اختلالات زنجیره تنفسی میتوکندری

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Introduction ٠ Mitochondrial disease was first identified in 1962 in a patient whose mitochondria showed structural abnormalities and loss of coupling between oxidation and phosphorylation. it was not until 20 years later that the relevance of mutated mitochondrial DNA (mtDNA) to human disease began to be appreciated. The small circular double-stranded mtDNA contains genes coding for ribosomal RNA (rRNA) production and various transfer RNAs (tRNA) required for mitochondrial protein biosynthesis, as well as some of the proteins involved in electron transport. 

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Mitochondrial disorders + Because most mitochondrial proteins, including subunits involved in electron transport, are encoded by nuclear genes, these most often follow autosomal recessive inheritance, but autosomal dominant and X-linked forms also occur. ۰ The clinical features are mainly a combination of neurological signs (encephalopathy, dementia, ataxia, dystonia, neuropathy, and seizures) and myopathic signs (hypotonia, weakness, and cardiomyopathy with conduction defects). + Other symptoms and signs may include deafness, diabetes mellitus, retinal pigmentation, and acidosis may occur. 

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1- Leber's hereditary optic neuropathy + Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision. + this affects predominantly young adult males. LHON is only transmitted through the mother, as it is primarily due to mutations in the mitochondrial (not nuclear) genome, and only the egg contributes mitochondria to the embryo. 

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OHistory * This disease was first described by the German ophthalmologist Theodor Leber in 1871. In this paper Leber described four families in which a number of young men suffered abrupt loss of vision in both eyes either simultaneously or sequentially. This disease was initially thought to be X linked but was subsequently shown to be mitochondrial. The nature of the causative mutation was first identified in 1988 by Wallace et al. who discovered the guanine (G) to adenosine (A) mutation at nucleotide position 11778 in nine families.This mutation converts a highly conserved arginine to histidine at codon 340 in the NADH dehydrogenase subunit 4 of complex | of the mitochondrial respiratory chain. 

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OGenetics Leber hereditary optic neuropathy is a condition related to changes in mitochondrial DNA. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. These mutations are at nucleotide positions 11778 G to A, 3460 G to A and 14484 T to C, respectively in the ND4, ND1 and ND6 subunit genes of complex | of the oxidative phosphorylation chain in mitochondria. Mutations in any of the genes disrupt this process to cause a variety of syndromes depending on the type of mutation and other factors. It remains unclear how these genetic changes cause the death of cells in the optic nerve and lead to the specific features of Leber hereditary optic neuropathy. 

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QO Environmental triggers + There is now strong evidence pointing towards the role of environmental triggers in LHON, in particular smoking . + Interestingly, an in vitro study using patient-derived fibroblasts suggest that cigarette smoke exerts a toxic effect on cell survival by affecting mtDNA copy number, oxidative phosphorylation, and ROS detoxification. + Accidental exposure to industrial toxins and certain drugs with putative mitochondrial toxic effects, such as ethambutol and antiretroviral agents, has also been linked with the onset of visual loss in LHON. 

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OSigns and symptoms * This typically evolves to very severe optic atrophy and a permanent decrease of visual acuity. Both eyes become affected either simultaneously (25% of cases) or sequentially (75% of cases) with a median inter-eye delay of 8 weeks. Rarely only one eye may be affected. A pupillary defect may be visible in the acute stage as well. Examination reveals decreased visual acuity, loss of color vision and a cecocentral scotoma on visual field examination. 

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00 رس ‎mona fy Eto‏ ‎ed ae‏ 2 2 Normal Loss of Terminal Vision ۲ [Serene | @ vision Vision Loss * Natural history of LHON; Loss of vision during the acute phase of LHON is thought to be a result of a loss of RGC function, whereas during the atrophic phase this loss of vision is made irreversible by a terminal loss of RGC together with a degeneration of the optic nerve. During the acute phase of LHON, the possibility for natural recovery of vision highlights that pharmacological interference at this time with the aim to restore RGC function could also rescue visual acuity. 

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+ (a) A 23-year-old male with Leber hereditary optic neuropathy in the subacute stage. There is mild pallor of the right optic disc and hyperemia of the left optic disc. (b) Fluorescein angiography does not show any late leakage, confirming that there is no true optic disc swelling. 

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Acute phase of LHON. Optic disc appearance; Optical coherence tomography (OCT) imaging of the optic nerve head and macula. A 29- year-old male presented with visual loss in his left eye followed by his right eye loss 1 month later. 

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Normal vision LHON vision 

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» LHON with demyelinating lesions (LHON Plus) + "LHON Plus" is a name given to a rare variant of the disorder with eye disease together with other conditions. + The symptoms of this higher form of the disease include loss of the brain's ability to control the movement of muscles, tremors, and cardiac arrhythmia. Many cases of LHON plus have been comparable to multiple sclerosis because of the lack of muscular control and because of the presence of demyelinating lesions in the CNS. It is therefore a subtype of MS according to McDonalds definition. 

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OEpidemiology In Northern European populations about one in 9000 people carry one of the three primary LHON mutations. There is a prevalence of between 1:30,000 to 1:50,000 in Europe. The LHON ND4 G11778A mutation dominates as the primary mutation in most of the world with 70% of Northern European cases and 90% of Asian cases. More than 50 percent of males with a mutation and more than 85 percent of females with a mutation never experience vision loss or related medical problems. The particular mutation type may predict the likelihood of penetrance, severity of illness and probability of vision recovery in the affected. 

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ODiagnosis For several reasons, it is a disease with a difficult diagnosis. First of all, itis a hereditary disease, but it does not manifest itself in all people suffering the mutation. For this reason, it may arise with no evidence of a family history of the disease. In order to diagnose it, it is usually necessary to perform a comprehensive neuro-ophthalmology examination and a blood test that examines the mitochondrial DNA. In an eye fundus examination, a micro angiopathy may be seen initially, and a puffiness of the peripapillary nervous fibers layer, which progresses to an optic atrophy. 

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* Molecular diagnostic algorithm for a patient with suspected LHON 

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0 ۲۳۵۲۵۵6۷۲۱ ۵0۵۲۵۵65 ۶۵۲ ۵ 1. Pharmacological treatments Idebenone is a short-chain benzoquinone that interacts with the mitochondrial electron transport chain to enhance cellular respiration. When used in individuals with LHON, it is believed to allow electrons to bypass the dysfunctional complex I. 2. Gene therapy by an indirect strategy, known as allotopic gene expression, where the gene of interest is delivered with an appropriate viral vector, for example, an adeno- associated virus (AAV), to the nuclear genome. The mRNA transcript has a mitochondrial targeting sequence (MTS) that directs it to mitochondria and the resultant protein is eventually imported and localized to the intended mitochondrial compartment. 

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3. Mitochondrial replacement therapy Preventing the maternal transmission of pathogenic mtDNA mutations from mother to child is an important focus of research. Two modified in vitro fertilization (IVF) techniques have been developed, namely, pronuclear transfer and maternal spindle transfer, both of which require donor oocytes that only carry wild-type mtDNA molecules. Y Pronuclear transfer involves the fertilization of the maternal oocyte with the paternal sperm and then Pens of the zygote nucleus into an enucleated Conor OOCYtE secondary oocyte with pathologic mtDNA and pour 0 ey fret canted یه : مس ‎bo‏ ‏“ »0 ۳ 3 مي مس 0 2 از 7ي؟ 0 مر سس 12 oytoplast (enucleated ygote) Implantation 

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¥ Inthe maternal spindle transfer method, the metaphase II spindle of the matemal oocyte is transferred into the enucleated donor oocyte, followed by fertilization with paternal sperm, ‘oocyte with ‘pathologic mtONA 1 Karyoplast — Reconstituted Secondary oocyte Embryo with functional mtONA (wild-type ‏حدر‎ ۱ Py) & cy? ۳۲ cytoplast Implantation + Another important factor to consider in relation to mitochondrial replacement therapy is the possibility of nuclear mitochondrial mismatch that could result in long-term deleterious consequences. 

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2- Myoclonic Epilepsy and Ragged Red Fiber Disease (MERRF) + MERRF disease was first described in 1973 and so called because Gomori’s trichrome staining of muscle revealed abnormal deposits of mitochondria as ‘ragged red’. + In 1988 it was determined that the condition was maternally inherited. ۰ The classic picture is of progressive myoclonic epilepsy, myopathy, and slowly progressive dementia. Optic atrophy is frequently present and the electroencephalogram is characteristically abnormal. Post-mortem brain examination reveals ides tees ۱۳ In 1990 it was reported that MERRF results froma e for lysine tRNA. 

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3- Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) First delineated in 1984, this extremely variable condition is now recognized as one of the most common mitochondrial disorders. Short stature may be a feature, but it is stroke-like episodes that mark out this particular disorder, although these episodes do not necessarily occur in all affected family members. When they do occur, they may manifest as vomiting, headache, or visual disturbance, and sometimes lead to transient hemiplegia or hemianopia. Acommon presenting feature of MELAS is type 2 diabetes mellitus, and a sensorineural hearing loss may also occur (described as maternally inherited diabetes and deafness). These latter clinical features are associated with the most common mutation, an A > G substitution at nucleotide m.3243, which affects tRNA leucine. 

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4-Neurodegeneration, Ataxia, and Retinitis Pigmentosa (NARP) + The early presenting feature is night blindness, which may be followed years later by neurological symptoms. » Dementia may occur in older patients, but seizures can present at almost any age and younger patients show developmental delay. + The majority of cases are due to a single mutation—the T > G substitution at nucleotide m.8993, which occurs in the coding region of subunit 6 of ATPase. This change is often referred to as the NARP mutation. 

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