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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. MT-RNR1 (encoding mitochondrial 12S ribosomal RNA) and MT-TS1 (encoding mitochondrial transfer RNA serine 1) are the two genes currently known to be associated with nonsyndromic mitochondrial hearing loss and deafness. Targeted mutation analysis and sequence analysis can be used to identify mutations in the two genes. Such testing is clinically available.
Management. Treatment of manifestations: appropriate rehabilitation (hearing aids, speech therapy, culturally appropriate language training, cochlear implantation, educational programs for the hearing impaired). Prevention of primary manifestations: avoidance of aminoglycosides. Surveillance: annual audiometric assessment to evaluate stability/progression of hearing loss. Agents/circumstances to avoid: aminoglycosides and noise exposure, especially in those with normal hearing who have the 1555A>G mutation in MT-RNR1. Testing of relatives at risk: testing maternal relatives for the 1555A>G mutation to identify those who should avoid use of aminoglycosides.
Genetic counseling. Nonsyndromic mitochondrial hearing loss and deafness is caused by mutations in mitochondrial DNA (mtDNA) and is transmitted by maternal inheritance. The father of a proband does not have the deafness-causing mtDNA mutation. The mother of a proband (usually) has the mtDNA mutation and may or may not have hearing loss. All offspring of females with an mtDNA mutation are at risk of inheriting the mutation. Offspring of males with an mtDNA mutation are not at risk of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mtDNA mutation in the family is known. Because of mitotic segregation, the mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues. Furthermore, the presence of the mtDNA mutation does not predict the age of onset or severity of hearing loss.
Nonsyndromic mitochondrial hearing loss and deafness is diagnosed with certainty in an individual with the following:
Moderate to profound hearing loss. Hearing loss graded by level of severity:
Mild (26-40 dB)
Moderate (41-55 dB)
Moderately severe (56-70 dB)
Severe (71-90 dB)
Profound (90 dB)
Hearing is assessed by a variety of methods; see Hereditary Hearing Loss and Deafness Overview.
No other systemic findings on history or physical examination
A mutation in either the MT-RNR1 gene encoding mitochondrial 12S ribosomal RNA (12S rRNA) or the MT-TS1 gene encoding mitochondrial transfer RNA serine 1 [tRNA-Ser(UCN)].
Nonsyndromic mitochondrial hearing loss is suspected in individuals with moderate-to-profound hearing loss when one of the following is present:
A family history of hearing loss suggestive of maternal inheritance (i.e., no transmission by a male)
Onset of hearing loss following administration of an aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin [Bates 2003]
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genes. MT-RNR1 and MT-TS1 are the two genes currently known to be associated with nonsyndromic mitochondrial hearing loss and deafness.
Clinical testing
Targeted mutation analysis and sequence analysis can be used to identify the following specific mutations known to be associated with nonsyndromic mitochondrial hearing loss and deafness:
MT-RNR1. 961delT+(C)n [Casano et al 1999]; 1555A>G
MT-TS1. 7443A>G, 7444A>G, 7445A>G/C, 7510T>C, 7511T>C [Sevior et al 1998, Pandya et al 1999, Hutchin et al 2000, del Castillo et al 2002].
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency 1, 2 | Test Availability |
|---|---|---|---|---|
| MT-RNR1 | Targeted mutation analysis | 1555A>G | 21% | Clinical
 |
| 961delT+(C)n | 50% | |||
| Sequence analysis | Other MT-RNR1 sequence variants | <1% | ||
| MT-TS1 | Targeted mutation analysis | 7443A>G | 14% | Clinical
|
| 7444A>G | ||||
| 7445A>G | ||||
| Sequence analysis | Other MT-TS1 sequence variants | 15% |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To confirm the diagnosis in a proband
If hearing loss has followed aminoglycoside exposure, test for mutations in the MT-RNR1 gene.
In a familial case involving matrilineal inheritance with no aminoglycoside exposure, test both the MT-RNR1 and MT-TS1 genes.
Presymptomatic diagnosis to identify relatives at risk for aminoglycoside ototoxicity requires prior identification of the disease-causing mutation in the family.
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.
For other phenotypes associated with mutations in mitochondrial DNA, see Mitochondrial Disorders Overview.
Aminoglycoside ototoxicity. A single base-pair substitution from A to G at nucleotide 1555 that is homoplasmic (present in all mitochondria of a cell and/or tissue) predisposes an individual to hearing loss caused by aminoglycoside exposure.
Hearing loss occurs within a few days to weeks after administration of any amount (including a single dose) of aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin [Bates 2003].
Hearing loss is bilateral and severe to profound. Once it appears, hearing loss is irreversible but not progressive. Hearing loss associated with the 1555A>G mutation results from hair cell dysfunction and hence is cochlear in nature [Bravo et al 2006].
Vestibular symptoms are uncommon.
Note: Aminoglycoside ototoxicity secondary to presence of a predisposing mtDNA mutation appears to be related to administration of aminoglycosides (independent of dose) in contrast to "dose-related" aminoglycoside ototoxicity that is related to the dose and/or plasma concentration of aminoglycosides in individuals who do not have a predisposing mtDNA mutation.
Sensorineural hearing loss independent of aminoglycoside exposure. The median age of onset of sensorineural hearing loss in individuals who have a mutation in MT-RNR1 but are not exposed to aminoglycosides is around age 20 years [Estivill et al 1998]. For an individual with the 1555A>G substitution who is not exposed to aminoglycosides, the probability of developing hearing loss is about 40% by age 30 years [Estivill et al 1998]. Thus, other as-yet unknown genes (possibly the mitochondrial haplotype or a major modifying nuclear gene) and/or environmental factors influence penetrance and age of onset of hearing loss in these individuals [Bykhovskaya et al 2001, Johnson et al 2001]. A small percent of individuals with the 1555A>G mutation who did not develop hearing loss had subclinical findings of a lower amplitude of response to DPOAE, indicating a deficit in cochlear physiology [Bravo et al 2006].
Other. Although hearing loss associated with MT-RNR1 is considered nonsyndromic, a constellation of digital, spinal, and pigmentary disturbances has been reported in a family with the 1555A>G substitution. Pigmentary findings in family members included development of gray hair with a salt-and-pepper distribution in teenagers and hypopigmented skin patches ranging in size from 2 to 10 cms on the wrist, knee, and groin [Nye et al 2000]. The correlation between the mitochondrial substitution and the presence of pigmentary changes remains unclear.
Sensorineural hearing loss. The different MT-TS1 mutations associated with sensorineural hearing loss are heteroplasmic (i.e., both wild-type and mutant mtDNA are present in a cell and/or tissue). (See Mitochondrial Disorders Overview.)
Age of onset of sensorineural hearing loss is during childhood [Sevior et al 1998, Pandya et al 1999, Hutchin et al 2001]. The severity of hearing loss is highly variable, ranging from mild to severe. Progression in the severity of hearing loss is characteristic.
Other. Although hearing loss associated with MT-TS1 is considered nonsyndromic, the 7445A>G substitution is associated in some families with palmoplantar keratoderma in addition to hearing loss. The skin changes can appear as early as age four to five years and consist of scaling, hyperkeratosis, and honeycomb appearance of the skin of the palms, soles, and heels [Sevior et al 1998]. Callus formation occurs on the heels and toes. Hyperkeratosis of palms with erythema is reported in a few individuals; marked variability in the severity and extent of involvement is characteristic. Individuals who have both the 7444A>G and 1555A>G mutations or the 7443A>G mutation alone do not have skin findings.
See Clinical Description.
MT-RNR1
The 1555A>G mutation occurs as a homoplasmic change; hence the penetrance of hearing loss is 100% in those with the mutation who receive aminoglycoside antibiotics (i.e., all individuals with this mutation will become deaf with any amount of aminoglycoside in a single dose).
In individuals who have the mutation but are not exposed to aminoglycoside antibiotics, the penetrance for hearing loss is approximately 80% by age 65 years.
Note: It has been suggested that penetrance for hearing loss is lower in some families from China [Young et al 2005].
MT-TS1. The mutations are heteroplasmic; therefore, the severity of hearing loss and age of onset vary depending on the mutational load in an individual.
MT-RNR1. Hearing loss caused by the 1555A>G substitution in the MT-RNR1 gene has been observed worldwide, e.g., in the Arab-Israeli, Japanese, Mongolian, Zairean, Spanish, Chinese, Turkish, and Balinese populations [Jaber et al 1992, Hutchin et al 1993, Matthijs et al 1996, El-Schahawi et al 1997, Pandya et al 1997, Usami et al 1997, Malik et al 2003, Tekin et al 2003, Yuan et al 2005, Mkaouar-Rebai et al 2006, Wang et al 2006].
The prevalence of the 1555A>G mutation varies by population:
Between 20% and 30% in deaf individuals from Spain and Asia
Fifteen percent of all individuals with hearing loss and a history of aminoglycoside administration [Fischel-Ghodsian et al 1997]
Three of 955 (0.3%) deaf probands ascertained throughout the US [Arnos et al 2003]
Six percent of postlingual hearing loss in deaf probands form the UK and souther Italy [Jacobs et al 2005]
Seventeen percent in deaf probands from Spain [Bravo et al 2006]
The prevalence of the 961delT+(C)n mutations in deaf probands has not yet been determined; screening of anonymized blood spots from newborns in the state of Texas revealed a prevalence of approximately 1% [Tang et al 2002].
MT-TS1. The prevalence of mutations, especially in the 3' end of the precursor, is 0.8-1.1% in deaf probands studied from the United States and from Mongolia [Arnos et al 2003]. A Japanese family with the 7511T>C mutation has been reported [Li et al 2005].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Other genetic causes of nonsyndromic hearing loss and deafness need to be considered (see Hereditary Hearing Loss and Deafness Overview).
Aminoglycoside drug toxicity. The hearing loss seen after use of aminoglycosides in individuals without the MT-RNR1 mutations 961delT+(C)n or 1555A>G results from drug toxicity and is related to the dose administered and the metabolism of the drug (i.e., the peak and trough serum concentrations).
Maternally inherited diabetes mellitus and deafness (MIDD). A single base-pair substitution of A to G at position 3243 in the MTTL1 gene, which encodes tRNA leucine, is associated with MIDD [Suzuki et al 2003, Wang et al 2006]. MIDD accounts for 0.5%-2.8% of diabetes mellitus. The onset of diabetes mellitus occurs in the third decade or later in non-obese individuals. The disease can be acute or slowly progressive with or without insulin dependence, and is characterized by absence of anti-GAD (glutamic acid decarboxylase) antibodies and by rapidly progressive advanced microvascular complications. The deafness is progressive and sensorineural [Suzuki et al 2003].
To establish the extent of hearing loss in an individual diagnosed with nonsyndromic mitochondrial hearing loss and deafness, a complete auditory assessment is appropriate (see Hereditary Hearing Loss and Deafness Overview).
Treatment includes the following:
Appropriate rehabilitation, e.g., hearing aids, speech therapy, culturally appropriate language training, and evaluation for eligibility for cochlear implantation [Sinnathuray et al 2003]
Enrollment in educational programs appropriate for the hearing impaired
For mild keratoderma, use of lotions and emollients; for severe keratoderma, dermatologic evaluation
MT-RNR1-related aminoglycoside-induced ototoxicity [Fischel-Ghodsian 2003]. In the US, aminoglycoside use is most common in the neonatal intensive care unit, However, the therapeutic imperative of treatment with antibiotics in a neonatal intensive care unit setting does not always lend itself to pre-treatment screening by molecular genetic testing.
Physicians can inquire about a family history of aminoglycoside-induced hearing loss prior to the administration of aminoglycosides, either systemically or locally (e.g., into the cochlea as treatment for Meniere disease). In individuals with a positive family history, alternatives to aminoglycoside treatment should be considered when possible.
The following assessments are indicated:
Annual audiometric assessment to evaluate stability or progression of hearing loss
Annual examination by a physician to assess for related clinical findings, (e.g., palmoplantar keratosis)
Aminoglycosides and noise exposure should be avoided, particularly in individuals with normal hearing who have the 1555A>G mutation in MT-RNR1.
Retrospective studies in the US have shown that about 10% of individuals with hearing loss attributed to aminoglycoside administration have the 1555A>G mutation in MT-RNR1 [Fischel-Ghodsian et al 1997]. Thus detection of the 1555A>G mutation in an individual with hearing loss secondary to aminoglycoside exposure can be of value in identifying maternal relatives who are at risk for aminoglycoside ototoxicity and would thus benefit from avoiding the use of aminoglycosides.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Nonsyndromic mitochondrial hearing loss and deafness is caused by mutations in mtDNA and is transmitted by maternal inheritance.
Parents of a proband
The father of a proband does not have the deafness-causing mtDNA mutation.
The mother of a proband (usually) has the mtDNA mutation and may or may not have hearing loss.
Alternatively, the proband may have a de novo (somatic) mtDNA mutation.
Sibs of a proband
The risk to the sibs depends on the genetic load of the mitochondrial mutation in the mother (e.g., homoplasmic versus heteroplasmic mutation).
If the mother has the mtDNA mutation, all sibs will inherit the mutation; however, the risk of hearing loss depends on (a) the mutational load and (b) exposure to aminoglycosides.
Offspring of a proband
All offspring of females with an mtDNA mutation are at risk of inheriting the mutation.
Offspring of males with an mtDNA mutation are not at risk of inheriting the mutation.
Other family members. The risk to other family members depends on the genetic status of the proband's mother. If the mother of the proband has an mtDNA mutation, her sibs and mother are also at risk.
Many culturally deaf individuals view medical advances in hearing loss as a threat to the existence of their culture; it is important to acknowledge this point of view. A skilled sign language interpreter should be present during counseling sessions. The counseling session provides an opportunity to educate the individual regarding the etiology and natural history of the hearing loss and to discuss appropriate resources for services and information; such counseling is generally well received. Issues of prevention, cochlear implants, reproduction, and family planning should be dealt with in a culturally sensitive manner [Arnos & Oelrich 2002]. (See also Hereditary Hearing Loss and Deafness Overview).
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See DNA Banking for a list of laboratories offering this service.
Prenatal diagnosis for MT-RNR1-related sensorineural and MT-TS1-related hearing loss is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling at about ten to 12 weeks' gestation. The specific MT-RNR1 or MT-TS1 mutation in the mother must be identified before prenatal testing can be performed. Accurate interpretation of a positive prenatal test result is difficult for the following reasons:
Because of mitotic segregation, the mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues.
The presence of the mtDNA mutation does not predict the age of onset or severity of hearing loss.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for hearing loss are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| MT-TS1 | Mitochondrial | Unknown |
| MT-RNR1 | Mitochondrial | Unknown |
| 561000 | RIBOSOMAL RNA, MITOCHONDRIAL, 12S; MTRNR1 |
| 580000 | DEAFNESS, AMINOGLYCOSIDE-INDUCED |
| 590080 | TRANSFER RNA, MITOCHONDRIAL, SERINE, 1; MTTS1 |
MT-RNR1. The 1555A>G mutation lies in a highly conserved region of the MT-RNR1 product, mitochondrial 12S rRNA, which is involved in the binding of aminoglycosides in bacteria. Mutations in this region alter the susceptibility of ribosomes to aminoglycosides by making the rRNA more similar to a bacterial rRNA, leading to increased binding of aminoglycosides to the mitochondrial rRNA, which results in destruction of the sensory hair cells in the inner ear that are involved with auditory function [Bates 2003]. Hamasaki & Rando (1997) demonstrated specific binding of aminoglycosides to the 1555A>G transition in a 12S rRNA construct. However, the mechanism of action for hearing loss in the absence of exposure to aminoglycosides is unclear. Although linkage analysis has implicated a locus on chromosome 8 as a nuclear modifier [Bykhovskaya et al 2000], at least in some families, no gene has been identified [Carelli et al 2003]. More recently, Ballana et al (2006) have suggested that the reduced penetrance observed in individuals with the 1555A>G mutation results from an alteration in the secondary structure of RNA caused by additional sequence changes in the MT-RNR1 gene.
MT-TS1. The base pairs at 7443, 7444, and 7445 are in the precursor for tRNA-Ser(UCN), with bp 7445 being adjacent to the 3' endonuclease cleavage site. The pathogenic mechanism for the 7445A>G mutation in the 3' end of tRNA-Ser(UCN) precursor is suggested to be secondary to the decreased rate of tRNA-Ser(UCN) production and an overall reduction in mitochondrial protein synthesis [Guan et al 1998]. In vitro studies indicate an endonucleolytic processing defect (caused by the placement of a non-cleavable C at the processing junction) as the basis of nonsyndromic hearing loss for the 7445A>G mitochondrial mutation [Levinger et al 2001]. Because the two adjoining mutations at positions 7444 and 7443 do not alter the cleavage and processing of the tRNA-Ser(UCN) in a similar fashion, they are unlikely to share this pathogenic mechanism. These three base pairs also encode the stop codon in COX I mRNA on the H strand, and each one converts this "stop" to a sense codon with elongation of the COX I reading frame by three amino acids, after which it encounters a stop codon.
For information on allelic variants and abnormal gene products, see Mitochondrial Disorders Overview.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
24 July 2007 (me) Comprehensive update posted to live Web site
22 October 2004 (me) Review posted to live Web site
13 August 2003 (ap) Original submission
