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Leber's optic atrophy(LHON)

MedGen UID:
182973
Concept ID:
C0917796
Disease or Syndrome
Synonyms: Hereditary optic neuroretinopathy; Leber Hereditary Optic Neuropathy; Leber optic atrophy; Leber's disease; Leber's Hereditary Optic Neuropathy; Leber's optic neuropathy; LHON; Optic Atrophy, Hereditary, Leber; Optic atrophy, Leber type
Modes of inheritance:
Heterogeneous
MedGen UID:
5539
Concept ID:
C0019409
Qualitative Concept
Made up of elements or ingredients that are not alike.
Mitochondrial inheritance
MedGen UID:
504838
Concept ID:
CN001305
Finding
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).
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: ND6; ND5; ND4L; ND4; ND2; ND1; CYTB; COX3; ATP6
OMIM®: 535000

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 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.  http://ghr.nlm.nih.gov/condition/leber-hereditary-optic-neuropathy

Clinical features

Centrocecal scotoma
MedGen UID:
82870
Concept ID:
C0271196
Finding
Visual loss
MedGen UID:
504502
Concept ID:
CN000537
Finding
Loss of visual acuity (implying that vision was better at a certain timepoint in live - otherwise the term is impaired vision or a subclass of that).
Optic atrophy
MedGen UID:
504537
Concept ID:
CN000609
Finding
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Leber optic atrophy
MedGen UID:
504730
Concept ID:
CN001044
Finding
Degeneration of retinal ganglion cells and their axons.
Optic neuropathy
MedGen UID:
504742
Concept ID:
CN001070
Finding
Central retinal vessel vascular tortuosity
MedGen UID:
446856
Concept ID:
CN006814
Finding
The presence of an increased number of twists and turns of retinal blood vessels (arteries, arterioles, veins, venules).
Ataxia
MedGen UID:
504767
Concept ID:
CN001146
Finding
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).
Polyneuropathy
MedGen UID:
504780
Concept ID:
CN001165
Finding
A generalized disorder of peripheral nerves.
Dystonia
MedGen UID:
504804
Concept ID:
CN001220
Finding
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.
Postural tremor
MedGen UID:
505141
Concept ID:
CN001971
Finding
A type of tremors that is triggered by holding a limb in a fixed position.
Arrhythmia
MedGen UID:
66750
Concept ID:
C0237314
Finding
Central retinal vessel vascular tortuosity
MedGen UID:
446856
Concept ID:
CN006814
Finding
The presence of an increased number of twists and turns of retinal blood vessels (arteries, arterioles, veins, venules).
Myopathy
MedGen UID:
505479
Concept ID:
CN002886
Finding
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews
  • CROGLeber's optic atrophy

Recent clinical studies

Etiology

Kulkarni R, Marples B, Balasubramaniam M, Thomas RA, Tucker JD
Radiat Res 2010 May;173(5):635-44. doi: 10.1667/RR1737.1. PMID: 20426663
Elliott WJ
Curr Hypertens Rep 2003 Dec;5(6):486-92. PMID: 14594569
DeCarlo DK, Nowakowski R
J Am Optom Assoc 1999 Oct;70(10):647-52. PMID: 10561923
Holt IJ, Miller DH, Harding AE
J Neurol Neurosurg Psychiatry 1988 Aug;51(8):1075-7. PMID: 2905730Free PMC Article
Seidenwurm D, Novotny E Jr, Marshall W, Enzmann D
AJNR Am J Neuroradiol 1986 Jul-Aug;7(4):629-32. PMID: 3088941

Diagnosis

Beard D
Occup Health (Lond) 1990 Dec;42(12):365. PMID: 2255471
Lauer SA, Ackerman J, Sunness J, Bluth EM, Kim CK
Ann Ophthalmol 1985 Feb;17(2):146-8. PMID: 3994214
van Lith GH
Doc Ophthalmol 1980 Apr 15;48(2):255-9. PMID: 7398525
McLeod JG, Low PA, Morgan JA
Proc Aust Assoc Neurol 1975;12:23-5. PMID: 1215391
de Weerdt CJ, Went LN
Acta Neurol Scand 1971;47(5):541-54. PMID: 5139723

Therapy

Elliott WJ
Curr Hypertens Rep 2003 Dec;5(6):486-92. PMID: 14594569
Cotticelli L, Rinaldi E, D'Alessandro L, Russo S, Libondi T, Costagliola C
Metab Ophthalmol 1984-1985;8(1):31-4. PMID: 6521627
van Lith GH
Doc Ophthalmol 1980 Apr 15;48(2):255-9. PMID: 7398525
Calabrese EJ
Med Hypotheses 1979 Sep;5(9):1045-9. PMID: 522706
Davies DW, Kadar D, Steward DJ, Munro IR
Can Anaesth Soc J 1975 Sep;22(5):547-52. PMID: 1156938

Prognosis

Elliott WJ
Curr Hypertens Rep 2003 Dec;5(6):486-92. PMID: 14594569
Sadun AA, Martone JF, Muci-Mendoza R, Reyes L, DuBois L, Silva JC, Roman G, Caballero B
Arch Ophthalmol 1994 May;112(5):691-9. PMID: 8185530
Calabrese EJ
Med Hypotheses 1979 Sep;5(9):1045-9. PMID: 522706

Clinical prediction guides

Elliott WJ
Curr Hypertens Rep 2003 Dec;5(6):486-92. PMID: 14594569
Bruyn GW, Vielvoye GJ, Went LN
J Neurol Sci 1991 Jun;103(2):195-202. PMID: 1880538
Holt IJ, Miller DH, Harding AE
J Neurol Neurosurg Psychiatry 1988 Aug;51(8):1075-7. PMID: 2905730Free PMC Article
Calabrese EJ
Med Hypotheses 1979 Sep;5(9):1045-9. PMID: 522706
Adams JH, Blackwood W, Wilson J
Brain 1966 Mar;89(1):15-26. PMID: 5910901

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