Mitochondrial Hearing Loss

Definition and epidemiology

Mitochondria are organelles that produce most of the cell’s energy molecule, ATP, and carry their own small circular DNA (mtDNA). The cochlea, with its high energy demand, particularly in the stria vascularis and hair cells, is very sensitive to mitochondrial dysfunction. Mitochondrial hearing loss falls into two main groups: non-syndromic forms that affect only hearing (best known are variants in the MT-RNR1 gene that cause aminoglycoside susceptibility) and syndromic forms with diabetes and muscle, eye and brain involvement (most often MIDD and MELAS due to the m.3243A>G variant). For genetic causes in nuclear DNA, see non-syndromic hearing loss.

The MT-RNR1 m.1555A>G variant was found in 18 of 9,371 children not selected for hearing loss, a frequency of 0.19% (1 in 520) (Bitner-Glindzicz et al., 2009). The m.3243A>G variant is found in about 1 in 400 people in population studies and is the commonest disease-causing mtDNA variant. In a UK cohort of 129 patients, 30% had maternally inherited diabetes and deafness (MIDD), 10% classical MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), 3% isolated sensorineural hearing loss, and 9% were asymptomatic carriers (Nesbitt et al., 2013).

Symptoms and signs

People carrying an MT-RNR1 variant usually have normal hearing unless they are exposed to aminoglycosides. In a UK birth cohort, children carrying m.1555A>G had clinically normal hearing at age 9 (Bitner-Glindzicz et al., 2009). After aminoglycoside exposure, however, bilateral, often severe or profound permanent loss can develop quickly; profound loss has been reported even after a single dose (McDermott, Wolf et al., 2022).

With m.3243A>G, hearing loss usually begins after speech has developed, often in young or middle adulthood, and is bilateral, symmetrical and progressive. Mild losses show an audiogram sloping towards the high frequencies, while severe and profound losses are flat across frequencies (Cadoni et al., 2023). Hearing loss may be accompanied by diabetes, muscle weakness and exercise intolerance, drooping eyelids and restricted eye movements (PEO), cardiomyopathy, migraine-like headaches, seizures and stroke-like episodes. Even within a family carrying the same variant, the picture can range from asymptomatic carriage to severe MELAS (Nesbitt et al., 2013).

Causes and risk factors

mtDNA is inherited only from the mother: the egg passes its mitochondria to the child, while sperm does not. All children of an affected mother therefore inherit the variant, whereas children of an affected father do not, and the condition typically runs down the maternal line of the family tree (McDermott, Wolf et al., 2022). Each cell contains hundreds of copies of mtDNA. The coexistence of variant and normal mtDNA in the same cell is called heteroplasmy, and the proportion of variant copies can differ between tissues and between siblings. With m.3243A>G, the severity of hearing loss has been linked to the proportion of mutant mtDNA in skeletal muscle (Chinnery et al., 2000). This explains why the same family can include people with very different degrees of severity.

The MT-RNR1 gene encodes the 12S rRNA of the mitochondrial ribosome. The m.1555A>G and m.1494C>T variants make this RNA resemble the bacterial ribosome, so aminoglycosides bind to the mitochondrial ribosome and disrupt protein synthesis in hair cells. The Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline rates the evidence as high for m.1555A>G and m.1494C>T and moderate for m.1095T>C; because no safe heteroplasmy threshold has been defined, it advises treating heteroplasmic carriers in the same way as homoplasmic carriers (McDermott, Wolf et al., 2022). m.3243A>G, by contrast, affects the mitochondrial leucine tRNA (MT-TL1) and impairs energy production. Other syndromic forms include PEO and Kearns-Sayre syndrome caused by mtDNA deletions, and defects in nuclear genes that regulate mitochondrial function (such as POLG and OPA1) (Cadoni et al., 2023).

Audiological and clinical assessment

The diagnosis rests on the history, audiological findings and genetic testing together. Hearing loss running through the maternal line, loss beginning after aminoglycosides, or hearing loss accompanied by diabetes and neurological signs should all raise the possibility of a mitochondrial cause. Because heteroplasmy can make the variant level in blood low, the genetics laboratory may also test tissues other than blood.

• Pure-tone audiometry: bilateral, symmetrical sensorineural loss. Mild losses are mostly high-frequency sloping, severe losses flat (Cadoni et al., 2023). The rate of progression should be documented over time.
• Speech audiometry: in cochlear losses, scores are usually consistent with thresholds; disproportionately poor scores suggest retrocochlear involvement.
• OAEs: absent with moderate or worse loss (Chinnery et al., 2000), indicating outer hair cell involvement.
• ABR: latencies are normal with moderate or milder loss, and the loss is mainly cochlear in origin (Chinnery et al., 2000). In a series of 34 adults, 84% of losses were cochlear and 16% retrocochlear (Cadoni et al., 2023).
• Tympanometry and acoustic reflexes: the tympanogram is normal, and reflexes are interpreted in line with a cochlear loss.
• Drug monitoring: for audiological monitoring before and during aminoglycoside treatment, see ototoxicity.

The differential diagnosis includes inherited losses due to nuclear genes, noise-induced loss and early-onset loss resembling presbycusis. A person diagnosed with m.3243A>G should also be assessed for diabetes and cardiac, eye and neurological involvement, and genetic counselling should be offered to maternal relatives (Nesbitt et al., 2013).

Treatment and audiological rehabilitation

For MT-RNR1 variants, prevention is the most effective approach. The CPIC guideline strongly recommends that carriers avoid aminoglycosides unless the risk of permanent hearing loss is outweighed by the risk of infection and no safe, effective alternative exists (McDermott, Wolf et al., 2022). Because aminoglycosides are widely used for suspected sepsis in neonatal intensive care and standard genetic testing takes days, point-of-care genotyping has been developed. In two UK neonatal intensive care units, the test was used in 751 babies and identified m.1555A>G in 26 minutes; the 3 babies carrying the variant were not given aminoglycosides, and time to antibiotics was equivalent to previous practice (McDermott, Mahaveer et al., 2022). NICE has stated that the Genedrive MT-RNR1 ID Kit can be used, while further evidence is generated, in newborns being considered for aminoglycoside treatment; it advises confirming positive results in the laboratory and using the test only within a treatment plan that aims to give antibiotics within one hour, without causing delay (National Institute for Health and Care Excellence [NICE], 2023). If the genotype is unknown or the result is not available in time, treatment of a life-threatening infection must not be delayed. The choice and dose of antibiotic are decisions for the doctor.

For permanent hearing loss, hearing aids are fitted and settings are updated regularly as the loss progresses. For severe and profound loss, a cochlear implant (CI) is a good option: because the hearing nerve is usually intact in cochlear loss, outcomes are favourable. A systematic review of 11 studies covering 17 patients reported good hearing outcomes and gains in speech perception in all implanted patients; however, follow-up ranged from one week to 12 months and the evidence came from case reports and retrospective series (Zia et al., 2021). In syndromic forms, anaesthetic, diabetic and cardiac issues should be assessed with the relevant doctors before surgery.

Genetic counselling is part of management. Because all maternal relatives are at risk, the mother, siblings and maternal aunts of a person found to carry a variant, and the children of female carriers, should be informed, and an aminoglycoside alert should be added to the health records of MT-RNR1 carriers. Because of heteroplasmy, it is hard to predict how severely the children of a mother carrying m.3243A>G will be affected.

Impact on quality of life and advice

Aminoglycoside-related loss is often sudden and bilateral, which is a great shock to the family; learning later that the loss was preventable can lead to guilt and anger. In babies, early detection and rapid rehabilitation are decisive for language development. With m.3243A>G, hearing loss progresses alongside diabetes, fatigue, muscle weakness and sometimes cognitive problems, increasing the burden on work and social life and requiring regular follow-up across several specialties.

Practical advice: if you or a family member have been found to carry an MT-RNR1 variant, carry this information in writing and mention it at every hospital visit; inform your maternal relatives too. Wear your hearing aids consistently and keep up with fitting checks as the loss progresses. If you have diabetes, pay attention to blood glucose control and do not change your medicines without asking your doctor. Seek help promptly if you notice a new change in hearing, headache, seizures or muscle weakness. If you are planning a family, ask for genetic counselling.