Mutations mtDNA

Because few reference values are generally available for neonates, it is recommended to perform a muscle biopsy after the first month of life, unless a life-threatening situation exists. mtDNA analysis can, in principle, be performed in all types of tissues or cells available. However, the extent of heteroplasmy, i.e. the percentage of mutated mtDNA related to the total amount of DNA, varies from tissue to tissue. 

Myoclonic epilepsy with ragged-red fibers (MERPF) is a rare syndrome which shows clear maternal inheritance and a variable clinical pattern including progressive myoclonus, cerebellar ataxia, dementia, and muscle weakness. It is associated with an A-to-G transition at position 8344 of the tRNA Lys gene in the mtDNA. The mutation is heteroplasmic and produces similar multicomplex deficiencies as are seen in KSS. 

Thus, in diseases resulting from mutations of mtDNA, an affected mother would in theory pass the disease to all of her children but only her daughters would transmit the trait. However, in some cases, deletions in mtDNA occur during oogenesis and thus are not inherited from the mother. A number of diseases have now been shown to be due to mutations of mtDNA. These include a variety of myopathies, neurologic disorders, and some cases of diabetes mellitus. 

TABLE 42-1 Clinical features of mitochondrial diseases associated with mtDNA mutations... 

As described above, maternal inheritance has been documented in diseases due to point mutations of mtDNA, while most diseases due to mtDNA deletions or duplications are sporadic. 

Mutations in dGK tend to cause the hepatocerebral phenotype and mutations in TK2 are generally associated with the myopathic variant. However, there are many patients with mtDNA depletion but without mutations in either gene clearly, more genes are implicated and have to be identified. 

All disorders except those in group 5 are due to defects of nDNA and are transmitted by Mendelian inheritance. Disorders of the respiratory chain can be due to defects of nDNA or mtDNA. Usually, mutations of nDNA cause isolated, severe defects of individual respiratory complexes, whereas mutations in mtDNA or defects of intergenomic communication cause variably severe, multiple deficiencies of respiratory chain complexes. The description that follows is based on the biochemical classification. 

Complex I deficiency due to mtDNA mutations (seven subunits of complex I are encoded by mtDNA) can be divided into encephalomyopathies and myopathies. The most important encephalomyopathy is Leber s hereditary optic neuropathy, characterized by acute or subacute loss of vision due to severe bilateral optic atrophy, with onset usually between 18 and 30 years and marked predominance in men. Three mutations (in ND1, ND4 and ND6)... 

Defects of complex III. Like defects of complex I, these can be due to nDNA mutations or to mtDNA mutations. The only nuclear defect described thus far does not affect a complex III subunit, but an ancillary protein needed for proper assembly, BCS1L. Mutations in BCS1L can cause a Leigh s-syndrome-like disorder or a fatal infantile disease called GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death). 

Mutations in the only mtDNA-encoded subunit of complex III (cytochrome b) can cause multisystem disorders or - more commonly - isolated myopathies, manifested by exercise intolerance with or without exercise-related myoglobinuria. Patients with myopathy are almost invariably sporadic, suggesting that the cytochrome b mutations are... 

Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body s systems. These mutations disrupt the mitochondria s ability to generate energy efficiently for the cell. 

Pang, C.Y., Ma, Y.S. and Wei, YU. (2008) MtDNA mutations, functional decline and turnover of mitochondria in aging. Frontiers in Bioscience a Journal and Virtual Library, 13, 3661-3675. 

Mitochondrial diseases are caused by mutations in various mtDNA-encoded genes, most of which result in defective mitochondrial protein synthesis. 

Leber hereditary optic neuroretinopathy [18] A rapid bilateral central vision loss due to optic nerve death. The disease has been associated with several missense mutations in the mtDNA that can act autonomously or in association with each other to cause the disease. 

MNGIE [21] Intermittent diarrhea and intestinal pseudo-obstruction (myoneurogastrointestinal encephalopathy). Mutations in the thymidine-phosphorylase-encoding gene leads to multiple mtDNA deletion and anomalies in mtDNA synthesis. 

PEO [25] A myopathy with progressive muscle weakness and external ophthalmoplegia. Ataxia, episodic ke-toacidotic coma, and early death have been reported associated with single or multiple DNA deletions. Mutations in the gene encoding the muscle isoform of the adenylate carrier (ANTI) have been reported to cause PEO, presumably due to abnormal nucleotide availability for mtDNA synthesis. 

Wolfram syndrome [26] A syndrome of DIDMOAD. While most cases have been ascribed to an autosomal recessive gene mapping to chromosome 4pl6, some cases of early-onset DIDMOAD might result from mtDNA mutations or deletions. 

Fialuridine causes inhibition of mtDNA replication. This inhibition and also mutations of mtDNA, which can result from treatment with the drug, lead eventually to reduced numbers of mitochondria. 

Mutations in mtDNA are responsible for some cases of mitochondrial diseases, such as Leber hereditary optic neuropathy. 

A mutation in any of the 13 protein subunits, the 22 tRNAs, or the two rRNAs whose genes are carried in mitochondrial DNA may possibly cause disease. The 13 protein subunits are all involved in electron transport or oxidative phosphorylation. The syndromes resulting from mutations in mtDNA frequently affect oxidative phosphorylation (OXPHOS) causing what are often called "OXPHOS diseases."3-6 Mitochondrial oxidative phosphorylation also depends upon 100 proteins encoded in the nucleus. Therefore, OXPHOS diseases may result from defects in either mitochondrial or nuclear genes. The former are distinguished by the fact that they are inherited almost exclusively maternally. Most mitochondrial diseases are rare. However, mtDNA is subject to rapid mutation, and it is possible that accumulating mutants in mtDNA may be an important component of aging.h k... 

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