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Leber optic atrophy(LHON)

MedGen UID:
182973
Concept ID:
C0917796
Disease or Syndrome
Synonyms: Leber Hereditary Optic Neuropathy; Leber optic atrophy features; Leber optic degeneration; Leber's disease; Leber's optic atrophy; LHON; Optic Atrophy, Hereditary, Leber; Optic atrophy, Leber type
Modes of inheritance:
Heterogeneous
MedGen UID:
67020
Concept ID:
C0242960
Organism Attribute
Source: HPO
The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)
Mitochondrial inheritance
MedGen UID:
165802
Concept ID:
C0887941
Genetic Function
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on the mitochondrial genome. Because the mitochondrial genome is essentially always maternally inherited, a mitochondrial condition can only be transmitted by females, although the condition can affect both sexes. The proportion of mutant mitochondria can vary (heteroplasmy).
Mitochondrial inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Leber hereditary optic neuropathy (58610003); LHON - Leber hereditary optic neuropathy (58610003); LHON - Leber's hereditary optic neuropathy (58610003); Leber optic atrophy (58610003); Leber's optic atrophy (58610003)
 
Genes (locations): MT-ATP6; MT-CO3; MT-CYB; MT-ND1; MT-ND2; MT-ND4; MT-ND4L; MT-ND5; MT-ND6
OMIM®: 535000
HPO: HP:0001112
Orphanet: ORPHA104

Definition

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 mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many individuals with a mutation of mtDNA 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, which is well-illustrated by the overlapping spectrum of disease phenotypes (including mitochondrial recessive ataxia syndrome (MIRAS) resulting from mutation of the nuclear gene POLG, which has emerged as a major cause of mitochondrial disease. Common clinical features of mitochondrial disease – whether involving a mitochondrial or nuclear gene – 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. [from GeneReviews]

Additional descriptions

From GeneReviews Overview
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 mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many individuals with a mutation of mtDNA 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, which is well-illustrated by the overlapping spectrum of disease phenotypes (including mitochondrial recessive ataxia syndrome (MIRAS) resulting from mutation of the nuclear gene POLG, which has emerged as a major cause of mitochondrial disease. Common clinical features of mitochondrial disease – whether involving a mitochondrial or nuclear gene – 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.  https://www.ncbi.nlm.nih.gov/books/NBK1224
From OMIM
LHON presents in midlife as acute or subacute central vision loss leading to central scotoma and blindness. The disease has been associated with many missense mutations in the mtDNA that can act autonomously or in association with each other to cause the disease. The 18 allelic variants are MTND6*LDYT14459A (516006.0002); MTND4*LHON11778A (516003.0001); MTND1*LHON3460A (516000.0001); MTND6*LHON14484C (516006.0001); MTCYB*LHON15257A (516020.0001); MTCO3*LHON9438A (516050.0001); MTCO3*LHON9804A (516050.0002 ); MTND5*LHON13730A (516005.0002); MTND1*LHON4160C (516000.0002); MTND2*LHON5244A (516001.0002); MTCOI*LHON7444A (516030.0001); MTND1*LHON3394C (516000.0004); MTND5*LHON13708A (516005.0001); MTCYB*LHON15812A (516020.0002); MTND2*LHON4917G (516001.0001); MTND1*LHON4216C (516000.0003); MTND1*LHON4136G (516000.0002); MTATP6*LHON9101C (516060.0003); MTND4L*LHON10663C (516004.0002). The first 17 of these variants are summarized in Table M1, MIM12. As pointed out by Riordan-Eva and Harding (1995), although the plethora of mtDNA mutations identified in families with LHON had resulted in confusion as to the pathogenic significance of each mutation, it had been established that the 3 primary mutations at basepairs 11778 (516003.0001), 3460 (516000.0001), and 14484 (516006.0001) are present in at least 90% of families. The correlation between the 14484 mutation and a good visual prognosis provides not only hope for affected patients, but also an approach for further research into the pathogenesis of LHON. Yu-Wai-Man et al. (2009) provided a detailed review of LHON and autosomal dominant optic atrophy (OPA1; 165500), with emphasis on the selective vulnerability of retinal ganglion cells to mitochondrial dysfunction in both disorders.  http://www.omim.org/entry/535000
From GHR
Leber hereditary optic neuropathy (LHON) is an inherited form of vision loss. Although this condition usually begins in a person's teens or twenties, rare cases may appear in early childhood or later in adulthood. For unknown reasons, males are affected much more often than females.Blurring and clouding of vision are usually the first symptoms of LHON. These vision problems may begin in one eye or simultaneously in both eyes; if vision loss starts in one eye, the other eye is usually affected within several weeks or months. Over time, vision in both eyes worsens with a severe loss of sharpness (visual acuity) and color vision. This condition mainly affects central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. Vision loss results from the death of cells in the nerve that relays visual information from the eyes to the brain (the optic nerve). Although central vision gradually improves in a small percentage of cases, in most cases the vision loss is profound and permanent.Vision loss is typically the only symptom of LHON; however, some families with additional signs and symptoms have been reported. In these individuals, the condition is described as "LHON plus." In addition to vision loss, the features of LHON plus can include movement disorders, tremors, and abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects). Some affected individuals develop features similar to multiple sclerosis, which is a chronic disorder characterized by muscle weakness, poor coordination, numbness, and a variety of other health problems.  https://ghr.nlm.nih.gov/condition/leber-hereditary-optic-neuropathy

Clinical features

Cardiac arrhythmia
MedGen UID:
2039
Concept ID:
C0003811
Finding
A disorder in which there is abnormal electrical activity in the heart.
Central retinal vessel vascular tortuosity
MedGen UID:
867211
Concept ID:
C4021569
Finding
The presence of an increased number of twists and turns of retinal blood vessels (arteries, arterioles, veins, venules).
Ataxia
MedGen UID:
849
Concept ID:
C0007758
Sign or Symptom
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dystonia
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
Polyneuropathy
MedGen UID:
57502
Concept ID:
C0152025
Disease or Syndrome
A disease or disorder affecting more than one nerve.
Postural tremor
MedGen UID:
66696
Concept ID:
C0234378
Sign or Symptom
A type of tremors that is triggered by holding a limb in a fixed position.
Bilateral basal ganglia lesions
MedGen UID:
870485
Concept ID:
C4024932
Finding
Muscular Diseases
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Abnormality of metabolism/homeostasis
MedGen UID:
867398
Concept ID:
C4021768
Finding
Central retinal vessel vascular tortuosity
MedGen UID:
867211
Concept ID:
C4021569
Finding
The presence of an increased number of twists and turns of retinal blood vessels (arteries, arterioles, veins, venules).
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
A disorder characterized by loss of optic nerve fibers. It may be inherited or acquired. Acquired causes include ischemia, optic nerve neuropathy, glaucoma, trauma, radiation, brain tumors, and multiple sclerosis. It leads to vision disturbances.
Papilledema
MedGen UID:
10565
Concept ID:
C0030353
Finding
Papilledema refers to edema (swelling) of the optic disc secondary to any factor which increases cerebral spinal fluid pressure.
Centrocecal scotoma
MedGen UID:
82870
Concept ID:
C0271196
Finding
A scotoma (area of diminished vision within the visual field) located between the central point of fixation and the blind spot with a roughly horizontal oval shape.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disk (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.
Leber optic atrophy
MedGen UID:
182973
Concept ID:
C0917796
Disease or Syndrome
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 mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many individuals with a mutation of mtDNA 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, which is well-illustrated by the overlapping spectrum of disease phenotypes (including mitochondrial recessive ataxia syndrome (MIRAS) resulting from mutation of the nuclear gene POLG, which has emerged as a major cause of mitochondrial disease. Common clinical features of mitochondrial disease – whether involving a mitochondrial or nuclear gene – 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.
Visual loss
MedGen UID:
784038
Concept ID:
C3665386
Finding
Disturbance of eyesight.
Central retinal vessel vascular tortuosity
MedGen UID:
867211
Concept ID:
C4021569
Finding
The presence of an increased number of twists and turns of retinal blood vessels (arteries, arterioles, veins, venules).
Large central visual field defect
MedGen UID:
871312
Concept ID:
C4025800
Finding
Sudden loss of visual acuity
MedGen UID:
893113
Concept ID:
C4072828
Finding
Severe loss of visual acuity within hours or days. This is characteristic of Leber hereditary optic neuropathy.

Term Hierarchy

Conditions with this feature

Mitochondrial encephalomyopathy
MedGen UID:
57960
Concept ID:
C0162666
Disease or Syndrome
A heterogenous group of disorders characterized by alterations of mitochondrial metabolism that result in muscle and nervous system dysfunction. These are often multisystemic and vary considerably in age at onset (usually in the first or second decade of life), distribution of affected muscles, severity, and course. (From Adams et al., Principles of Neurology, 6th ed, pp984-5)
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke
MedGen UID:
56485
Concept ID:
C0162671
Disease or Syndrome
MELAS syndrome, comprising mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, is a genetically heterogeneous mitochondrial disorder with a variable clinical phenotype. The disorder is accompanied by features of central nervous system involvement, including seizures, hemiparesis, hemianopsia, cortical blindness, and episodic vomiting (Pavlakis et al., 1984; Montagna et al., 1988). Other mitochondrial encephalomyopathies include Leigh syndrome (LS; 256000), Kearns-Sayre syndrome (KSS; 530000), MERRF syndrome (545000), and Leber optic atrophy (535000).
Myoclonus with epilepsy with ragged red fibers
MedGen UID:
56486
Concept ID:
C0162672
Disease or Syndrome
A condition that can be caused by mutation(s) in more than one mitochondrial gene. It is characterized by myoclonic epilepsy and ragged-red fibers present on muscle biopsy.
Hepatic failure, early-onset, and neurologic disorder due to cytochrome C oxidase deficiency
MedGen UID:
75662
Concept ID:
C0268237
Congenital Abnormality
Leigh syndrome (or subacute necrotizing encephalomyelopathy) is characterized by decompensation (often with elevated lactate levels in blood and/or CSF) during an intercurrent illness. It is typically associated with psychomotor retardation or regression, often followed by transient or prolonged stabilization or even improvement, but inevitably resulting in eventual progressive neurologic decline, typically occurring in stepwise decrements. Neurologic manifestations include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy. Extraneurologic manifestations may include hypertrophic cardiomyopathy, hypertrichosis, anemia, renal tubulopathy, liver involvement, ptosis, and muscle weakness. Onset is typically between ages three and 12 months; about 50% of affected individuals die by age three years, most often as a result of respiratory or cardiac failure. Later onset (including in adulthood) and long-term survival may occasionally occur.
Exercise intolerance
MedGen UID:
603270
Concept ID:
C0424551
Finding
A reduction in the ability to perform or withstand activities that induce physical or mental exertion.
Multisystem disorder
MedGen UID:
107853
Concept ID:
C0559758
Disease or Syndrome
Leber optic atrophy
MedGen UID:
182973
Concept ID:
C0917796
Disease or Syndrome
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 mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many individuals with a mutation of mtDNA 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, which is well-illustrated by the overlapping spectrum of disease phenotypes (including mitochondrial recessive ataxia syndrome (MIRAS) resulting from mutation of the nuclear gene POLG, which has emerged as a major cause of mitochondrial disease. Common clinical features of mitochondrial disease – whether involving a mitochondrial or nuclear gene – 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.
Oxyphilic adenoma
MedGen UID:
307150
Concept ID:
C1510502
Neoplastic Process
Oncocytomas are usually benign tumors that occur in various organs but particularly in the kidneys. Histologic evaluation of renal oncocytomas shows that they are composed entirely of peculiar epithelial cells with granular eosinophilic cytoplasm. Ultrastructural characterization exhibits densely packed cells with mitochondria, which show morphologic differences from those in normal cells. On the average they are larger than those in renal carcinoma cells and their shape is abnormal (summary by Welter et al., 1989).
Cancers, Colorectal
MedGen UID:
287122
Concept ID:
C1527249
Neoplastic Process
The colon and rectum are part of the large intestine. Colorectal cancer occurs when tumors form in the lining of the large intestine. It is common in both men and women. The risk of developing colorectal cancer rises after age 50. You're also more likely to get it if you have colorectal polyps, a family history of colorectal cancer, ulcerative colitis or Crohn's disease, eat a diet high in fat, or smoke. Symptoms of colorectal cancer include. -Diarrhea or constipation. -A feeling that your bowel does not empty completely. -Blood (either bright red or very dark) in your stool. -Stools that are narrower than usual. -Frequent gas pains or cramps, or feeling full or bloated. -Weight loss with no known reason. -Fatigue. -Nausea or vomiting. Because you may not have symptoms at first, it's important to have screening tests. Everyone over 50 should get screened. Tests include colonoscopy and tests for blood in the stool. Treatments for colorectal cancer include surgery, chemotherapy, radiation, or a combination. Surgery can usually cure it when it is found early. NIH: National Cancer Institute.
Infantile histiocytoid cardiomyopathy
MedGen UID:
310844
Concept ID:
C1708371
Disease or Syndrome
Histiocytoid cardiomyopathy, which was initially described by Voth (1962), goes by various names, including infantile xanthomatous cardiomyopathy (MacMahon, 1971), focal lipid cardiomyopathy (Bove and Schwartz, 1973), oncocytic cardiomyopathy (Silver et al., 1980), infantile cardiomyopathy with histiocytoid change (Ferrans et al., 1976), and foamy myocardial transformation of infancy (Yatani et al., 1988). The disorder is a rare but distinctive entity of infancy and childhood characterized by the presence of characteristic pale granular foamy histiocyte-like cells within the myocardium. It usually affects children younger than 2 years of age, with a clear predominance of females over males. Infants present with dysrhythmia or cardiac arrest, and the clinical course is usually fulminant, sometimes simulating sudden infant death syndrome (Andreu et al., 2000).
Aminoglycoside-induced deafness
MedGen UID:
374074
Concept ID:
C1838854
Disease or Syndrome
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).
Recurrent myoglobinuria
MedGen UID:
333201
Concept ID:
C1838877
Finding
Recurring episodes of myoglobinuria, i.e., of the presence of myoglobin in the urine. This is usually a consequence of rhabdomyolysis, i.e., of the destruction of muscle tissue.
Leigh syndrome due to mitochondrial complex I deficiency
MedGen UID:
333220
Concept ID:
C1838951
Disease or Syndrome
Striatal necrosis, bilateral, with dystonia
MedGen UID:
325555
Concept ID:
C1838954
Finding
Mitochondrial complex I deficiency
MedGen UID:
374101
Concept ID:
C1838979
Disease or Syndrome
Isolated complex I deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders (McFarland et al., 2004; Kirby et al., 2004). It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome (256000), Leber hereditary optic neuropathy (535000), and some forms of Parkinson disease (see 556500) (Loeffen et al., 2000; Pitkanen et al., 1996; Robinson, 1998). Genetic Heterogeneity of Complex I Deficiency Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible (summary by Haack et al., 2012). However, the majority of cases are caused by mutations in nuclear-encoded genes (Loeffen et al., 2000; Triepels et al., 2001). Complex I deficiency with autosomal recessive inheritance results from mutation in nuclear-encoded subunit genes, including NDUFV1 (161015), NDUFV2 (600532), NDUFS1 (157655), NDUFS2 (602985), NDUFS3 (603846), NDUFS4 (602694), NDUFS6 (603848), NDUFS7 (601825), NDUFS8 (602141), NDUFA2 (602137), NDUFA11 (612638), NDUFAF3 (612911), NDUFA10 (603835), NDUFB3 (603839), NDUFB8 (602140), NDUFB9 (601445), and the complex I assembly genes NDUFAF2 (609653), NDUFAF4 (611776), NDUFAF5 (612360), NUBPL (613621), NDUFAF1 (606934), TMEM126B (615533), TIMMDC1 (615534), and NDUFA13 (609435). The disorder can also be caused by mutation in other nuclear-encoded genes, including FOXRED1 (613622), ACAD9 (611103; see 611126), and MTFMT (611766; see 256000). X-linked inheritance is observed with mutations in the NDUFA1 (300078) and NDUFB11 (300403) genes. Complex I deficiency with mitochondrial inheritance has been associated with mutation in 6 mitochondrial-encoded components of complex I: MTND1 (516000), MTND2 (516001), MTND3 (516002), MTND4 (516003), MTND5 (516005), MTND6 (516006). Most of these patients have a phenotype of Leber hereditary optic neuropathy (LHON; 535000) or Leigh syndrome (256000). Features of complex I deficiency may also be caused by mutation in other mitochondrial genes, including MTTS2 (590085).
Leber hereditary optic neuropathy with dystonia
MedGen UID:
333240
Concept ID:
C1839040
Disease or Syndrome
Leber optic atrophy, susceptibility to
MedGen UID:
374333
Concept ID:
C1839891
Finding
Susceptibility to obesity
MedGen UID:
356231
Concept ID:
C1866432
Finding
Deafness, nonsyndromic sensorineural, mitochondrial
MedGen UID:
463247
Concept ID:
C3151897
Disease or Syndrome
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).
PARKINSON DISEASE 6, MODIFIER OF
MedGen UID:
865035
Concept ID:
C4016598
Finding
Exercise intolerance, cardiomyopathy, and septooptic dysplasia
MedGen UID:
865036
Concept ID:
C4016599
Finding
Parkinsonism/MELAS overlap syndrome
MedGen UID:
865037
Concept ID:
C4016600
Finding
Sideroblastic anemia, acquired idiopathic
MedGen UID:
865038
Concept ID:
C4016601
Finding
Cytochrome c oxidase i deficiency
MedGen UID:
865039
Concept ID:
C4016602
Finding
Seizures and lactic acidosis
MedGen UID:
865040
Concept ID:
C4016603
Finding
Mitochondrial complex IV deficiency with recurrent myoglobinuria
MedGen UID:
866063
Concept ID:
C4017626
Finding

Recent clinical studies

Etiology

Kulkarni R, Reither A, Thomas RA, Tucker JD
Mutat Res 2009 Apr 26;663(1-2):46-51. Epub 2009 Feb 4 doi: 10.1016/j.mrfmmm.2009.01.004. PMID: 19428369

Diagnosis

Kulkarni R, Reither A, Thomas RA, Tucker JD
Mutat Res 2009 Apr 26;663(1-2):46-51. Epub 2009 Feb 4 doi: 10.1016/j.mrfmmm.2009.01.004. PMID: 19428369
McLeod JG, Low PA, Morgan JA
Neurology 1978 Feb;28(2):179-84. PMID: 563998

Clinical prediction guides

Kulkarni R, Reither A, Thomas RA, Tucker JD
Mutat Res 2009 Apr 26;663(1-2):46-51. Epub 2009 Feb 4 doi: 10.1016/j.mrfmmm.2009.01.004. PMID: 19428369

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