Nonsyndromic Hearing Loss And Deafness, Mitochondrial

Clinical characteristics.

Mitochondrial nonsyndromic hearing loss and deafness is characterized by sensorineural hearing loss (SNHL) of variable onset and severity.

Pathogenic variants in MT-RNR1 can be associated with predisposition to aminoglycoside ototoxicity and/or late-onset SNHL. Hearing loss associated with aminoglycoside ototoxicity is bilateral and severe to profound, occurring within a few days to weeks after administration of any amount (even a single dose) of an aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin.

Pathogenic variants in MT-TS1 are usually associated with childhood onset of SNHL that is generally nonsyndromic – although the MT-TS1 substitution m.7445A>G has been found in some families who also have palmoplantar keratoderma (scaling, hyperkeratosis, and honeycomb appearance of the skin of the palms, soles, and heels).

Diagnosis/testing.

The diagnosis of mitochondrial nonsyndromic hearing loss and deafness is established in a proband with hearing loss and identification of a pathogenic variant in MT-RNR1 or MT-TS1, or one of the eight additional mitochondrial genes known to cause nonsyndromic hearing loss and deafness.

Management.

Treatment of manifestations: Appropriate rehabilitation (hearing aids, speech therapy, culturally appropriate language training, cochlear implantation, educational programs for the hearing impaired). Electric acoustic stimulation for individuals with mitochondrial hearing loss with residual hearing in the lower frequencies. Lotions and emollients for mild keratoderma; dermatology referral for severe keratoderma.

Prevention of primary manifestations: Avoidance of aminoglycosides.

Surveillance: Annual audiometric assessment to evaluate stability/progression of hearing loss. Annual physical exam for related clinical findings.

Agents/circumstances to avoid: Aminoglycosides and noise exposure, especially in those with normal hearing who have the m.1555A>G or m.1494C>T MT-RNR1 pathogenic variants.

Evaluation of relatives at risk: Molecular genetic testing of at-risk maternal relatives allows for early detection of those who have inherited the mtDNA pathogenic variant and would benefit from avoiding aminoglycosides and appropriate early support and management.

Genetic counseling.

Mitochondrial nonsyndromic hearing loss and deafness is caused by pathogenic variants in mitochondrial DNA (mtDNA) and is transmitted by maternal inheritance. The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have hearing loss. All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. Offspring of males with a mtDNA pathogenic variant are not at risk of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the mtDNA pathogenic variant in the family is known. Because of mitotic segregation, the mtDNA pathogenic variant load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues. Furthermore, the presence of the mtDNA pathogenic variant does not predict the age of onset or severity of hearing loss.

Suggestive Findings

Mitochondrial nonsyndromic hearing loss and deafness should be suspected in a proband 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.
• Mild to moderate high-frequency hearing loss
• No other systemic findings on history or physical examination
• A family history of hearing loss suggestive of maternal inheritance (i.e., no transmission through a male)
• Onset of hearing loss following administration of an aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin

Establishing the Diagnosis

The diagnosis of mitochondrial nonsyndromic hearing loss and deafness is established in a proband with the above Suggestive Findings and by identification of a pathogenic variant in one of the genes associated with mitochondrial nonsyndromic hearing loss and deafness on molecular genetic testing (see Table 1a, Table 1b).

Molecular genetic testing approaches can include targeted testing, a multigene panel, and complete mtDNA sequencing:

• Targeted testing. In individuals with hearing loss following aminoglycoside exposure, molecular testing for the pathogenic variants m.1555A>G and m.1494C>T in MT-RNR1 and m.7445A>C/T/G in MT-TS1 can be done first.
• A multigene panel that includes the mitochondrial genes listed in Table 1a and other genes of interest (see Table 1b and Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. (4) Some mitochondrial nonsyndromic deafness-causing pathogenic variants are heteroplasmic (i.e., both wild type and mutated mtDNA are present in a cell and/or tissue). When selecting a multigene panel, it is necessary to confirm that the test methods can identify heteroplasmic mitochondrial pathogenic variants.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Complete mtDNA sequencing may be considered if use of targeted testing and/or a multigene panel did not identify a pathogenic variant, clinical suspicion remains high, and there is no evidence of paternal transmission. Massively parallel DNA sequencing-based techniques are useful for identifying heteroplasmic mitochondrial pathogenic variants.
  Note: This testing may be performed before a multigene panel in the case of a clear mitochondrial inheritance pattern.

Clinical Description

Phenotype Correlations by Gene

See Clinical Description.

Genotype-Phenotype Correlations

MT-TS1. The m.7445A>G pathogenic variant is associated in some families with palmoplantar keratoderma in addition to hearing loss. Individuals who have both the m.7444G>A and m.1555A>G (MT-RNR1) pathogenic variants [Pandya et al 2004] or the m.7443A>G pathogenic variant alone do not have skin findings.

Penetrance

MT-RNR1

• Most m.1555A>G pathogenic variants occur as homoplasmic changes; the penetrance of hearing loss is believed to be 100% in those with the pathogenic variant who receive aminoglycoside antibiotics (i.e., all individuals with this pathogenic variant will become deaf with any amount of aminoglycoside in a single dose) – although neonates who were unaffected following treatment with aminoglycosides have been reported [Ealy et al 2011, Göpel et al 2014]. However, aminoglycoside exposure may increase the lifetime risk for developing deafness.
• The penetrance for hearing loss in individuals with the m.1555A>G pathogenic variant who are not exposed to aminoglycosides varies widely (0%-65%) [Bykhovskaya et al 1998, Estivill et al 1998, Ding et al 2009, Lu et al 2010b]. Zhu et al [2014] reported that the heteroplasmy level of the m.1555A>G pathogenic variant correlated with hearing loss penetrance in five families with different heteroplasmy levels; penetrance in these families was 52%, 18.2%, 10%, 26.7%, and 44%.
• The averaged penetrance of eight Chinese families harboring the m.1494C>T pathogenic variant was 31.7% when aminoglycoside-induced deafness was included and 17.5% when it was excluded [Zhao et al 2004, Chen et al 2007].
• Variants m.961T>G and m.961_962delTinsC(n) have been associated with SNHL [Guaran et al 2013] but may be either benign or low-penetrance pathogenic.

Note: It has been suggested that penetrance for hearing loss is lower in some families from China [Young et al 2005, Dai et al 2006, Tang et al 2007].

MT-TS1. The pathogenic variants exist as both homoplasmic and heteroplasmic; therefore, the severity of hearing loss and age of onset vary depending on the mutational load in an individual.

Prevalence

The prevalence of mitochondrial nonsyndromic hearing loss and deafness has been well studied for MT-RNR1 and MT-TS1 in many populations.

In a prospective study in the Tianjin Province in China in which 58,000 newborns were screened with both audiologic and genetic methods, Zhang et al [2013] identified a pathogenic mtDNA variant in 1.8% of newborns; however, only one newborn was found to have hearing loss.

MT-RNR1. Hearing loss caused by MT-RNR1 pathogenic variant m.1555A>G has been observed worldwide (e.g., in the Arab-Israeli, Japanese, Mongolian, Zairean, Spanish, Chinese, Turkish, Balinese, Moroccan, Greek, Polish, Tunisian, and American populations) and is identified in 15% of all individuals with hearing loss and a history of aminoglycoside administration [Fischel-Ghodsian et al 1997]

The prevalence of the m.1555A>G pathogenic variant varies by population (see Table 2).

The prevalence of MT-RNR1 pathogenic variant m.1494C>T varies by population (see Table 3).

The prevalence of the m.961_962delTinsC(n) pathogenic variants in deaf probands, initially determined by screening of anonymized blood spots from newborns in the state of Texas, revealed a prevalence of approximately 1% [Tang et al 2002]. More recent literature has identified varying frequencies for the three changes in this region [Guaran et al 2013, Yelverton et al 2013, Zhang et al 2013].

MT-TS1. The prevalence of pathogenic variants is 0.8%-1.1% in deaf probands studied from the United States [Arnos et al 2003] and from Mongolia [Pandya et al 1999], and 0.68% in probands from China [Tang et al 2015]. A Japanese family with the m.7511T>C pathogenic variant has been reported [Li et al 2005].

The prevalence of pathogenic variant m.7444G>A was 0.86% in individuals with hearing loss from the United States [Yelverton et al 2013] and 0.4% in individuals with hearing loss of Polish ancestry [Rydzanicz et al 2011], but it was not identified among 513 Greek individuals [Kokotas et al 2010] or 701 Chinese individuals [Chen et al 2014].

The prevalence of m.7511T>C was 1.2% in Japanese individuals with maternally inherited hearing loss [Yano et al 2014], and 0.04% in Chinese individuals with hearing loss [Tang et al 2015].

Evaluations Following Initial Diagnosis

To establish the extent of hearing loss and needs in an individual diagnosed with mitochondrial nonsyndromic hearing loss and deafness, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• A complete auditory assessment (see Hereditary Hearing Loss and Deafness Overview)
• Examination of the skin for evidence of keratoderma
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment includes the following:

• Appropriate rehabilitation including hearing aids, speech therapy, culturally appropriate language training, and evaluation for eligibility for cochlear implantation [Sinnathuray et al 2003]
• Electric acoustic stimulation (EAS) for individuals with mitochondrial hearing loss with residual hearing in the lower frequencies [Usami et al 2012a]
• Enrollment in educational programs appropriate for the hearing impaired
• For mild keratoderma, use of lotions and emollients; for severe keratoderma, dermatologic evaluation

Prevention of Primary Manifestations

MT-RNR1-related aminoglycoside-induced ototoxicity. 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's disease). In individuals with a family history of aminoglycoside-induced hearing loss, alternatives to aminoglycoside treatment should be considered when possible.

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.

• Bitner-Glindzicz et al [2009] report a population frequency of 0.19% for the A to G change in a European cohort of children age seven to nine years who had the pathogenic variant but did not have hearing loss because they were not exposed to aminoglycosides; they make an argument for screening on demand to avoid a preventable cause of hearing loss.
• In a commentary by Boles & Friedlich [2010], the authors suggest a prospective study into the feasibility of screening for these mitochondrial pathogenic variants (especially in busy neonatal units) in order to identify a preventable form of hearing loss.
• In the Tianjin Province in China, screening of 58,000 newborns by audiometry and molecular genetic testing determined that 1.8% of newborns had a pathogenic mitochondrial DNA variant and only one newborn had hearing loss [Zhang et al 2013].

Surveillance

The following are appropriate:

• 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)

Agents/Circumstances to Avoid

Aminoglycosides and noise exposure should be avoided, particularly in individuals with normal hearing who have the m.1555A>G or m.1494C>T MT-RNR1 pathogenic variant.

Evaluation of Relatives at Risk

In a family in which the mtDNA pathogenic variant is known, prospective molecular genetic testing of at-risk maternal relatives allows early detection of those who have inherited the mtDNA pathogenic variant and would benefit from:

• Avoiding aminoglycosides to prevent onset of hearing loss
• Appropriate early support and management

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Use of aminoglycoside antibiotics during pregnancy in a mother who has the MT-RNR1 m.1555A>G or m.1494C>T pathogenic variants should be considered only in the absence of other treatment options, as these antibiotics exhibit incomplete placental transfer.

Of note, if the mother has the MT-RNR1 m.1555A>G or m.1494C>T pathogenic variant, she will pass it on to the fetus; hence, use of aminoglycosides should be avoided in the newborn.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.