Nonsyndromic mitochondrial hearing loss and deafness is characterized by moderate-to-profound hearing loss and a mutation in either MT-RNR1 or MT-TS1. Mutations in MT-RNR1 can be associated with predisposition to aminoglycoside ototoxicity and/or late-onset sensorineural hearing loss. Mutations in MT-TS1 are usually associated with childhood onset of sensorineural hearing loss. 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. Although hearing loss associated with mutations in MT-TS1 is considered nonsyndromic, the m.7445A>G substitution is also associated with palmoplantar keratoderma (scaling, hyperkeratosis, and honeycomb appearance of the skin of the palms, soles, and heels) in some families.

MT-RNR1 (encoding mitochondrial 12S ribosomal RNA) and MT-TS1 (encoding mitochondrial transfer RNA serine 1) are the two genes in which mutations are currently known to cause nonsyndromic mitochondrial hearing loss and deafness. Molecular genetic testing is clinically available for both genes.

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.

Hereditary hearing loss and deafness may be conductive, sensorineural, or a combination of both; syndromic (associated with malformations of the external ear or other organs or with medical problems involving other organ systems) or nonsyndromic (no associated visible abnormalities of the external ear or any related medical problems); and prelingual (before language develops) or postlingual (after language develops).

Genetic forms of hearing loss must be distinguished from acquired (non-genetic) causes of hearing loss. The genetic forms of hearing loss are diagnosed by otologic, audiologic, and physical examination, family history, ancillary testing (e.g., CT examination of the temporal bone), and molecular genetic testing. Molecular genetic testing, available in clinical laboratories for many types of syndromic and nonsyndromic deafness, plays a prominent role in diagnosis and genetic counseling.

Hereditary hearing loss can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive manner, as well as by mitochondrial inheritance. Genetic counseling and risk assessment depend on accurate determination of the specific genetic diagnosis. In the absence of a specific diagnosis, empiric recurrence risk figures, coupled with GJB2 and GJB6 molecular genetic testing results, can be used for genetic counseling.

Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutations of nuclear or mitochondrial DNA (mtDNA). Some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), but many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many affected individuals display a cluster of clinical features that fall into a discrete clinical syndrome, such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). However, considerable clinical variability exists and many individuals do not fit neatly into one particular category. Common clinical features of mitochondrial disease include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Common central nervous system findings are fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. A high incidence of mid- and late pregnancy loss is a common occurrence that often goes unrecognized.

In some individuals, the clinical picture is characteristic of a specific mitochondrial disorder (e.g., LHON, NARP, or maternally inherited LS), and the diagnosis can be confirmed by molecular genetic testing of DNA extracted from a blood sample. In many individuals, such is not the case, and a more structured approach is needed, including family history, blood and/or CSF lactate concentration, neuroimaging, cardiac evaluation, and muscle biopsy for histologic or histochemical evidence of mitochondrial disease, and molecular genetic testing for a mtDNA mutation.

Mitochondrial disorders may be caused by defects of nuclear DNA or mtDNA. Nuclear gene defects may be inherited in an autosomal recessive or autosomal dominant manner. Mitochondrial DNA defects are transmitted by maternal inheritance. Mitochondrial DNA deletions generally occur de novo and thus cause disease in one family member only, with no significant risk to other family members. Mitochondrial DNA point mutations and duplications may be transmitted down the maternal line. The father of a proband is not at risk of having the disease-causing mtDNA mutation, but the mother of a proband (usually) has the mitochondrial mutation and may or may not have symptoms. A male does not transmit the mtDNA mutation to his offspring. A female harboring a heteroplasmic mtDNA point mutation may transmit a variable amount of mutant mtDNA to her offspring, resulting in considerable clinical variability among sibs within the same family. Prenatal genetic testing and interpretation of test results for mtDNA disorders are difficult because of mtDNA heteroplasmy.

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with onset typically in childhood. Early psychomotor development is usually normal, but short stature is common. Onset of symptoms is frequently between the ages of two and ten years. The most common initial symptoms are generalized tonic-clonic seizures, recurrent headaches, anorexia, and recurrent vomiting. Exercise intolerance or proximal limb weakness can be the initial manifestation. Seizures are often associated with stroke-like episodes of transient hemiparesis or cortical blindness. These stroke-like episodes may be associated with altered consciousness and may be recurrent. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, and mentation, often by adolescence or young adulthood. Sensorineural hearing loss is common.

The diagnosis of MELAS is based on a combination of clinical findings and molecular genetic testing. Mutations in the mitochondrial DNA (mtDNA) gene MT-TL1 encoding tRNA(Leu(UUA/UUG)) are causative. The most common mutation, present in about 80% of individuals with typical clinical findings, is an A-to-G transition at nucleotide 3243 (m.3243A>G). Mutations in MT-TL1 or other mtDNA genes, particularly MT-ND5, can also cause this disorder. Mutations can usually be detected in mtDNA from leukocytes in individuals with typical MELAS; however, the occurrence of "heteroplasmy" in disorders of mtDNA can result in varying tissue distribution of mutated mtDNA. Hence, the pathogenic mutation may be undetectable in mtDNA from leukocytes and may be detected only in other tissues, such as cultured skin fibroblasts, hair follicles, urinary sediment, or, most reliably, skeletal muscle.

MELAS is caused by mutations in mtDNA and is transmitted by maternal inheritance. The father of a proband is not at risk of having the disease-causing mtDNA mutation. The mother of a proband usually has the mtDNA mutation and may or may not have symptoms. A man with an mtDNA mutation cannot transmit the mutation to any of his offspring. A woman (affected or unaffected) transmits the mutation to all of her offspring. Prenatal diagnosis for MELAS is possible if a mtDNA mutation has been detected in the mother. However, because the mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues, and because the mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation, prediction of the phenotype from prenatal studies is not possible.