overview of genetic auditory syndromesj am acad audiol 6: 1-14 (1995) overview of genetic auditory...

J Am Acad Audiol 6: 1-14 (1995)

Overview of Genetic Auditory Syndromes Shelley D . Smith*

Abstract

Accurate determination of the cause of hearing loss is critically important for clinicians for prognosis and management . Recognition of genetic syndromes is especially important, but this is dependent upon clear delineation of the characteristics of the syndromes. Research into underlying mechanisms of hearing loss is also much more effective if the cause of the hearing loss is known to be the same in the subjects being studied . Family studies of hear-ing loss can be very important in determining the phenotypic range of the condition, but it has become clear that phenotypically similar families may not actually have the same genetic cause. Molecular genetic studies are needed to determine which genes, and even which mutations within genes, are responsible for specific syndromes. This paper reviews the methodology of gene localization (linkage) studies and describes a variety of genetic condi-tions, syndromic and nonsyndromic, which illustrate the varying relationships between genes, phenotypes, and mechanisms of hearing loss . Knowledge of the cause of hearing loss will facilitate understanding of the auditory system and development of optimum therapy.

Key Words: Deafness, genetic disorders, genetic linkage, hearing disorders, molecular genetics

T

horough phenotypic and genetic descrip-tion of conditions causing hearing loss is vital to clinical practice and to the

research into underlying causes . For the clini-cian, accurate diagnosis is possible when the phenotypic features of a syndrome have been well defined and distinguished from other sim-ilar conditions . Knowledge of the diagnosis leads to appropriate prognosis, therapy, and genetic counseling . In research, delineation of a popu-lation with the same condition will allow iden-tification of the pathology, even down to the molecular level. As the causes of individual con-ditions are understood, the mechanism of hear-ing becomes clearer, and therapies for genetic and nongenetic hearing loss become possible .

The process of finding the genotype (the genetic makeup) that fits a particular phenotype (the physical characteristics) can be somewhat circular. A particular gene may have a wide range of phenotypic expression (i .e ., it may cause

`Otolaryngology and Human Communication, Boys Town National Research Hospital, Omaha, Nebraska

Reprint requests : Shelley D . Smith, Department of Otolaryngology and Human Communication, Boys Town National Research Hospital, 555 North 30th Street, Omaha, NE 68131

a variety of phenotypic features), but different genes (or even nongenetic effects) may also cause very similar phenotypes (phenocopies) . The prob-lem is to define the syndrome broadly enough to include all of the manifestations for a particu-lar gene but not so broadly as to include the phe-nocopies . As a syndrome is being defined, it may go through a process of "lumping" and "splitting" as characteristics are added or subtracted from it. In this process, the genetic transmission must also be determined . The phenotypic variation will be determined in part by looking within fami-lies, since affected individuals within a family presumably share the same genotype . Gene localization, the identification of the position of a gene on a chromosome, can provide an impor-tant key into defining syndromes and groups of syndromes . As the diagnostic criteria become more accurate, it becomes possible to localize the gene or genes causing the syndrome ; once the genes are localized, the phenotypes can be refined further, until finally they are defined by specific genetic changes.

A gene is a sequence of DNA (deoxyribonu-cleic acid) that codes for the synthesis of a pro-tein product, which may be all or part of a par-ticular enzyme or structural protein. Variations in the code for a particular gene are called alle-

Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995

les, and alleles that disrupt the production or function of the gene product may cause a genetic disease. The pair of alleles carried by an indi-vidual at a specific gene locus, or location, is termed the genotype .

A linear, helical DNA molecule can carry hundreds of genes along its length . A strand of DNA is packaged into a chromosome, which is visible under light microscopy. Humans have 23 pairs of chromosomes, with one chromosome from each pair inherited from the mother and the other from the father. Similarly, one chro-mosome from each pair is randomly selected for transmission to the next generation . Mendel's law of "independent assortment" describes the randomness of this selection. The parental ori-gin of the chromosome (or gene) that is selected from one pair of chromosomes has no influence on which chromosome is selected from another pair. This leads to recombination of maternally derived genes with paternally derived genes. If two genes assort independently, recombination between them will be 50 percent. The excep-tion to this law of independent assortment comes when genes are close together on the same chro-mosome .

The process of gene localization takes advantage of the fact that segments of DNA that are close together on the same chromo-some (linked) will tend to be inherited together as the chromosome is transmitted to the next generation. If they are inherited together, recom-bination will be reduced, and this is how the linkage is identified . However, two genes on the same chromosome may not be linked if they are far enough apart. Recombination can occur between genes on the same chromosome through crossing over, in which there is actual exchange of chromosome material between the maternal and paternal chromosomes in a pair. The chance that a crossover will occur between two loci is proportional to the distance between them, so that the percentage of recombination can be taken as a measure of genetic distance . Recom-bination is certain between two genes on oppo-site ends of a chromosome ; the closer the two loci on the chromosome, the lower the recombina-tion fraction .

The first step in localizing a gene is to show that there is reduced recombination between the gene and a locus that is already known to be on a particular chromosome . The known locus or marker may be another gene or a sequence of DNA of unknown function . Through linkage analysis, the transmission through the family of the disorder and the marker is compared to

see if recombination between them is reduced. In the lod score method of linkage analysis, the probability of linkage within a family is com-puted for different levels of recombination, and the probabilities are converted to lod scores (log of odds of linkage, to the base 10) (Morton, 1955). Since logs are used, the lod scores can be summed between families . The recombination fraction giving the highest lod score is taken as the best estimate of the distance between the loci . A lod score greater than 3 is required for acceptance of linkage at a given recombination fraction, and a lod score less than -2 rejects link-age between the loci . If the lod scores are between these two values, more data must be collected until the lod score reaches one of these two standards.

Other methods of linkage analysis are based upon the comparison of markers in pairs of rel-atives (for example, sib pairs) . If the gene for a condition and a marker are linked on a given chromosome, pairs of relatives who both have the gene for the condition should have the same marker identical by descent (inherited from the same ancestor). Pairs of relatives who are dis-cordant for the condition should also be discor-dant for the linked markers (Haseman and Elston, 1972). Evidence for linkage is seen, then, when the proportion of marker alleles identical by descent is significantly increased in pairs of affected individuals.

The choice of marker loci may be based on candidate regions, such as genes thought to be involved in the disease process or positions of chromosomal translocations found in affected individuals. On the other hand, if there are no obvious candidates, one may have to do a "full genome search," utilizing markers spaced at intervals along the chromosomes until linkage is identified . Once linkage is found between a condition and a marker, molecular methods can be used to find closer markers that show even less recombination, until finally a candidate gene or sequence is identified that shows no recombination . Final proof that the actual gene for a disorder has been found lies in the identi-fication of mutations in that gene that are pre-sent only in affected individuals.

The identification of specific genes for hear-ing loss syndromes has already had a number of ramifications. In some cases, the exact gene and its function have been learned. The extent of genetic heterogeneity (i .e ., the number of genes producing indistinguishable phenotypes) is also becoming apparent . Finally, identification of the genes is leading to a refined nosology of

Genetic Auditory Syndromes/Smith

the syndromes. In the past, syndromes were grouped according to their phenotypic charac-teristics, and generally this provided an accurate reflection of etiologic similarity. However, as the molecular causes have been identified, some regrouping has been possible, and new modes of inheritance have even been found. Duyk et al (1992) have provided a summary updating the localization of genes for hearing loss .

The discussion of syndromes that follows is not an exhaustive summary of disorders but is meant to give examples of types of syndromes of hearing loss, with emphasis on those in which molecular studies illustrate particular genetic principles . For more complete descriptions of genetic syndromes with hearing loss, several reference books can be recommended: Konigs-mark and Gorlin, 1976 ; Jones, 1988 ; Buyse, 1990 ; Emery and Rimoin, 1990; Gorlin et al, 1990; and McKusick, 1992 . The syndromes cited in this review are summarized in Table 1, with incidence figures given where available.

SYNDROMES WITH PIGMENTARY/NEURAL CREST

INVOLVEMENT

T he discovery of the Waardenburg gene on chromosome 2, its homology with the splotch

mouse mutation, and the underlying defect in neuronal migration has proven to be a wonder-ful illustration of the process of linkage analy-sis and the potential outcomes . As described by Pikus and colleagues in this volume (1995), the candidate region was first identified through an inversion in the long arm of chromosome 2 in a baby who had features of Waardenburg syndrome, along with other birth defects (Ishi-kiriyama et al, 1989). Linkage was found with a gene in the region of the inversion, ALPP (pla-cental alkaline phosphatase) (Foy et al, 1990), and it was noted that, in the mouse, this gene was near the phenotypically similar splotch locus. Finally, the exact gene (named HuP2) and some of its mutations were described (Baldwin et al, 1992 ; Tassabehji et al, 1992). In this process, the etiologic distinction between Waardenburg syndrome type 1 (with dystopia canthorum) and type 2 (without dystopia) was supported, since the gene on chromosome 2 was almost exclusively associated with the type 1 phenotype, but the presence of a HuP2 mutation in a type II family (Read, 1992) means that this is not complete . It will be interesting to see if the precise mutations within the gene consistently produce the same phenotype. At the same time,

genetic heterogeneity within Waardenburg syn-drome type 1 has been established, since link-age to the HuP2 gene has been excluded in about 55 percent of families with type 1(Farrer et al, 1992). The suspicion that the Klein-Waar-denburg syndrome, with additional skeletal deformities, was a variant of type 1 has been sup-ported by the finding of deletions in the HuP2 gene in affected individuals (Milunsky et al, 1992 ; Pasteris et al, 1992). This may be an exam-ple of a contiguous gene syndrome, in that Mein-Waardenburg syndrome may be caused by dele-tion of the HuP2 gene along with an adjacent gene involving skeletal development.

Study of the gene sequence and splotch mouse model has given indications of how the gene acts . The sequence is that of a "paired-type" homeobox and codes for a DNA binding pro-tein (Goulding et al, 1991). In humans, this may regulate genes involved in the embryonic migra-tion of melanocytes derived from neural crest cells as they populate the skin, iris, inner ear, and gut. Melanocytes are found in the stria vas-cularis of the cochlea. Interestingly, the splotch mouse, like some individuals with Waarden-burg syndrome, does not appear to be deaf (Steel and Smith, 1992), but the homozygote has a high frequency of neural tube defects. Further study may demonstrate the factors, genetic or nongenetic, that determine deafness in Waar-denburg syndrome and how to prevent it.

There are a number of other disorders that involve deafness and disorders of melanocyte migration, which show up as variations in pig-mentation. Several also include Hirschsprung's megacolon, which probably reflects faulty neural crest cell migration and enervation . For exam-ple, the pigmentary features of piebaldism can be very similar to Waardenburg syndrome, and an increased incidence of deafness and mega-colon has been noted in some families. One gene causing piebaldism has been localized to chro-mosome 4 and found to be the c-kit proto-onco-gene (Spritz and Giebel, 1991). This is a tyrosine kinase growth factor receptor on stem cells. In mice, mutation in the kit gene produces the W mutation, and the heterozygous mouse is spot-ted white, anemic, sterile, and apparently is also deaf (Duyk et al, 1992). In humans who are heterozygous for the c-kit mutation, the effects on the migration of melanocytes are analogous, but the other features are not observed . There are several other spotted mouse mutations, as well as the deaf white cat, that may be models for piebaldism and deafness syndromes. A sim-ilar disorder of piebaldism in humans, called X-


Table 1 Summary of Cited Disorders

McKusick Mode of Disorder Number Inheritance Incidence' Hearing Loss

Pigmentary/Neural Crest Waardenburg Type I : 193500 AD 1 :20,000 Congenital sensorineural

Type 11 : 193510 Piebaldism 172800 AD Sensorineural Albinism and deafness 300700 X-linked 2 kindreds Congenital sensorineural Ocular albinism and 103470 AD Congenital sensorineural

deafness Ocular albinism and 300650 X-linked 1 kindred Late-onset sensorineural

deafness Oculocutaneous albinism 220900 AR? 1 kindred Congenital sensorineural

and deafness Hypopigmentation and 103500 AD 1 kindred Congenital severe to profound

deafness sensorineural Craniofacial Apert 101200 AD 1 :100,000 Conductive Saethre Chotzen 101400 AD Conductive Oculoauriculovertebral 164210 Multifactorial, 1 :5600 Conductive, occasionally mixed

spectrum (includes rarely AD hemifacial microsomia, Goldenhar syndrome)

Treacher Collins 154500 AD Conductive or mixed Branchio-oto-renal 113650 AD 1 :40,000 Sensorineural, conductive, or mixed Oto-palato-digital 311300 X-linked Severe conductive Stapes fixation with 304400 X-linked Mixed, progressive

perilymphatic gusher Connective Tissue Osteogenesis imperfecta I : 166200 AD 3.5 :100,000

11 : 166210 1 .6 :100,000 III : 259420' IV : 166220

Stickler 108300 AD 1 :20,000 Sensorineural, conductive, or mixed, progressive

Marshall 154780 AD Sensorineural, conductive, or mixed, progressive

Spondyloephiphyseal 183900 AD 1 :100,000 Sensorineural, conductive, or mixed, dysplasia congenita progressive

Nance-Isley 215150 AR Sensorineural, conductive, or mixed, progressive

Kneist 156550 AD Sensorineural, conductive, or mixed, progressive

Weissenbacher-Zweymuller 277610 AR Sensorineural, conductive, or mixed, progressive

Alport 301050 X-linked or 1 :200,000 Sensorineural progressive 104200 AD

Metabolic Hurler, Scheie (MPS I) 252800 AR 1 :100,000 Conductive or mixed, progressive Hunter (MPS II) 309900 X-linked 1 :100,000 Conductive or mixed, progressive

males?t Sanfilippo (MPS III) 252930 AR 1 :24,000t Conductive or mixed, progressive Morquio (MPS IV) 253000 AR <1 :100,000 Conductive or mixed, progressive Maroteaux-Lamy (MPS VI) 253200 AR rare Conductive or mixed, progressive Sly (MPS VII) 253220 AR rare Conductive or mixed, progressive Alpha-mannosidosis 248500 AR Sensorineural progressive Pendred syndrome 274600 AR 7:100,000 Variable sensorineural, progressive

Mitochondrial Kearns-Sayre 530000 Mitochondrial Sensorineural progressive Hearing loss and diabetes 520000 Mitochondrial 2 kindreds Sensorineural progressive Congenital sensorineural 221745 Mitochondrial 1 kindred Congenital profound sensorineural

hearing loss and AR

Neuromuscular Facioscapulohumeral 158900 AD High-frequency sensorineural

muscular dystrophy progressive Charcot-Marie-Tooth 302800 X-linked Sensorineural progressive

disease with deafness Cowchock disease 310490 X-linked Sensorineural progressive? Jervell and Lange-Nielsen 220400 AR 1 :250,000 Profound congenital sensorineural

Nonsyndromic Dominant progressive high freq : 124800 AD Common Sensorineural progressive

hearing loss mid freq : 124700 low freq : 124900

Recessive congenital I : 220700 AR 1 :5000 to Profound sensorineural deafness 11 : 220800 1 :330

Streptomycin sensitivity 580000 Mitochondrial Sensorineural or AD

. From Buyse (1990), except as noted. tFrom Neufeld and Muenzer (1989) . AD = autosomal dominant ; AR = autosomal recessive .

4


linked albinism and deafness, has been localized to the X chromosome, but the gene product is unknown (Shiloh et al, 1990). Ocular albinism has been associated with deafness, with an auto-somal-dominant congenital form and an X-linked form with late-onset hearing loss .

The association of complete albinism with deafness is less clear. A rare autosomal-reces-sive syndrome of oculocutaneous albinism and congenital deafness was described in an inbred kindred by Ziprkowski and Adam in 1964, but according to McKusick (1992), Fraser (1982) pointed out that the two features may actually be due to two separate recessive genes. Konigs-mark and Gorlin (1976) noted that all other descriptions of total albinism and deafness involved areas of hypo- and hyperpigmenta-tion (and, presumably, migration defects) . Inter-estingly, some forms of albinism are associ-ated with abnormal decussation of optical and auditory pathways (Creel et al, 1980), and both the irides and inner ear show depigmentation, but hearing loss is not a feature. In these con-ditions, melanosomes are present but lack melanin. Thus, the melanin itself is not criti-cal to hearing.

Tietz (1963) described a kindred with a dominant condition of generalized hypopig-mentation and congenital deafness, without ocular symptoms. Although Reed et al (1967) felt this might also be the fortuitous association of two separate conditions, our own ascertain-ment of this same kindred has shown that hypopigmentation of the hair and skin is invari-ably and exclusively found with deafness for at least four generations.

CRANIOFACIAL DISORDERS

T here are a number of disorders of craniofa-cial development that include conductive and/or sensorineural hearing loss . Examples include the craniosynostosis syndromes such as Apert and Saethre Chotzen, branchial arch syn-dromes such as Goldenhar, hemifacial micro-somia, Treacher Collins (see Jahrsdoerfer and Jacobson in this issue [1995]), and branchio-oto-renal, and clefting disorders such as the oto-palato-digital syndromes. Most of these disorders are easily recognized, but the branchio-oto-renal syndrome deserves special notice because of its variability and sometimes very subtle branchial features (auricular and cervical pits or fistu-lae), and the risk of renal malformation. The sig-nificance of earpits in individuals with a family history of hearing loss can be missed in routine

medical evaluations, since earpits alone can be inherited as a dominant trait. The hearing loss can be conductive and/or sensorineural and may be progressive. Renal malformation can be uni-lateral and asymptomatic, so that ultrasound is necessary for detection, or it may be bilateral and lethal . Any combination of the three cardinal fea-tures (branchial, audiologic, and renal) may be present. There has been some dispute as to whether there is a separate earpit-deafness syn-drome without risk for renal problems, and another similar syndrome with ureteral dupli-cation (fancifully nicknamed "BOW" by Fraser et al, 1983) has also been described. Since the gene causing BOR in three large kindreds has been localized to chromosome 8q (Kumar et al, 1992 ; Smith et al, 1992), these questions, as well as the question of heterogeneity within BOR, should be resolved . This syndrome is reviewed in detail by Coppage and Smith in this volume (1995) .

The underlying process accounting for effects on the renal system and inner and middle ears is unknown but appears to involve early cell differentiation and proliferation . There may be an enzyme or structural protein that is critical in the morphologic development or function of all three areas (Melnick, 1980). Identification of the gene product will help to determine the embryologic mechanism.

The X-linked syndrome of stapes fixation and perilymphatic gusher is not really a "cranio-facial disorder." It is a disorder of bone structure involving one small section of bone in the inner ear. As reported by Phelps et al (1991), a defi-ciency or absence of bone at the base of the cochlea results in communication between the subarachnoid CSF of the internal auditory mea-tus and the cochlear perilymph, with the accom-panying risk of perilymphatic gusher during surgery to release the stapes . The gene causing this abnormality has been localized to Xg21 (Bach et al, 1992) and produces a profound mixed loss and vestibular dysfunction in males and a milder loss in females. It is important to rule out this condition in a male with mixed loss before stapes surgery, particularly if the history is compatible with X-linkage. Computed tomography studies as described by Phelps and associates can assess for the clinical abnormal-ity. In addition, genetic studies have shown that some affected males have deletion of this gene that can be detected visually through high-resolution chromosome analysis or through mole-cular studies (Bach et al, 1992; Reardon et al, 1992). If the deletion spans several nearby genes,


a contiguous gene syndrome results that includes the deafness with perilymphatic gusher (Xg21), mental retardation (Xg13-21), and choroide-remia (Xg21.2) (Merry et al, 1989). Thus, the co-occurrence of deafness with choroideremia should automatically lead one to suspect this syn-drome and the attendant risk of perilymphatic gusher. Another form of X-linked deafness does not have the bony abnormality nor increased risk of perilymphatic gusher.

SYNDROMES WITH CONNECTIVE TISSUE INVOLVEMENT

C onnective tissues provide structure, support, and attachment for bones, tendons, liga- ments, and organs . There are two basic compo-nents of connective tissue : collagen, which forms a structure of fibers or networks, and proteo-glycans, which form a more amorphous gel asso-ciated with the collagen matrix . Since connec-tive tissue is found in all parts of the body, it is not surprising that some connective tissue dis-orders affect the auditory system .

Collagen

There are at least 13 different types of col-lagen that form different structures and can be found in different parts of the body. They all have a common structure, starting as a procollagen molecule composed of a rope-like triple-helical coil with globular proteins on each end. The exact composition of the triple helix and reten-tion or cleavage of the globular proteins varies between types. Also, in some types of collagen, the molecules come together to form larger fibers, while others may form sheets or lattice struc-tures (Horton, 1992). The genetic disorders caused by disruption of these molecules vary from minor to quite severe and can involve a number of different systems. Three examples of families of collagen disorders that can include hearing loss are the osteogenesis imperfecta (0I) syndromes; the family of syndromes includ-ing Stickler, Marshall, and spondyloepiphyseal dysplasia; and the Alport syndromes.

Clinically, OI has been divided into four subtypes, and there are subtypes within these. The four basic types are: OI type 1, with blue sclera, fractures occurring in early childhood but improving with age, and sometimes with dentinogenesis imperfecta and hearing loss ; type II, with severe fractures occurring even in utero and heath in the perinatal period ; type III, with more severe fracturing than type I and

progressive deformation on the bones; and type IV, similar to type I but with white sclera (Sil-lence, 1988). As the genes for the different types of collagen have been found, it has turned out that there is no one-to-one correspondence between the gene involved and the clinical type of Ol. All of the known mutations involve type I collagen, the collagen of skin, tendon, and bone, but the triple helix of this collagen is made up of molecules from two separate genes. Two of the helices are of the alpha 1 type (alpha 1[I]), and are from the COLlA1 gene on chromosome 17821, and the other helix, alpha 2(I), is from the COLlA2 gene on chromosome 7821 . Mutations in either of these genes can produce the differ-ent clinical types of OI, depending upon the nature of the mutation and its position in the helix. Hearing loss may occur in subtypes I, III, and IV (whether it occurs in type II is unknown) but is more frequent in types I and IV It is ini-tially conductive but progresses to sensorineural and tends to be more common in the more severe forms of type 101 and in mutations of COLIA1 (Sykes et al, 1990).

Spondyloepiphyseal dysplasia (SED), Stick-ler syndrome, Marshall syndrome, Wagner syn-drome, Kniest syndrome, Nance-Insley syn-drome, and Weissenbacher-Zweymuller syn-drome all have areas of similarity, and there has been considerable controversy as to whether some of these are actually different manifesta-tions of the same disorder. The features of these syndromes are summarized in Table 2. Hearing loss in these syndromes is generally progressive and may be sensorineural or conductive but varies in severity in the different syndromes and between family members (Jacobson et al, 1990b) . Stickler and Marshall syndromes are usually differentiated on the basis of the pro-nounced depression of the nasal bridge and the greater risk for clefting in Marshall syndrome and enlarged joints in Stickler. Wagner syn-drome is usually reserved for individuals with the eye findings of vitreoretinal degeneration without skeletal features . SED congenita and Kniest syndrome have more severe skeletal involvement, resulting in short stature and deformity. Kniest syndrome is a generalized metaphyseal and epiphyseal dysplasia, is more likely to include detached retina and more pro-nounced hearing loss (conductive or sen-sorineural), and has characteristic "swiss cheese cartilage." Platyspondyly and epiphyseal involve-ment are more typical in SED . Weissbacher-Zweymuller syndrome is characterized by short limbs at birth with dumbbell-shaped femurs,


Table 2

Stickler

Collage

Wagner

n Disorders and

Marshall SED

Hearing Loss

Kniest Weissenbacher- Zweymuller

Ocular Myopia + + + Vitreoretinal degen + + + Retinal detachment ++ +/- + rare + Cataracts + + +

Skeletal Dwarfism

(improves) Dysplasia + +

Craniofacial Flat nasal bridge + ++ Midface hypoplasia ++ + Micrognathia/cleft palate + +

Hearing Loss + - +

Inheritance AD AD AD AD AD AR

Nance-Isley

AR

AD = autosomal dominant ; AR = autosomal recessive .

but this improves with time . This may reflect a delayed maturation of collagen . As currently defined, this is a recessive condition without ocular findings . Nance-Insley syndrome is quite rare and is similar to Kniest syndrome but also appears to be recessive. Molecular genetic stud-ies have indicated that some of these syndromes, like the 01 syndromes, may be produced by dif-ferent genes. Kniest syndrome and SED are both produced by mutations in the type II col-lagen, the collagen of cartilage (COL2A1, chro-mosome 12813) . Some families with Stickler syndrome also have mutations in this gene, but others do not; at this time, the other collagen gene or genes involved have not been identi-fied . Similarly, linkage to COL2A1 has been excluded in families with Marshall and Wagner syndromes. It is likely that further genetic het-erogeneity will be found within and between the disorders in this group.

In a completely different mechanism, Helfgott et al (1991) have suggested that an autoimmune process against type 11 collagen may be a cause of acquired progressive deafness; however, other work did not replicate these find-ings (Sutjita et al, 1992). Enzymes involved in the degradation of collagen may also be involved in otosclerosis (McPhee et al, 1991).

Alport syndrome consists of hereditary nephritis, ocular abnormalities, and hearing loss . The most common form is X-linked, with severe manifestations in males and more minor problems in females, but there is also an auto-

somal dominant form . Hematuria in males is often evident in early childhood, especially after infection, and progresses to glomerular nephri-tis, with end-stage renal disease in late teens to early adulthood. The hearing loss is progres-sive and is usually noted in late childhood. The X-linked form has been found to be due to muta-tions in the alpha 5 chain of type IV collagen (COL4A5, Xg22), which forms a lattice structure in the basement membranes of the glomerulus and the cochlea (Barker et al, 1990). The muta-tions produce imperfections in this lattice so that they gradually split. As in 01, however, not all of the mutations in this gene have the same phenotypic effect ; some produce the kidney prob-lems without hearing loss . The mutation(s) caus-ing the autosomal dominant form ofAlport syn-drome have not been identified .

Proteoglycans and Storage Disorders

Proteoglycans aggregate to make the gel "cushion" within the collagen structure. The basic structure is that of a core protein with attached branches of glycosaminogycans, which used to be called mucopolysaccarides (Horton, 1992). Defects in the structure of the molecules making up the proteoglycans appear to produce several syndromes, which include skeletal mal-formation and dwarfism . The disorders involv-ing defects in the enzymes that break down the glycosaminoglycans illustrate another set of syndromes that include deafness, that of the


progressive storage disorders. These disorders, called the mucopolysaccaridoses (MPS), have also shown genetic heterogeneity; different alle-les in the same gene can produce variations in severity, as in the Hurler and less severe Scheie syndromes or the two different types of Hunter syndrome, while the four types of Sanfilippo syndrome are produced by different genes (McKusick, 1992). All are autosomal recessive except for Hunter syndrome, which is X-linked recessive . Diagnosis is by assay for the activity of the appropriate enzymes in leukocytes .

The prototypes of the MPS disorders are the Hunter and Hurler syndromes, which include generalized skeletal deformity (dysostosis mul-tiplex) and dwarfism, corneal clouding, coarse facial features, cardiovascular problems, hear-ing loss, and mental retardation. The other syn-dromes (Scheie, Sanfillipo, Morquio, Maroteaux-Lamy, and Sly) include some or all of these fea-tures to varying degrees. The enzyme defects result in an accumulation of mucopolysaccharide in the lysosomes, and this gradual accumulation accounts for the progressive nature of the phe-notypic features . In the severe forms, death can occur in childhood or adolescence from cardio-vascular or respiratory causes (Gorlin et al, 1990). When hearing loss is present, it is pro-gressive and generally conductive or mixed. Unfortunately, the hearing loss may be over-looked in the syndromes that include mental retardation.

Another group of storage disorders that phe-notypically resemble the MPS syndromes are the oligosaccharidoses, and these may also include hearing loss . Among them is alpha-mannosido-sis, which is an autosomal recessive syndrome . It is progressive but not as severe as Hurler syndrome, and sensorineural hearing loss is common .

PENDRED SYNDROME

P endred syndrome is another autosomal recessive metabolic disorder with deafness as a primary feature. It is characterized by sen-sorineural hearing loss, often (if not always) with Mondini malformation of the cochlea and enlargement of the thyroid gland (Fraser, 1965). Both the hearing loss and the thyroid enlarge-ment can be variable, however. The hearing loss may be congenital and profound or it may be pro-gressive, occasionally related to trauma or other symptoms of round window fistula. Cases of mild or unilateral hearing loss have also been described, and in at least three cases a Mondini-

type malformation was found with normal hear-ing (Johnsen et al, 1989). There also may be vestibular involvement (Johnsen et al, 1987). Increase in thyroid size may not appear until late childhood, or it may not be present at all. Thy-roid levels are usually normal but may be low. The metabolic defect is in the binding of iodine to the thyroid hormone, but the defective enzyme is not known. The defect can be detected by the perchlorate discharge test, which involves mea-surement of the uptake of radioactive iodine ; however, it may be normal in individuals known to have the syndrome (Johnsen et a1,1989) . Inter-estingly, these authors found increased perchlo-rate discharge in some apparent heterozygotes and suggested that the disorder might more prop-erly be considered a dominant . This is an inter-esting idea in view of the variability in families, which is more typical of a dominant condition. Because of the difficulty in diagnosis, the fre-quency of the disorder is not clear, but it may be quite common among cases of hereditary deafness (Konigsmark and Gorlin, 1976), and even more so when milder hearing losses are considered .

Based on the case of a girl with an unbal-anced translocation and features of Pendred syndrome (along with mental retardation), van Wouwe et al (1986) suggested that the gene may be on chromosome 8q, in the region of the thy-roglobulin gene . A mutation in that gene has been found to result in goiter and hypothy-roidism but not deafness (Ieiri et al, 1991); how-ever, it is still possible that another mutation in this gene causes Pendred syndrome . Definition of the gene may be of great help in establishing appropriate diagnostic criteria and mode of inheritance for the syndrome .

The mechanism relating thyroid hormono-genesis and Mondini malformation is also unknown. Lowering of thyroid levels with antithyroid medications can produce cochlear malformations in animals (Bargman, 1967), but there is no evidence for hypothyroidism in utero in Pendred syndrome (Dumont et al, 1989), so it appears likely that thyroid levels themselves are responsible.

DISORDERS OF MITOCHONDRIAL DNA

R ecently, a different sort of metabolic dis-order has been described . Mitochondria are intracellular organelles that serve as "energy factories," performing oxidative phos-phorylation . Oxidative phosphorylation involves a series of enzyme reactions, and the code for 13 of these enzymes is contained in a


small circle of DNA carried in the mitochondria itself. This unique extranuclear genome results in disorders with very interesting properties . There can be hundreds of mitochondria in cells with high energy requirements, and mutation in the mitochondrial DNA may be mosaic, that is, not all of the mitochondria in a cell may carry the mutation . While the decreased effi-ciency of energy production by the mutant mitochondria is detrimental to the cell, the mutant DNA may actually enjoy a replication advantage over the normal DNA, so that mutant mitochondria proliferate . The accu-mulated mitochondria stain red, resulting in the "ragged red fibers" seen on muscle biopsy. The level of mosaicism between individuals and between tissues in the same individual leads to phenotypic differences, even between individuals with the same mitochondrial dele-tion . Furthermore, as the mitochondria accu-mulate mutations normally in the aging process, the effects of a population of congen-itally mutant mitochondria can be magnified, leading to a progressively more severe disor-der (Shoffner and Wallace, 1992). The Kearns-Sayre syndrome demonstrates many of the features that can be seen in mitochondrial dis-orders, including neuromuscular involvement with ataxia, cardiomyopathy, and ophthalmo-plegia, along with retinal disorders and pro-gressive hearing loss .

Mitochondria are transmitted to offspring primarily through the cytoplasm of the egg; sperm carry few mitochondria . This leads to a unique maternal pattern of inheritance. Males and females are equally affected, but there is no transmission of the disorder through affected males. In addition, some cases of Kearns-Sayre syndrome are autoso-mal recessive, presumably due to defects in the mitochondrial enzymes coded for in nuclear DNA.

While most mitochondrial disorders are recognizable by the myopathies they produce, there have been two recent reports of disorders of hearing loss that do not include myopathy. In one family, hearing loss and diabetes were related to a large deletion in mitochondrial DNA that was mosaic (heteroplasmic) in a mother and all of her children by two differ-ent fathers. She had two grandchildren; one, the offspring of one of her daughters, appeared to be affected, while the other, through a son, was unaffected (Ballinger et al, 1992). In another report of a very large inbred kindred spanning five generations, isolated congenital

sensorineural hearing loss was consistent with a combination of a mitochondrial mutation and a recessive gene (Jaber et al, 1992). These reports widen the possible phenotypes that may be due to mitochondrial DNA mutations.

NEUROMUSCULAR. DISORDERS

F acioscapulohumeral muscular dystrophy is a slowly progressive form of muscular weakness that starts in the face and shoulder girdle and gradually includes the legs and pelvic gir-dle. It is quite variable, ranging in severity from an infantile type to mild disability to barely noticeable symptoms . High-frequency progres-sive sensorineural hearing loss is also part of the syndrome, which may onset before the neuro-muscular symptoms, and torturous retinal ves-sels are found that may reflect an increased risk for Coats' disease (exudative retinopathy) (Voit et al, 1986). It is an autosomal dominant condition, and nearly all of the people carrying the gene show some neuromuscular expression of it by age 20 . It has been localized to chromo-some 4835, and Wijmenga et al (1992) found that the mutation was a deletion within a region of tandem repeats, that is, a section of DNA within which pairs of the nucleotides cytosine and adenine (CA) were repeated . Tandem repeat regions have gained much interest lately, since amplification of similar repeats has been found in Fragile X syndrome, myotonic dystrophy, and Kennedy disease (Caskey et al, 1992). Fischbeck and Garbern (1992) also suggested that the gene could be a homeobox gene, one of a class of genes conserved in evolution to define anterior to pos-terior differentiation . A "gradient" effect could explain the progression of the disease down through the body. The nature of the defect, and the link between the cochlear hearing loss and the muscle disorder, is unknown. Carroll and Brooke (1979) suggested that pathology of the stapedial muscle might compromise the protec-tive effects of the stapedial reflex and result in cumulative noise damage to the cochlea.

Charcot-Marie-Tooth disease (CMT) is actu-ally a group of disorders of peripheral neuro-pathy, characterized by progressive weakness and wasting of the muscles and decreased sen-sation, usually pronounced first in the peroneal muscles and then the distal muscles of the feet and legs . There are at least two dominant forms of the disorder, one due to duplication of the peripheral myelin protein gene on chromosome 17 (Patel et al, 1992) and another localized to chromosome 1 (Bird et al, 1982). There are also


autosomal recessive and as many as three X-linked forms. Symptoms of peroneal weakness, ankle weakness, and foot contracture deformi-ties usually begin in late childhood to early adolescence and gradually progress to the legs and hands. Deafness can also be associated with CMT, again with autosomal dominant, recessive, and X-linked forms. One of the X-linked forms of CMT and deafness, Cowchock disease, localizes to the region of X-linked CMT at Xg13, although it is not clear whether they are allelic (Fischbeck et al, 1987). This syn-drome is more severe, has earlier onset, and also involves mental retardation. Interestingly, as mentioned above, the gene for mixed deafness with perilymphatic gusher has been localized to Xg21, just proximal to the choroideremia gene, and small deletions of this region have been seen in patients with this type of hearing loss (Rear-don et al, 1992). With this in mind, the CMT with deafness syndrome could be a contiguous gene-deletion syndrome encompassing CMT and the perilymphatic gusher gene . A deletion also could account for the greater severity of CMT in Cowchock disease and the associated mental retardation . Alternatively, the syndrome could be due to a more severe allele of the X-linked CMT gene or a separate gene . If it is a single gene disorder, a common feature of neural conduction or transmission in the neuromus-cular and cochlear systems could be sought to account for the peripheral neuropathy and the hearing loss .

Jervell and Lange-Nielsen (JLN [cardio-auditory]) syndrome is defined as an autosomal recessive condition combining congenital deaf-ness with disorders of cardiac rhythm, partic-ularly prolongation of the QT wave (long QT) as seen on EKG. Episodes of arrhythmia can result in dizziness, fainting, and even sudden death, especially in instances of sudden rage or fright . The deafness is usually profound, par-ticularly in the high frequencies (Fraser et al, 1964 ; Jacobson et al, 1990a) . The cardiac arrhythmia is treatable either medically or surgically ; in view of the life-threatening nature, it is important that the diagnosis be rec-ognized as soon as possible, and Cusimano et al (1991) have recommended that all children with congenital deafness that could fit an auto-somal recessive etiology have an EKG to screen for this disorder.

Just as there are syndromes of CMT with and without deafness, there is an autosomal dominant syndrome, the Long QT (LQT) syn-drome (also called Romano-Ward syndrome),

which has EKG findings similar to JLN. The LQT syndrome can be quite mild or even asymptomatic in expression, requiring EKG for detection. Interestingly, although JLN is thought to be recessive, parents and other rel-atives are sometimes reported to have abnor-mal EKGs (Fraser et al, 1964). Of four patients reported by Cusimano et al (1991), one had a deaf sister who had a normal EKG, and another, who had a positive family history of deafness and EKG abnormalities, had a parent who had LQT without deafness . We have also seen a patient with characteristics of JLN with repeated fainting episodes who had a mother and maternal uncle with asymptomatic long QT found on EKG. Also, Moss et al (1991) have reported that about 7 percent of family mem-bers with LQT have hearing loss . Thus, there are several possibilities : some cases of JLN are coincidental cases of recessive deafness and dominant LQT; JLN is due to a separate recessive locus, but heterozygous carriers for JLN are at risk for LQT; JLN is the expression of homozygosity for a known dominant LQT gene ; or deafness is a pleiotropic effect of a dominant LQT gene . One gene for the LQT syndrome has been localized to the HRAS gene region (if not the gene itself) on chromosome 11p (Keating et al, 1991), but this has been excluded as the location of JLN (Jeffery et al, 1991). However, subsequent observations have shown that not all families show the linkage of LQT to HRAS (Jiang et al, 1994), so another LQT locus could be related to the JLN. It is impor-tant to determine the appropriate mode of inheritance for this syndrome so that the risk for full expression of the arrhythmia can be known. Also, as in the CMT deafness syndrome, determination of a contiguous gene syndrome versus a single gene syndrome would tell whether there is a common mechanism behind the cardiac and cochlear effects.

NONSYNDROMIC HEARING LOSS

R ecognition of the correct etiology of hear-ing loss is most difficult in isolated cases

of nonsyndromic hearing loss . If only one indi-vidual in a family has congenital deafness, with no other features of a syndrome, the cause could be autosomal recessive inheritance, autosomal dominant new mutation, autosomal dominant inheritance with nonpenetrance or gonadal mosaicism in a parent, or X-linked inheritance or mutation in the case of a male . Alternatively, there would be about a 50 percent chance that

10


the cause could be nongenetic . A test to detect the presence of a gene could tell the family the appropriate mode of inheritance and possibly lead to therapy if the action of the gene was known. However, genes causing nonsyndromic deafness will be very difficult to identify because of genetic heterogeneity. In the recessive con-ditions alone, there may be about 20 fairly com-mon loci with indistinguishable phenotypes and many more rare ones (Morton, 1991). Studies of isolates, inbred populations, or large kin-dreds can help reduce the heterogeneity so that at least a few of these genes can be localized (Morton, 1991) . Another approach is homozy-gosity mapping of the affected offspring of con-sanguineous parents (Duyk et al, 1992). In this technique, candidate loci are those that are homozygous and for which the alleles are iden-tical by descent, that is, both alleles in the pair are actually copies of one allele carried by an ancestor common to both parents. If there are multiple affected family members, the number of candidate loci would be greatly reduced by identifying only the loci that fulfill those crite-ria in all affected members. Finally, the use of mouse models to identify candidate genes for hearing loss would increase the efficiency of the above procedures (Brown et al, 1991) . Knowledge of the function of just a few genes causing nonsyndromic hearing loss could have a cascading effect once their action is under-stood, since other genes with related functions would become candidates for the other types.

Dominant Progressive Hearing Loss

lies showed the rapid progression of loss seen in the Costa Rican kindred (Smith et al, 1992). Identification of the genes responsible for pro-gressive hearing loss may provide the clues needed to determine the pathologic processes and, hopefully, the means to counteract them.

Susceptibility to Hearing Loss

The genes that cause some syndromes are characterized by reduced penetrance for hear-ing loss, that is, hearing loss is not present in every person who carries the gene . Presum-ably, this variation is due in part to other alle-les at the same or other loci, unidentified non-genetic influences, and random variations in development.

This demonstrates the fine line between single gene inheritance and multifactorial inher-itance . Documentation of single genes that con-fer susceptibility to nonsyndromic hearing loss will be difficult until the other influencing fac-tors have been identified . Increased susceptibility to the ototoxic effects of streptomycin appears to be an example of this type of inheritance. It has been reported to be due to a dominant gene in some families (Viljoen et al, 1983). Mito-chondrial inheritance was suggested by studies done by Hu et al (1991) and has recently been confirmed by the finding of a mutation in mito-chondrial DNA by Prezant et al (1993) . Other possible examples could be increased suscepti-bility to noise damage or to viral embryopathy. Identification of these factors could help develop ways to prevent damage by such agents .

Dominant progressive hearing loss (DPHL) is, as the name tells, a dominant disorder of late-onset progressive hearing loss . In contrast to otosclerosis, it is defined as a strictly sen-sorineural loss . There is considerable inter-family variability, with differences in the age of onset, rate of progression, and frequencies first affected (Konigsmark and Gorlin, 1976). This suggests that there is genetic heterogeneity. A gene causing one form of DPHL, Monge deafness, has been localized to chromosome 5831 in a large kindred from Costa Rica (Leon et al, 1992). This disorder has a relatively early onset, around 10 years of age, and starts in the low frequen-cies . It is rapidly progressive, so that affected individuals have profound loss across all fre-quencies by age 30 . This linkage was rejected in three other families with DPHL, but although the hearing loss in two of the families involved the low frequencies initially, none of the fami-

CONCLUSION

T he complexity of the auditory system is reflected by the many ways in which its

structure and function are affected by genes. For example, genes causing syndromes such as Pendred syndrome, Waardenburg syndrome, or branchio-oto-renal syndrome affect early embry-onic development of the structures of the mid-dle and/or inner ear; collagen disorders affect the integrity of these structures ; storage diseases interfere with the metabolism of the cells ; neuro-logic disorders such as Charcot-Marie-Tooth may affect the transmission of impulses to the brain stem; otosclerosis and neurofibromatosis can create physical obstructions to the trans-mission of sound; and other genes may enhance the destructive effects of environmental influ-ences. Some genes appear to be only crucial to the auditory system, and their deficiency pro-


duces isolated hearing loss . Other gene products are active in pathways in other systems and create genetic syndromes. Some syndromes may not be the result of damage to a common path-way but may just be the result of proximity of separate genes. Still other syndromes may be caused by mitochondrial rather than chromo-somal genes. A number of approaches are avail-able to localize and characterize these genes at the phenotypic and molecular levels, with the ultimate goal of understanding the mechanisms of their effects on the auditory system .

Acknowledgment. This work was supported by NIH-NIDCD Research and Training Center Grant P60 D000982, Project III.

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