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Abstract
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 mutations of nuclear or mtDNA. Some mitochondrial disorders only affect a single organ (such as LHON), but many involve multiple organ systems and often present with prominent neurologic and myopathic features (Arpa et al., 2003).
Mitochondrial disorders may be caused by defects of nuclear DNA or mtDNA. Nuclear gene defects may be inherited in an autosomal recessive manner or an autosomal dominant manner. Mitochondrial DNA defects are transmitted by maternal inheritance. Mitochondrial DNA deletions generally occur de novo and thus cause disease in one family member only, with no significant risk to other family members (Chinnery et al., 2004).
Mitochondrial DNA point mutations and duplications may be transmitted down the maternal line. The father of a proband is not at risk of having the disease-causing mtDNA mutation, but the mother of a proband (usually) has the mitochondrial mutation and may or may not have symptoms. A male does not transmit the mtDNA mutation to his offspring. A female harboring a heteroplasmic mtDNA point mutation may transmit a variable amount of mutant mtDNA to her offspring, resulting in considerable clinical variability among sibs within the same family. Prenatal genetic testing and interpretation of test results for mtDNA disorders are difficult because of mtDNA heteroplasmy (Leonard and Schapira, 2000a).
A mitochondrial dysfunction and oxidative damage play role s in the pathogenesis of numerous disorders, e.g. PD, AD, HD, ALS, Wilson’s disease, Friedreich’s ataxia , multiple sclerosis and a number of inherited disorders of the mitochondrial genome, the mitochondrial encephalomyopathies (e.g., Leber’s disease with optic a trophy and dystonia, MELA S, MERR F, Leigh’ s disease , Kearns –Sayre syndrome). The list of mitochondria- related diseases is growing rapidly: cancer, heart failure, diabetes, obesity, ischemia-reperfusion injury, atherosclerosis, certain liver diseases and asbestosis. They all share the common features of disturbances of the mitochondrial Ca2+, ATP or ROS metabolism (Van Houten et al., 2006).
Mitochondrial disorders may present at any age. In general terms, nuclear DNA mutations present in childhood and mtDNA mutations (primary or secondary to a nuclear DNA abnormality) present in late childhood or adult life. Many affected individuals display a cluster of clinical features that fall into a discrete clinical syndrome, such as KSS, CPEO, MELAS, MERRF, NARP or LS. However, considerable clinical variability exists and many individuals do not fit neatly into one particular category (Arpa et al., 2003).
Common clinical features of mitochondrial disease include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. The central nervous system findings are often 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 (Arpa et al., 2003).
In some individuals, the clinical picture is characteristic of a specific mitochondrial disorder (e.g., LHON, NARP, or maternally inherited LS), and the diagnosis can be confirmed by molecular genetic testing of DNA extracted from a blood sample. In many individuals, such is not the case, and a more structured approach is needed, including family history, blood and/or CSF lactate concentration, neuroimaging, cardiac evaluation, and muscle biopsy for histologic or histochemical evidence of mitochondrial disease, and molecular genetic testing for a mtDNA mutation (Barragan-Campos et al., 2005).
The management of mitochondrial disease is largely supportive. Management issues may include early diagnosis and treatment of diabetes mellitus, cardiac pacing, ptosis correction, and intraocular lens replacement for cataracts. Individuals with complex I and/or complex II deficiency may benefit from oral administration of riboflavin (Chinnery and Turnbull, 2001).