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.