Mitochondrial encephalomyopathies, with

MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) resuits from a point mutation in the mitochondriai tRNA gene. 

M13. Mirabella, M., Di Giovanni, S., Silvestri, G., Tonali, P., and Servidei, S., Apoptosis in mitochondrial encephalomyopathies with mitochondrial DNA mutations A potential pathogenic mechanism. Brain 123, 93-104 (2000). 

Abnormalities of the respiratoiy chain. These are increasingly identified as the hallmark of mitochondrial diseases or mitochondrial encephalomyopathies [13]. They can be identified on the basis of polarographic studies showing differential impairment in the ability of isolated intact mitochondria to use different substrates. For example, defective respiration with NAD-dependent substrates, such as pyruvate and malate, but normal respiration with FAD-dependent substrates, such as succinate, suggests an isolated defect of complex I (Fig. 42-3). However, defective respiration with both types of substrates in the presence of normal cytochrome c oxidase activity, also termed complex IV, localizes the lesions to complex III (Fig. 42-3). Because frozen muscle is much more commonly available than fresh tissue, electron transport is usually measured through discrete portions of the respiratory chain. Thus, isolated defects of NADH-cytochrome c reductase, or NADH-coenzyme Q (CoQ) reductase suggest a problem within complex I, while a simultaneous defect of NADH and succinate-cytochrome c reductase activities points to a biochemical error in complex III (Fig. 42-3). Isolated defects of complex III can be confirmed by measuring reduced CoQ-cytochrome c reductase activity. 

Coenzyme Q10 (CoQlO) deficiency. This mitochondrial encephalomyopathy has three main clinical presentations. A predominantly myopathic form is characterized by the triad of exercise intolerance, recurrent myoglobinuria, and CNS involvement. A more frequent ataxic form is dominated by ataxia and cerebellar atrophy, variously associated with weakness, developmental delay, seizures, pyramidal signs, and peripheral neuropathy, often simulating spinocerebellar atrophy. A third presentation with fatal infantile encephalomyopathy and renal involvement, has been described in two families. The biochemical defect (or defects) presumably involve different steps in the biosynthesis of CoQlO, but are still unknown, as are the molecular defects. Diagnosis, however, is important because all patients - and especially those with the myopathic and infantile forms - benefit from CoQlO supplementation [13,14]. 

G4. Goto, Y., Nonaka, I., and Horai, S., A mutation in the tRNA1 111 gene associated with file MELAS subgroup of mitochondrial encephalomyopathies. Nature 348, 651—653 (1990). 

H5. Hess, J. F., Parisi, M. A., Bennett, J. L., and Clayton, D. A., Impairment of mitochondrial transcription termination by a point mutation associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 351, 236-239 (1991). 

L12. Liou, C. W., Huang, C. C., Lin, T. K., Tsai, J. L., and Wei, Y. H., Correction of pancreatic /3-cell dysfunction with coenzyme Qio in a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome and diabetes mellitus. Eur. Neurol. 43, 54-55 (2000). 

Figure 8-4. The effect of the MELAS mutation on mitochondrial function is to interfere with function of respiratory Complex I or I and IV, leading to increased levels of NADH and thus also of lactate. CoQ, coenzyme Q MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes RC, respiratory complex.

Borchert, A., E. Wilichowski, and F. Hanefeld, Supplementation with creatine monohydrate in children with mitochondrial encephalomyopathies. Muscle Nerve, 22 1299-1300, 1999. 

This complex contains 11 polypeptide subunits of which only one is encoded by mtDNA. Defects of complex III are relatively uncommon and clinical presentations vary. Fatal infantile encephalomyopathies have been described in which severe neonatal lactic acidosis and hypotonia are present along with generalized amino aciduria, a Fanconi syndrome of renal insufficiency and eventual coma and death. Muscle biopsy findings may be uninformative since abnormal mitochondrial distribution is not seen, i.e., there are no ragged-red fibers. Other patients present with pure myopathy in later life and the existence of tissue-specific subunits in complex III has been suggested since one of these patients was shown to have normal complex 111 activity in lymphocytes and fibroblasts. 

Although DNA mutations in nuclear DNA may cause mitochondrial dysfunction, the majority of genetically defined mitochondrial diseases are caused by mutations in mtDNA (M15, PI, S4). Point mutations and deletions of mtDNA have been reported to be associated with or responsible for mitochondrial myopathies and/or encephalomyopathies (M15, PI, S4). Patients with such diseases usually manifest major clinical symptoms early in life and at a later stage may develop additional multisystem disorders such as encephalopathy and/or peripheral neuropathy. Most of the mitochondrial myopathies occur sporadically and are often caused by large-scale mtDNA deletions (PI). However, there are several reports on maternally inherited mitochondrial myopathy and familial mitochondrial myopathy. These patients usually harbor a specific mtDNA mutation and often exhibit defects in NADH-CoQ reductase and/or cytochrome c oxidase. 

K7. Kovalenko, S. A., Tanaka, M., Yoneda, M., Iakovlev, A. F., and Ozawa, T., Accumulation of somatic nucleotide substitutions in mitochondrial DNA associated with the 3243 A-to-G tRNALe" UURl mutation in encephalomyopathy and mitochondrial myopathy. Biochem. Biophys. Res. Commun. 222, 201-207 (1996). 

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