Учебники / Genetics and Auditory Disorders Keats 2002

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(Figure caption followed on pp. 124–125)

124 A.J. Griffith and T.B. Friedman

FIGURE 6.1. Diagram of a normal male karyotype (46,XY) showing the location of the centromeres, the chromosome arms (short or p-arm and long or q-arm) and the major Giemsa-bands. The autosomes are numbered from 1 to 22. The designations for DFNA loci are shown as A1 to A36, while DFNB loci are shown as B1 to B28. The symbols for syndromic and nonsyndromic hearing loss loci that have been identified are underlined. When the same gene has been identified with mutant alleles associated with more than one syndrome and/or more than one nonsyndromic locus, the loci are separated by a slash (/). Loci separated by a comma map to a similar chromosomal interval. Notice that loci for syndromic and nonsyndromic deafness are found on all the autosomes and X-chromosome. The gene symbols for the syndromic deafness loci are listed in Table 6.5, along with a brief description of the phenotype. ACS1, Apert syndrome; ACS5, Pfeiffer syndrome; ADFN, Albinismdeafness syndrome; AGU, Aspartylglucosaminuria; ALD, Adrenoleukodystrophy; ALSS, Alström syndrome; BJS, Bjornstad syndrome; ATS, X-linked Alport syndrome; BOR, Branchio-oto-renal syndrome; BOR2, Branchio-otic syndrome with commissural lip pits; BOS, Branchio-otic syndrome; BTD, Biotinidase deficiency; CCD, Cleidocranial dysplasia; CDHS, Craniofacial-deafness-hand syndrome; CFD1, Crouzon syndrome; CLS, Coffin-Lowry syndrome; CMDJ Craniometaphyseal dysplasia, Jackson type; CMT1A, Charcot-Marie-Tooth disease, type 1A; CMT1B, Charcot-Marie-Tooth disease, type 1B; CMT2, Charcot-Marie-Tooth disease, type 2; CMT4A, Charcot-Marie-Tooth disease, type 4A; CMT4B, Charcot-Marie- Tooth disease, type 4B; CMTX, Charcot-Marie-Tooth disease, X-linked dominant; CMTX2, Charcot-Marie-Tooth disease, X-linked recessive; CSA, Cockayne syndrome, type I/A; CSB, Cockayne syndrome, type II/B; dRTA, Renal tubular acidosis with sensorineural deafness; DGS, DiGeorge syndrome; DGS2, DiGeorge syndrome; EEC1, Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, type I; EEC2, Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, type II; FGS, FG syndrome; FRDA, Friedreich ataxia type I; GALC, Krabbe disease; GJB3, gap junction protein b-3; GLA, Fabry disease; GUST, Gustavson syndrome; HMSN IV, Refsum disease; HMSNL, Hereditary motor and sensory neuropathy, Lom type; HYP1, Hypophosphatemia Type I; HYP2, Hypophosphatemia Type II; IDS, Hunter syndrome; IDUA, Hurler syndrome; IRD, Refsum disease, infantile form; JLNS1, Jervell and Lange-Nielsen syndrome; JLNS2, Jervell and LangeNielsen syndrome; KHM, Vohwinkel syndrome, classic form; KAL1, Kallmann syndrome; LOR, Vohwinkel syndrome, variant form; MANB1, Beta mannosidosis; Marshall, Marshall syndrome MFS1, Marfan syndrome; MFS2, Marfan syndrome; MTS, Mohr-Tranebjaerg syndrome, Jensen syndrome; ND, Norrie disease; NEU, Sialidosis; NF2, Neurofibromatosis type 2; NPC, Niemann-Pick type C disease; NS1, Noonan syndrome; OASD, Ocular albinism with sensorineural deafness; OFD1, Orofaciodigital syndrome, type 1; OI, Osteogeneis imperfecta; OPD1, Otopalatodigital syndrome, type I; OPTA2, Osteopetrosis type II; OPTB1, Osteopetrosis; OSMED, Chondrodystrophy with sensorineural deafness; OTS, otosclerosis; PBT, Piebaldism; PDB1, Paget disease; PDB2, Paget disease; PDS, Pendred syndrome; SCS, Saethre-Chotzen syndrome; SEDC, Spondyloepiphyseal dysplasia congenita; SMS, Smith-Magenis syndrome; STL1, Stickler syndrome; STL2, Stickler syndrome; STL3, Stickler syndrome; SYM1, Symphalangism; SYNS1, Multiple synostoses syndrome; TBS, Townes-Brocks syndrome; TCOF1, Treacher Collins’ syndrome; TIETZ, Tietze’s syndrome; TSD, Tay-Sachs disease; USH1A, Usher syndrome type 1A; USH1B, Usher syndrome type 1B; USH1C, Usher syndrome type 1C; USH1D,

Usher syndrome type 1D; USH1E, Usher syndrome type 1E; USH1F, Usher syndrome type 1F; USH2A, Usher syndrome type 2A; USH2B, Usher syndrome type 2B; USH3, Usher syndrome type 3; VBCH, van Buchem disease; VCFS, Velocardiofacial syndrome; WFS, Wolfram syndrome; WS1, Waardenburg syndrome type 1; WS2, Waardenburg syndrome type 2; WS3, Waardenburg syndrome type 3; WS4, Waardenburg syndrome type 4; XPA, Xeroderma pigmentosum.

component (Fischel-Ghodsian 1998). Since hearing loss can be acquired, it is to be expected that, among hearing impaired members of a large family with a high incidence of deafness, some individuals may have hearing loss due to a nongenetic cause. These individuals are said to be phenocopies (Hadorn 1961). Audiological evaluations may not be able to distinguish between hereditary and acquired deafness, in which case the information derived from a thorough clinical history is invaluable.

The ongoing identification and inevitable elucidation of the functions of the genes for hearing loss provides entry points toward an integrated understanding of auditory system structure, function, and development. From a public health perspective, the insights gained from molecular genetic studies may guide the development of strategies to slow the rate of progressive hearing loss. Even without specific medical treatment, knowledge of impending hearing loss allows timely speech and communication rehabilitation. It is also anticipated that results of genetic tests will be used to counsel individuals who are at risk for hearing loss.

2. Classification and Evaluation of Hearing Loss

2.1 Audiometric

Pure-tone audiometry can be used to classify hearing loss as conductive, sensorineural, or mixed, which is a combination of conductive and sensorineural. Conductive hearing loss is associated with pathology affecting any of the anatomic components that mechanically transduce sound to the cochlea. Thus, abnormalities of the external ear, ear canal, tympanic membrane (eardrum), ossicles, oval window (the interface of the ossicular chain with the cochlea), round window, or middle ear space may cause conductive hearing loss. Sensorineural hearing loss may be associated with dysfunction of any of the components of the auditory pathway that convert the physical stimulus of sound into an electrical stimulus that is transmitted to the auditory cortex. Sensorineural hearing loss may therefore be caused by lesions of the cochlea, auditory (cochlear; eighth cranial) nerve, auditory brainstem, or even higher order auditory structures within the brain.

The severity of hearing loss is also routinely categorized. Measured puretone hearing thresholds may be used to classify hearing loss as mild (26 to

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40 dBHL), moderate (41 to 55 dBHL), moderately severe (56 to 70 dBHL), severe (71 to 90 dBHL), or profound (greater than 90 dBHL). Thresholds less than 25 dBHL are considered normal. The degree of hearing loss is often not uniform across the tested frequencies (typically 250 Hz to 8 kHz). For example, there may be normal hearing at low and middle frequencies, with severe hearing loss at high frequencies. This type of hearing loss is described as high-frequency or down-sloping sensorineural hearing loss, since the line connecting the pure-tone threshold levels slopes down in the higher frequencies, which are recorded on the right side of an audiogram. Sensorineural hearing loss may also be low-frequency or up-sloping (Lesperance et al. 1995), or it may be U-shaped, predominantly affecting middle frequencies. A flat audiogram refers to relatively similar thresholds across the tested frequencies.

Figure 6.2 illustrates several of the many possible distinct audiometric patterns of hearing loss. These descriptions provide concise and useful categorizations of audiometric findings, but in practice many audiograms do not fit neatly into any one category. Furthermore, the degree and type of hearing loss between two ears of a given patient may be asymmetric. In a family segregating a gene causing hearing loss, subjective evaluations of audiometric data are sometimes required to distinguish between an affected and an unaffected individual. This distinction needs to be made before genotyping begins, since mistakes in assigning affection status can jeopardize a genetic analysis, particularly in families with progressive or late-onset deafness. Based on data of hearing thresholds of ageand sexmatched normal-hearing individuals, Govaerts and coworkers (1998) have proposed an algorithm to more objectively differentiate between affected and unaffected persons. Furthermore, ageand sex-specific reference ranges for hearing levels and longitudinal changes are available for a Caucasian population of 681 men and 416 women (Morrell et al. 1996). The subjects were rigorously screened for otological disorders and noise exposure in order to remove these confounding variables and provide a normative data set.

2.2 Clinical

It is important to distinguish between syndromic and nonsyndromic hearing impairment. Specifically, it should be noted whether the hearing loss is inherited in association with any other disorders or abnormalities, even if they do not fit neatly into any previously described syndromes. An additional distinction regards the onset of hearing loss, which is often described in relation to the development of speech because adequate auditory function is important for the development of spoken language. Hearing impairment occurring prior to speech development is called prelingual, whereas that occurring after speech development is called postlingual. Given the wide range of age of onsets of postlingual hearing loss, this term is impre-

cise and, for most purposes, probably best replaced by a simple description of age of onset (e.g., onset in adolescence, third decade, etc.).

Except in cases of congenital profound deafness, the temporal course of the hearing impairment is also described. Hearing loss may be stable or progressive, and progression is often observed in association with dominant inheritance of hearing loss (Table 6.1). Fluctuation may be present in other types of hearing loss, such as that associated with recurrent otitis media or Meniere’s disease (see DFNA9, 3.7.2). Fluctuating or incremental hearing loss may also be associated with head trauma or congenital inner ear malformations such as Mondini dysplasia or enlarged vestibular aqueducts, or a combination of these two factors (Jackler and De La Cruz 1989; Levenson et al. 1989; Schuknecht 1980). These inner ear malformations sometimes have a genetic basis, as there have been several reports of familial cases (Abe et al. 1997; Chan et al. 1991; Griffith et al. 1996; Griffith et al. 1998).

2.3 Temporal Bone Histopathology

Inner ear neurosensory tissue for histologic examination is almost never accessible in the living patient. Therefore, histopathologic studies of postmortem human temporal bone specimens can be helpful for correlating anatomic and histologic findings with clinical observations in the myriad disorders affecting auditory and vestibular function (Schuknecht 1993). However, it has been difficult to derive broad conclusions about the pathogenesis of hereditary hearing loss due to the paucity or absence of specimens for many of the disorders, as well as artifactual changes arising from delayed or inadequate preservation of the specimens.

FIGURE 6.2. Pure-tone audiograms: (A) Bilateral conductive hearing loss associated with bilateral otitis media; (B) Bilateral high-frequency sensorineural hearing loss due to noise exposure, demonstrating a typical “noise notch” at 4,000 Hz; (C) Unilateral moderate to profound sensorineural hearing loss in a patient who received intratympanic gentamicin (aminoglycoside therapy); (D, E, F) Differing patterns of sensorineural hearing loss in three affected members of a single kindred segregating Waardenburg syndrome. Panel D illustrates a unilateral low-frequency hearing loss, panel E illustrates a symmetric, fairly flat mild to moderate loss, and panel F shows a profound right-sided loss with a left-sided, mild to moderate high-frequency loss. SRT is the speech reception threshold, the softest level at which a person can understand 50% of spoken words. SDS is the speech discrimination score, the percentage of word stimuli that are perceived correctly. Although bone conduction thresholds are not shown in B and E, previous audiometric evaluations on these patients had demonstrated that the hearing loss was sensorineural, with no significant difference between boneand air-conduction thresholds. Reliable speech discrimination scores were not obtained as part of the evaluations shown in C and E due to the young age of the patients.

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