onset, low-frequency hearing impairment which is bilateral and symmetrical. There is good speech discrimination and sometimes the hearing impairment may be asymptomatic as hearing at and below 2 kHz is predominantly affected. With the onset of presbyacusis, there is some flattening of the audiogram or even down-sloping configuration in older people. In a family from Newfoundland, the age of onset of hearing impairment was reported as the second decade although affected children could be identified before school age by an ‘S-shaped’ pure tone audiogram⁵⁹. By the age of 40 years, hearing impairment was moderate-to-severe across all frequencies with males appearing to be more severely affected than females.

Mutation analysis studies of the WFS1 gene have shown that it is a common cause of dominantly inherited low frequency hearing loss⁶⁰, but not of sporadic, low-frequency hearing impairment⁶¹. The lower mutation pick-up rate in simplex cases suggests that there may be other non-genetic causes as well as genetic causes. It should be noted that mutations in the same gene cause Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness inherited in an autosomal recessive manner)⁶². Mutations which cause Wolfram syndrome appear to be, in the most part, inactivating and tend to be spread throughout the gene. In contrast, the heterozygous missense mutations associated with low-frequency sensorineural hearing impairment tend to be non-inactivating and cluster at the C-terminal protein domain, an observation which may simplify mutation analysis of the 8 exons of the gene⁶¹. In summary, it is probably worthwhile screening the WFS1 gene in cases of low-frequency sensorineural hearing impairment where there is a positive family history.

Hearing impairment caused by mutations in the COCH gene (DFNA9) – familial progressive vestibulocochlear dysfunction with ‘Menière-like’ symptoms

The clinical presentation of mutations in this gene is remarkable in its consistency. Most families have presented at 40–60 years of age with a progressive autosomal dominant sensorineural hearing loss⁶³. The exception to this is the family reported by Robertson et al in which the age of onset was somewhat younger, at 20–40 years of age⁶⁴. Initially, high frequencies are affected but progression ultimately involves all frequencies so that severe-to-profound loss is seen by 60–80 years. However, the most notable feature is that of the vestibular symptoms, which may be present in some or all affected family members. Many individuals report a feeling of unsteadiness, difficulty walking in the dark, on uneven ground or up and down steps and vertigo has been reported in some individuals although it is not present in all. In some families, vestibular dysfunction has shown complete penetrance⁶³ but reduced penetrance in others^64–66. The episodes of vertigo, tinnitus, aural fullness and progressive hearing impairment are reminiscent of symptoms of Menière's disease.

Endolymphatic hydrops, a characteristic of Menière's disease, has been confirmed in one patient histopathologically. Histopathological examination in the original DFNA9 families is said to have a unique appearance⁶⁷ with degeneration and acellularity of the spiral ligament, spiral limbus and stroma of the cristae and maculae, and replacement by eosinophilic acellular material. The actual function of the COCH gene product is, however, unknown, although it is likely to be a secreted protein⁶⁴.

The clinical presentation of this disorder does differ from classical Menière's disease in which the hearing loss usually begins as low-frequency as opposed to high-frequency in DFNA9. Meticulous clinical characterisation of this disorder has been described by Bom et al in a large Dutch family⁶⁸. The progression of vestibular involvement was clearly documented and vestibular areflexia was found from the age of 47 years onwards, whereas younger individuals showed either severe hyporeflexia or unilateral caloric areflexia. In summary, it would appear that familial progressive hearing loss associated with progressive vestibular dysfunction is a good indication for mutation screening of the COCH gene.

Mid-frequency hearing loss (mutations at DFNA12, DFNA13 and DFNA21)

COL11A2 (DFNA12)
Mutations at three deafness loci (DFNA12, DFNA13 and DFNA21) are characterised by hearing impairment that affects the mid-frequencies.

Mutations at the locus DFNA13, in the COL11A2 gene, give rise to a mid-frequency, or U-shaped (‘cookie-bite’) hearing loss with no significant progression beyond presbyacusis^69,70, which eventually produces a flattened audiogram⁷¹. Most individuals noted hearing problems 20–40 years of age, although actual age of onset may have been prelingual in some families. Study of a Dutch family revealed that about half of the mutation carriers also had caloric abnormalities⁷¹. It should be noted that mutations in the same gene, COL11A2, may cause Stickler syndrome without eye involvement. However, detailed clinical evaluation of the families described above confirms that their hearing impairment is non-syndromic.

Detailed clinical evaluation of a family with hearing impairment linked to DFNA13, but without a known mutation, again showed mid-frequency hearing impairment which became apparent at about the age of 30 years, but there was no evidence for congenital or prelingual onset. Speech had developed normally in all cases. Vestibular function as assessed by bithermal calorics was intact in most cases⁷².

Studies of the hearing impaired Col11a2^–/– mouse have shown that the tectorial membrane appeared to be thicker and less compacted than normal, due to disorganization of the type 2 collagen fibrils, which were not arranged in their usual parallel, evenly spaced manner⁷⁰. It has been hypothesized that the type XI collagen is needed in the tectorial membrane for even spacing between type 2 collagen fibrils, the major collagen in the tectorial membrane. Col11a2 mRNA was observed in vestibular sensory areas, compatible with the vestibular findings in some of the human families. Thus structural disorganization of the tectorial membrane appears to cause congenital, permanent hearing impairment, which is stable and affects the mid-frequencies predominantly.

Although the phenotype of mid-frequency hearing loss caused by mutations in this gene is more distinctive than many other autosomal dominant non-syndromic forms of hearing loss, the gene is large, consisting of 67 exons; therefore, prior linkage probably needs to be established in a family before mutation screening can be offered.

TECTA (DFNA8/12)
It is interesting to note that another component of the tectorial membrane, tectorin, causes a form of autosomal dominant deafness with a similar phenotype. Mutations in the zona pellucida domain of the TECTA gene, which encodes -tectorin, also cause prelingual non-progressive, mid-frequency hearing impairment^73–75. However, mutations in a different domain, the zonadhesin-like domain, cause autosomal dominant progressive high frequency hearing impairment which may be prelingual or postlingual in onset^76,77. Homozygous loss of function mutation of TECTA may also result in the phenotype of severe-to-profound non-syndromic autosomal recessive hearing loss⁷⁸, DFNB21.

DFNA21
Mutation at the DFNA21 locus, mapped to 6p21-22, also may give rise to progressive non-syndromic mid-frequency sensorineural hearing impairment, with an age of onset estimated at around 3–4 years⁷⁹. The gene responsible has not yet been identified.

	Maternally inherited hearing impairment

Top Abstract Introduction Epidemiology of hearing... Autosomal recessive deafness Autosomal dominant non-syndromic... Maternally inherited hearing... Conclusions Key points for clinical... References

 
The importance of maternally inherited hearing impairment, due to mutations in the mitochondrial genome, has only come to light in the last decade or so^80,81. Mitochondria are intracellular organelles which are responsible for the generation of energy through oxidative phosphorylation. They contain their own DNA (mtDNA), which encodes 13 mRNAs (components of five enzymatic complexes necessary for oxidative phosphorylation), two rRNAs and twenty-two tRNAs. At fertilization, only the ovum contributes mitochondria to the zygote and; therefore, mutations in the mitochondrial genome are only inherited through the maternal line and are never transmitted by the father. Usually all the mitochondrial chromosomes in a cell carry identical copies of mtDNA (homoplasmy), but some mutations may be heteroplasmic (wild-type and mutant mitochondria in the same cell). Random distribution of mutations between cells following cell division may lead to differences in mutational loads between different cells and tissues.

Estimates of the contribution made by mitochondrial genes to inherited deafness vary between populations. Mitochondrial genes appear to be a rare cause of prelingual hearing loss⁸³, although data suggest that a considerable proportion of post-lingual hearing loss may be maternally inherited (T Hutchin, personal communication)^82,84.

A comprehensive description of the biology and phenotypes associated with mitochondrial hearing impairment is beyond the scope of this review and is available elsewhere^82,83, but suffice it to say that hearing impairment may be non-syndromic or syndromic and varies greatly in severity and age of onset even within families. Other systems which may be involved tend to include organs and tissues with a high energy requirement such as muscle, central nervous system, retina, heart, and gut, besides the ear. Symptoms such as ataxia, seizures, hypotonia, myopathy, ophthalmoplegia, optic atrophy, cardiomyopathy, retinopathy and endocrinopathies often occur in mitochondrial diseases (e.g. MERRF, MELAS, Pearson syndrome, Kearns-Sayre syndrome and maternally inherited diabetes and deafness). The hearing loss associated with these conditions tends to be of childhood or early adult onset, to involve high frequencies and is often progressive⁸¹. The hearing impairment appears to be cochlear in origin due to loss of outer hair cell function, and successful cochlear implantation indicates that the cochlear nerve is unaffected.

A number of mitochondrial mutations have been described which give rise to non-syndromic hearing impairment. The most important of these is the A1555G mutation in the 12SrRNA gene, which was originally described in a large Arab-Israeli family demonstrating maternally inherited deafness^80,81. Most of the affected individuals had early onset severe to profound hearing loss in infancy, although other family members had adult onset hearing loss and some had normal hearing. It has subsequently been shown that the deafness phenotype in this family is probably modified by an unknown autosomal gene on chromosome 8⁸⁷. In other cases, this mutation has been reported in families where there is deafness following exposure to aminoglycosides^84,88,89 in which case the age of onset of deafness in exposed individuals is younger⁸⁴. Aminoglycoside-induced hearing impairment appears to be particularly common in some countries. For example, in one region of China, 25% of deaf mutes associated their hearing loss with aminoglycoside exposure, and where deafness was familial, transmission was compatible with maternal inheritance⁹⁰. The A1555G mutation appears to be highly prevalent among Spanish deaf individuals where it is found in 27% of multigeneration families (with and without aminoglycoside exposure)⁸⁴, and also in Japanese where 10% of profoundly deaf individuals without aminoglycoside exposure carry the mutation⁹¹. A second mutation, 961delT, has also been associated with aminoglycoside induced deafness⁹².

Other mutations, A7445G, 7472insC, T7510C and T7511C, in the tRNA^Ser(UCN) gene, have been reported to cause non-syndromic hearing impairment, although A7445G has also been reported with palmoplantar keratoderma⁹³, and 7472insC with ataxia and myoclonus⁹⁴.

In summary, non-syndromic mitochondrial deafness should be considered in all multigeneration families, with and without exposure to aminoglycoside antibiotics, unless there is reliable documentation of transmission of deafness from a male. Syndromic mitochondrial deafness may underlie symptoms in multiple organ systems.

	Conclusions

Top Abstract Introduction Epidemiology of hearing... Autosomal recessive deafness Autosomal dominant non-syndromic... Maternally inherited hearing... Conclusions Key points for clinical... References

 
Thorough investigation of the aetiology of hearing loss is necessary for accurate genetic counselling and for the implementation and assessment of any future gene therapy. Investigation of non-syndromic deafness should include analysis of GJB2 since it is the most common cause of inherited hearing loss and its clinical presentation is unremarkable. However, genetic heterogeneity underlying syndromic and non-syndromic deafness greatly complicates further genetic testing and diagnosis in small families and sporadic cases of deafness. Until genetic testing for large numbers of genes becomes cheaper, faster and less labour-intensive, clinicians must rely on the few audiological, vestibular and radiological clues that may suggest mutation at a particular locus. Detailed clinical description of the effects of gene mutations is an important part in realising the full potential.

	Key points for clinical practice

Top Abstract Introduction Epidemiology of hearing... Autosomal recessive deafness Autosomal dominant non-syndromic... Maternally inherited hearing... Conclusions Key points for clinical... References

 

• Characterize the hearing loss (audiology, vestibular tests and radiology)
  
• Rigorously exclude syndromic causes of hearing impairment, by history, examination and specialised investigation (ophthalmology, renal ultrasound, neuro-imaging)
  
• Consider GJB2 mutation screen in all non-syndromic cases with unknown aetiology (common cause of hearing loss with few clinical pointers)
  
• Always consider mitochondrial inheritance in multigeneration families unless there is clear evidence of transmission from a male
  

	Footnotes

 
Correspondence to: Dr Maria Bitner-Glindzicz, Unit of Clinical and Molecular Genetics, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK

	References

Top Abstract Introduction Epidemiology of hearing... Autosomal recessive deafness Autosomal dominant non-syndromic... Maternally inherited hearing... Conclusions Key points for clinical... References

 

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