Mitochondrial disorders

The metabolic myopathies are exceptionally complex. Mitochondrial disorders are usually multisystem disorders, in which metabolic dysfunction affects muscle, liver, CNS, and special senses (especially vision) in almost any combination. There is evidence that some forms of mitochondrial disease are inherited, and the preponderance of maternal rather than paternal inheritance is consistent with an abnormality in the mitochondrial genome because almost all (and perhaps all) mitochondria are derived from the ovum. 

In addition to the conditions described above, which involve deficiencies of individual respiratory complexes, there is another important group of mitochondrial disorders which are associated with defects of multiple respiratory complexes. The underlying abnormalities in these disorders are to be found within the mitochondrial genome, which encodes some subunits of all the respiratory complexes except complex II (Figure 12). 

Zeviani M, Tiranti V, Piantadosi C. Mitochondrial disorders. Medicine (Baltimore) 1998 77[1] 59—72. 

Human creatine kinase -MM MAK33 IgGl Cardiac disease, mitochondrial disorders, inflammatory myopathies, myasthenia, polymyositis, McArdle s disease, NMJ disorders, muscular dystrophy, ALS, hypo and hyperthyroid disorders, central core disease, acid maltase deficiency, myoglobinuria, rhabdomyolysis, motor neuron diseases, A. thaliana A. thaliana 2S2 seed storage protein SP + 0.02-0.4% TSP of fresh leaf extract (10-12% TSP of intercellular fluid) 52... 

This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Mitochondria, which are structures in each cell that convert molecules into energy, each contain a small amount of DNA. Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children. 

There was a considerable increase in interest in adult-onset mitochondrial disorders when the American cyclist,... 

Chariot, P. et al. (1999) Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. Journal of Hepatology, 30 (1), 156-160. 

The answer is B. LHON often has an onset in early adulthood. It is a mitochondrial disorder usually resulting from a mutation in one of the proteins of the electron transport chain, particularly complex I, encoded by the mitochondrial genome so there is no chance that the patient can pass the disorder to his children (see Chapter 13). Cataracts would have been detected as opacity in the lenses, and glaucoma would have been identified by an elevated intraocular pressure. Macular degeneration is also associated with central vision loss but is found mainly in patients over age 65. 

F. Mitochondrial disorders exhibit a maternal inheritance pattern. 

Mitochondrial disorders are maternally transmitted because the ovum provides all mitochondria to the fertilized embryo (Figure 13-4). 

Figure 13-4. Pedigrees illustrating inheritance of (A) a mitochondrial disorder and (B) an autosomal dominant disorder exhibiting anticipation. In pedigree A note the similarity to the X-linked dominant inheritance pattern (Figure 13-3A), but incomplete penetrance as exemplified by individuals 11-4 and 111-4. In pedigree B, the age of onset, indicated next to the symbols for affected individuals, becomes progressively earlier with each generation.

The answer is B. The presence of many affected persons in multiple generations of this family suggests autosomal dominant inheritance. Male-to-male transmission of the condition in several generations would rule out both X-linked and mitochondrial disorders. Each affected person has an affected parent and there are multiple affected persons in several successive generations. 

The answer is B. The clinical symptoms in this case strongly suggest a mitochondrial disorder affecting both neurologic and musculoskeletal functions. In such cases, no male-to-male transmission is possible because the mother s ovum provides all the cytoplasmic components, including the mitochondria, for the fertilized egg. A pedigree for this family would resemble the inheritance pattern of an X-linked disorder with the likelihood of variable expression. 

The clinical symptoms of mitochondrial diseases are highly varied and include seizures, vomiting, deafness, dementia, stroke-like episodes, and short stature. Although there are many types of mitochondrial disorders, four of the most common types are as follows Kearns-Sayre syndrome, Leber s hereditary optic atrophy, MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) and MERRE (myoclonic epilepsy with ragged red fibres). 

Since mitochondria are essential to cell health, mitochondrial diseases tend to be severe but, thankfully, relatively uncommon. Accordingly, the medicinal chemistry of mitochondrial disorders is still in its infancy. There are no truly effective drug therapies for mitochondrial disorders, but several agents have been reported to be of some benefit in some individuals. These agents include ubiquinone (coenzyme QIO), carnitine, and riboflavin. These compounds may assist the ailing mitochondria to better complete their metabolic tasks. However, mitochondrial medicinal chemistry is an area of research in need of additional attention. 

Munnich A, Rustin P, Rotig A, Chretien D, Bonnefont JP, Nuttin C, Cormier V, Vassault A, Parvy P, Bardet J, et al (1992) Clinical aspects of mitochondrial disorders. J Inherit Metab Dis 15 448-455... 

Mitochondrial disorders are not commonly regarded as causes of malformations. Facial features included round face, high forehead, small nose, and long flat philtrum, reminiscent of the fetal alcohol syndrome. Limb and trunk involvements included short hands, brachydactyly, hypoplasia of the distal and middle phalanges, hypoplastic nails, and the VACTERL [vertebral anomalies, anal atresia, cardiovascular anomalies, tracheoesophageal fistula, esophageal atresia, renal (kidney) and/or radial anomalies, and preaxial limb anomalies (in front of or above the central axis of the limb)] association [50]. 

In view of the various clinical presentations possibly associated with OXPHOS diseases, it is becoming increasingly important for clinicians to recognize at least the syndromic presentations that are strongly suggestive of a mitochondrial disorder. In addition, however, any unexplained combination of neuromuscular and/or... 

N4. Nishino, I., Spinazzola, A., and Hirano, M., Thymidinephosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283, 689-692 (1999). 

Mitochondrial Disorders of the Nervous System Clinical, Biochemical, and Molecular Genetic Features... 

The presence of lactic acidosis, bilateral hearing loss, progressive muscle weakness, and strokelike episodes was suggestive of a mitochondrial disorder. DNA extracted from peripheral blood cells from the patient, her mother, grandmother, mother s brother, and symptomless younger sister was positive for a mutation... 

At this point, if the results have suggested a specific mitochondrial disorder (e.g., MELAS), then mtDNA isolated from blood cells can be tested for any known mutations associated with the suspected disorder. Unfortunately, many disease-causing mutations are not detectable in mtDNA isolated from blood cells (because of the rapid turnover in these cells, defective mitochondria are often lost). Therefore, inconclusive results may warrant further testing. 

A recurring feature of MELAS and many other mitochondrial disorders is the presence of ragged red fibers that are demonstrable after treating the muscle cells with modified Gomori trichome stain (Fig. 8-2). The muscle biopsy is positive for ragged red fibers in at least 85% of... 

For patients with MELAS and other mitochondrial disorders, this reaction can result in... 

Mutations in the nuclear genes that specify mitochondrial proteins can lead to mitochondrial disorders that obey Mendelian genetics. For... 

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