Genetic defects causing mitochondrial respiratory chain disorders and disease
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Abstract:
Genetic defects of the mitochondrial respiratory chain show marked phenotypic variability. Laboratory diagnosis is complicated and includes biochemical screening tests, tissue histopathology, functional enzyme studies, and molecular tests where available. Normal respiratory chain function necessitates the co-ordinated expression of over 100 different gene loci, and the interaction of two genetic systems, the nuclear and mitochondrial genomes. Thus genetic counselling for the mitochondrial disorders is extremely challenging. In this review, the classes of mitochondrial and nuclear defects that give rise to functional abnormalities of the mitochondrial respiratory chain are discussed, with specific instructive examples described in some detail.Keywords:
Mitochondrial disease
Mitochondrial respiratory chain
Nuclear gene
Lactic acidosis
Mitochondrial respiratory chain
Mitochondrial disease
Nuclear gene
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Mitochondrial disorders have the highest incidence among congenital metabolic diseases, and are thought to occur at a rate of 1 in 5000 births. About 25% of the diseases diagnosed as mitochondrial disorders in the field of pediatrics have mitochondrial DNA abnormalities, while the rest occur due to defects in genes encoded in the nucleus. The most important function of the mitochondria is biosynthesis of ATP. Mitochondrial disorders are nearly synonymous with mitochondrial respiratory chain disorder, as respiratory chain complexes serve a central role in ATP biosynthesis. By next-generation sequencing of the exome, we analyzed 104 patients with mitochondrial respiratory chain disorders. The results of analysis to date were 18 patients with novel variants in genes previously reported to be disease-causing, and 27 patients with mutations in genes suggested to be associated in some way with mitochondria, and it is likely that they are new disease-causing genes in mitochondrial disorders. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.
Mitochondrial disease
Mitochondrial respiratory chain
Human mitochondrial genetics
Exome
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The first observation of mitochondrial respiratory chain dysfunction was made in 1959 with the report of a biochemical defect in the skeletal muscle of a euthyroid patient with hypermetabolism. Since then, numerous disorders have been found to be associated with mitochondrial respiratory chain dysfunction, the nervous system being particularly affected. In 1988, the discovery of large-scale deletions of mitochondrial DNA (mtDNA) in mitochondrial myopathies and a point mutation associated with Leber's hereditary optic neuropathy marked the beginning of a new era of mitochondrial research with the identification of many more pathogenic mutations. More recently, there has been great interest in the role of mitochondrial dysfunction in neurodegenerative diseases and aging. In this review, we discuss inborn and acquired mitochondrial abnormalities and the relationship of mitochondrial respiratory chain dysfunction to neurological disorders.
Mitochondrial disease
Mitochondrial respiratory chain
Kearns–Sayre syndrome
Mitochondrial Encephalomyopathies
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Mitochondrial disorders, once thought to be relatively rare, are now thought to be the most prevalent metabolic disease. They represent a challenge to clinicians, especially in children, in whom clinical presentation and course show enormous variation. We report a respiratory chain enzyme activity disorder (complex I, III and IV) in a girl, with a severe presentation since the perinatal period. An older female sibling had died at the age of 11 months from an encephalopathy, with a similar clinical presentation. Enzyme activity disorders could not been disclosed. This association has been described only rarely. Mitochondrial disorders associated with defects in the respiratory chain can be attributable to mutations in the mitochondrial genome (mitochondrial DNA) or the nuclear genome (nuclear DNA). The diagnosis is based on the presence of clusters of abnormal mitochondria in muscle cells and a biochemically defined defect in the respiratory chain enzymes or, more recently, also on mutations in the mitochondrial DNA. In our case muscular biopsy to assess enzymatic activity of the respiratory chain complexes disclosed defects in respiratory chain complexes I, III and IV (cytochrome c oxidase). The patients, as our case, usually present early in life and are more severely affected than patients with isolated complex deficiencies. Therapy remains largely ineffective.
Mitochondrial disease
Mitochondrial respiratory chain
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Genetic defects of the mitochondrial respiratory chain show marked phenotypic variability. Laboratory diagnosis is complicated and includes biochemical screening tests, tissue histopathology, functional enzyme studies, and molecular tests where available. Normal respiratory chain function necessitates the co-ordinated expression of over 100 different gene loci, and the interaction of two genetic systems, the nuclear and mitochondrial genomes. Thus genetic counselling for the mitochondrial disorders is extremely challenging. In this review, the classes of mitochondrial and nuclear defects that give rise to functional abnormalities of the mitochondrial respiratory chain are discussed, with specific instructive examples described in some detail.
Mitochondrial disease
Mitochondrial respiratory chain
Nuclear gene
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Mitochondrial respiratory chain
Mitochondrial disease
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Mitochondrial disease
Mitochondrial respiratory chain
Mitochondrial matrix
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Abstract Two homoplasmic variants in tRNA Glu (m.14674T>C/G) are associated with reversible infantile respiratory chain deficiency. This study sought to further characterize the expression of the individual mitochondrial respiratory chain complexes and to describe the natural history of the disease. Seven patients from four families with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant were investigated. All patients underwent skeletal muscle biopsy and mtDNA sequencing. Whole‐genome sequencing was performed in one family. Western blot and immunohistochemical analyses were used to characterize the expression of the individual respiratory chain complexes. Patients presented with hypotonia and feeding difficulties within the first weeks or months of life, except for one patient who first showed symptoms at 4 years of age. Histopathological findings in muscle included lipid accumulation, numerous COX‐deficient fibers, and mitochondrial proliferation. Ultrastructural abnormalities included enlarged mitochondria with concentric cristae and dense mitochondrial matrix. The m.14674T>C variant in MT ‐ TE was identified in all patients. Immunohistochemistry and immunoblotting demonstrated pronounced deficiency of the complex I subunit NDUFB8. The expression of MTCO1, a complex IV subunit, was also decreased, but not to the same extent as NDUFB8. Longitudinal follow‐up data demonstrated that not all features of the disorder are entirely transient, that the disease may be progressive, and that signs and symptoms of myopathy may develop during childhood. This study sheds new light on the involvement of complex I in reversible infantile respiratory chain deficiency, it shows that the disorder may be progressive, and that myopathy can develop without an infantile episode.
Mitochondrial respiratory chain
Mitochondrial disease
Mitochondrial matrix
Congenital myopathy
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