Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0751651 (mitochondrial disease)
 1,844 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leber's hereditary optic neuropathy (LHON) is an inherited mitochondrial disease that usually leads to acute or subacute bilateral central vision loss. In 95% of cases, LHON is caused by one of three primary mutations of the mitochondrial DNA (mtDNA), m.11778G>A in the MT-ND4 gene, m.14484T>C in the MT-ND6 gene, or m.3460G>A in the MT-ND1 gene. Here we characterize clinically, genetically, and biochemically a LHON family with multiple patients harboring two of these primary LHON mutations, m.11778G>A homoplasmic and m.14484T>C heteroplasmic. The unusually low male-to-female ratio of affected family members is also seen among the other patients previously reported with two primary LHON mutations m.11778G>A and m.14484T>C. While the index patient had very late onset of symptoms at 75years and severe visual loss, her two daughters had both onset in childhood (6 and 9years), with moderate to mild visual loss. A higher degree of heteroplasmy of the m.14484T>C mutation was found to correlate with an earlier age at onset in this family. Ours is the first LHON family harboring two primary LHON mutations where functional studies were performed in several affected family members. A more pronounced bioenergetic defect was found to correlate with an earlier age at onset. The patient with the earliest age at onset had a more significant complex I dysfunction than all controls, including the LHON patient with only the m.11778G>A mutation, suggesting a synergistic effect of the two primary LHON mutations in this patient.
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PMID:Characterization of a Leber's hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m.11778G>A and m.14484T>C of the mitochondrial DNA. 2772 Oct 48

Leber's hereditary optic neuropathy (LHON) is a relatively common, rapidly progressing inherited optic neuropathy wherein LHON-affected eyes undergo optic nerve atrophy due to retinal ganglion cell (RGC) loss. It is a maternally inherited (or sporadic) mitochondrial disorder caused primarily by mutations in genes that encode components of respiratory complex (RC)1 in mitochondria. Mitochondrial deficiency of RC1 compromises ATP production and oxidative stress management in RGCs. The most common LHON-causing mutations are 11778G>A, 3460G>A, and 14484T>C point mutations in MT-ND4, MT-ND1, and MT-ND6. The unusually high mitochondrial load of RGCs makes them particularly sensitive to these mutations. Patients with LHON may be prescribed ubiquinone (a component of RC3) or idebenone, a ubiquinone analogue with enhanced bioavailability to act downstream of RC1. The challenge of accessing the inner mitochondrial membrane with gene therapy for LHON, and other mitochondrial diseases, may be overcome by incorporation of a specific mitochondrion-targeting sequence (MTS) that enables allotropic expression of a nucleus-transcribed ND4 transgene. Because LHON penetrance is incomplete among carriers of the aforementioned mutations, identification of environmental factors, such as heavy smoking, that interact with genetics in the phenotypic expression of LHON may be helpful toward preventing or delaying disease development. LHON has become a model for mitochondrial and neurogenerative diseases owing to it having a clearly identified genetic cause and its early onset and rapid progression characteristics. Hence, LHON studies and genetic treatment advances may inform research of other diseases.
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PMID:Leber's Hereditary Optic Neuropathy as a Promising Disease for Gene Therapy Development. 3160 6