MedGen

Mitochondrial complex IV deficiency nuclear type 1 (MC4DN1) is an autosomal recessive metabolic disorder characterized by rapidly progressive neurodegeneration and encephalopathy with loss of motor and cognitive skills between about 5 and 18 months of age after normal early development. Affected individuals show hypotonia, failure to thrive, loss of the ability to sit or walk, poor communication, and poor eye contact. Other features may include oculomotor abnormalities, including slow saccades, strabismus, ophthalmoplegia, and nystagmus, as well as deafness, apneic episodes, ataxia, tremor, and brisk tendon reflexes. Brain imaging shows bilateral symmetric lesions in the basal ganglia, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Some patients may also have abnormalities in the brainstem and cerebellum. Laboratory studies usually show increased serum and CSF lactate and decreased levels and activity of mitochondrial respiratory complex IV in patient tissues. There is phenotypic variability, but death in childhood, often due to central respiratory failure, is common (summary by Tiranti et al., 1998; Tiranti et al., 1999; Teraoka et al., 1999; Poyau et al., 2000) Genetic Heterogeneity of Mitochondrial Complex IV Deficiency Most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare (Shoubridge, 2001; Sacconi et al., 2003). Mitochondrial complex IV deficiency caused by mutation in nuclear-encoded genes, in addition to MC4DN1, include MC4DN2 (604377), caused by mutation in the SCO2 gene (604272); MC4DN3 (619046), caused by mutation in the COX10 gene (602125); MC4DN4 (619048), caused by mutation in the SCO1 gene (603664); MC4DN5 (220111), caused by mutation in the LRPPRC gene (607544); MC4DN6 (615119), caused by mutation in the COX15 gene (603646); MC4DN7 (619051), caused by mutation in the COX6B1 gene (124089); MC4DN8 (619052), caused by mutation in the TACO1 gene (612958); MC4DN9 (616500), caused by mutation in the COA5 gene (613920); MC4DN10 (619053), caused by mutation in the COX14 gene (614478); MC4DN11 (619054), caused by mutation in the COX20 gene (614698); MC4DN12 (619055), caused by mutation in the PET100 gene (614770); MC4DN13 (616501), caused by mutation in the COA6 gene (614772); MC4DN14 (619058), caused by mutation in the COA3 gene (614775); MC4DN15 (619059), caused by mutation in the COX8A gene (123870); MC4DN16 (619060), caused by mutation in the COX4I1 gene (123864); MC4DN17 (619061), caused by mutation in the APOPT1 gene (616003); MC4DN18 (619062), caused by mutation in the COX6A2 gene (602009); MC4DN19 (619063), caused by mutation in the PET117 gene (614771); MC4DN20 (619064), caused by mutation in the COX5A gene (603773); MC4DN21 (619065), caused by mutation in the COXFA4 gene (603883); MC4DN22 (619355), caused by mutation in the COX16 gene (618064); and MC4DN23 (620275), caused by mutation in the COX11 gene (603648). Mitochondrial complex IV deficiency has been associated with mutations in several mitochondrial genes, including MTCO1 (516030), MTCO2 (516040), MTCO3 (516050), MTTS1 (590080), MTTL1 (590050), and MTTN (590010). [from OMIM]

Aminoglycosides are widely used antibiotics which inhibit protein synthesis in bacteria by binding to bacterial 16S ribosomal subunits. Aminoglycosides are associated with a number of adverse events, including nephrotoxicity and ototoxicity. The risk of aminoglycoside-induced ototoxicity is increased in patients who carry certain variants in the MT-RNR1 gene. MT-RNR1 is found in the mitochondrial genome and encodes the 12S ribosomal subunit. Some MT-RNR1 variants cause the 12S subunit to more closely resemble the bacterial 16S subunit, which can lead to aminoglycoside molecules binding to the ribosome. This ultimately results in hearing loss due to cell death in the cochlea. The Clinical Pharmacogenetics Implementation Consortium (CPIC) have published recommendations on aminoglycoside use in patients carrying MT-RNR1 variants in the journal Clinical Pharmacology and Therapeutics. These recommendations are also available on the CPIC and PharmGKB websites. [from PharmGKB]

Aminoglycosides are widely used antibiotics which inhibit protein synthesis in bacteria by binding to bacterial 16S ribosomal subunits. Aminoglycosides are associated with a number of adverse events, including nephrotoxicity and ototoxicity. The risk of aminoglycoside-induced ototoxicity is increased in patients who carry certain variants in the MT-RNR1 gene. MT-RNR1 is found in the mitochondrial genome and encodes the 12S ribosomal subunit. Some MT-RNR1 variants cause the 12S subunit to more closely resemble the bacterial 16S subunit, which can lead to aminoglycoside molecules binding to the ribosome. This ultimately results in hearing loss due to cell death in the cochlea. The Clinical Pharmacogenetics Implementation Consortium (CPIC) have published recommendations on aminoglycoside use in patients carrying MT-RNR1 variants in the journal Clinical Pharmacology and Therapeutics. These recommendations are also available on the CPIC and PharmGKB websites. [from PharmGKB]

Aminoglycosides are widely used antibiotics which inhibit protein synthesis in bacteria by binding to bacterial 16S ribosomal subunits. Aminoglycosides are associated with a number of adverse events, including nephrotoxicity and ototoxicity. The risk of aminoglycoside-induced ototoxicity is increased in patients who carry certain variants in the MT-RNR1 gene. MT-RNR1 is found in the mitochondrial genome and encodes the 12S ribosomal subunit. Some MT-RNR1 variants cause the 12S subunit to more closely resemble the bacterial 16S subunit, which can lead to aminoglycoside molecules binding to the ribosome. This ultimately results in hearing loss due to cell death in the cochlea. The Clinical Pharmacogenetics Implementation Consortium (CPIC) have published recommendations on aminoglycoside use in patients carrying MT-RNR1 variants in the journal Clinical Pharmacology and Therapeutics. These recommendations are also available on the CPIC and PharmGKB websites. [from PharmGKB]

Aminoglycosides are widely used antibiotics which inhibit protein synthesis in bacteria by binding to bacterial 16S ribosomal subunits. Aminoglycosides are associated with a number of adverse events, including nephrotoxicity and ototoxicity. The risk of aminoglycoside-induced ototoxicity is increased in patients who carry certain variants in the MT-RNR1 gene. MT-RNR1 is found in the mitochondrial genome and encodes the 12S ribosomal subunit. Some MT-RNR1 variants cause the 12S subunit to more closely resemble the bacterial 16S subunit, which can lead to aminoglycoside molecules binding to the ribosome. This ultimately results in hearing loss due to cell death in the cochlea. The Clinical Pharmacogenetics Implementation Consortium (CPIC) have published recommendations on aminoglycoside use in patients carrying MT-RNR1 variants in the journal Clinical Pharmacology and Therapeutics. These recommendations are also available on the CPIC and PharmGKB websites. [from PharmGKB]

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). [from GeneReviews]

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). [from GeneReviews]

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). [from GeneReviews]

Diseases caused by abnormal function of the MITOCHONDRIA. They may be caused by mutations, acquired or inherited, in mitochondrial DNA or in nuclear genes that code for mitochondrial components. They may also be the result of acquired mitochondria dysfunction due to adverse effects of drugs, infections, or other environmental causes. [from MeSH]

Nonsyndromic hearing loss is a partial or total loss of hearing that is not associated with other signs and symptoms. In contrast, syndromic hearing loss occurs with signs and symptoms affecting other parts of the body.

Depending on the type, nonsyndromic hearing loss can become apparent at any time from infancy to old age. Hearing loss that is present before a child learns to speak is classified as prelingual or congenital. Hearing loss that occurs after the development of speech is classified as postlingual.

Nonsyndromic hearing loss can be classified in several different ways. One common way is by the condition's pattern of inheritance: autosomal dominant (DFNA), autosomal recessive (DFNB), X-linked (DFNX), or mitochondrial (which does not have a special designation). Each of these types of hearing loss includes multiple subtypes. DFNA, DFNB, and DFNX subtypes are numbered in the order in which they were first described. For example, DFNA1 was the first type of autosomal dominant nonsyndromic hearing loss to be identified.

The characteristics of nonsyndromic hearing loss vary among the different types. Hearing loss can affect one ear (unilateral) or both ears (bilateral). Degrees of hearing loss range from mild (difficulty understanding soft speech) to profound (inability to hear even very loud noises). The term "deafness" is often used to describe severe-to-profound hearing loss. Hearing loss can be stable, or it may be progressive, becoming more severe as a person gets older. Particular types of nonsyndromic hearing loss show distinctive patterns of hearing loss. For example, the loss may be more pronounced at high, middle, or low tones.

Most forms of nonsyndromic hearing loss are described as sensorineural, which means they are associated with a permanent loss of hearing caused by damage to structures in the inner ear. The inner ear processes sound and sends the information to the brain in the form of electrical nerve impulses. Less commonly, nonsyndromic hearing loss is described as conductive, meaning it results from changes in the middle ear. The middle ear contains three tiny bones that help transfer sound from the eardrum to the inner ear. Some forms of nonsyndromic hearing loss, particularly a type called DFNX2, involve changes in both the inner ear and the middle ear. This combination is called mixed hearing loss. [from MedlinePlus Genetics]

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with protean manifestations. The vast majority of affected individuals develop signs and symptoms of MELAS between ages two and 40 years. Common clinical manifestations include stroke-like episodes, encephalopathy with seizures and/or dementia, muscle weakness and exercise intolerance, normal early psychomotor development, recurrent headaches, recurrent vomiting, hearing impairment, peripheral neuropathy, learning disability, and short stature. During the stroke-like episodes neuroimaging shows increased T2-weighted signal areas that do not correspond to the classic vascular distribution (hence the term "stroke-like"). Lactic acidemia is very common and muscle biopsies typically show ragged red fibers. [from GeneReviews]