Disorders of the respiratory chain

Deficient activity of muscle cytochrome c oxidase has also been reported in a patient with a mitochondrial myopathy associated with chronic lactic acidaemia, growth failure and nerve deafness (Monnens etaL, 1975) and in a patient with subacute necrotizing encephalomyelopathy (Leigh s disease) 

(1979), Carrier detection of pyruvate carboxylase deficiency in fibroblasts and lymphocytes. Pediatr. Res., 13,1101. 

Leiter, A.B. and Barker, B.Q. (1979a), Pyruvate carboxylase deficiency and lactic acidosis in a retarded child without Leigh s disease. Pediatr. Res., 13,109. 

and Weinberg, M.B. (1979b), Pyruvate carboxylase and phosphoenolpyruvate carboxykinase activity in leukocytes and fibroblasts from a patient with pyruvate carboxylase deficiency. Pediatr. Res., 13,38. 

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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. 

Wanders RJ, Ruiter JP, Wijburg FA, Zeman J, Klement P, Houstek J. Prenatal diagnosis of systemic disorders of the respiratory chain in cultured chorionic villus fibroblasts by study of ATP-syndiesis in digitonin-permeabiUzed cells. J. Inherit. Metab Dis. 1996 19 133-136. 

There are several disorders of the respiratory chain. Many are transmitted by maternal inheritance as generally aU mitochondria in the ovum are of maternal origin. The thousands of mtDNA molecules in one cell are distributed randomly to the daughter cells, therefore different tissues may harbour a mixture of both normal and mutant mtDNA (heteroplasmy). Accordingly the clinical phenotype is highly variable. Mutations in nuclear genes encoding proteins for the respiratory chain are transmitted autosomally and usually cause a more severe disease. 

Mitochondria are unique organelles in that they contain their own DNA (mtDNA), which, in addition to ribosomal RN A (rRNA) and transfer RN A (tRNA)-coding sequences, also encodes 13 polypeptides which are components of complexes I, III, IV, and V (Anderson et al., 1981). This fact has important implications for both the genetics and the etiology of the respiratory chain disorders. Since mtDNA is maternally-inherited, a defect of a respiratory complex due to a mtDNA deletion would be expected to show a pattern of maternal transmission. However the situation is complicated by the fact that the majority of the polypeptide subunits of complexes I, III, IV, and V, and all subunits of complex II, are encoded by nuclear DNA. A defect in a nuclear-coded subunit of one of the respiratory complexes would be expected to show classic Mendelian inheritance. A further complication exists in that it is now established that some respiratory chain disorders result from defects of communication between nuclear and mitochondrial genomes (Zeviani et al., 1989). Since many mitochondrial proteins are synthesized in the cytosol and require a sophisticated system of posttranslational processing for transport and assembly, it is apparent that a diversity of genetic errors is to be expected. 

Defects of nuclear DNA also cause mitochondrial diseases. As mentioned above, the vast majority of mitochondrial proteins are encoded by nDNA, synthesized in the cytoplasm and imported into the mitochondria through a complex series of steps. Diseases can be due to mutations in genes encoding respiratory chain subunits, ancillary proteins controlling the proper assembly of the respiratory chain complexes, proteins controlling the importation machinery, or proteins controlling the lipid composition of the inner membrane. All these disorders will be transmitted by mendelian inheritance. From a biochemical point of view, all areas of mitochondrial metabolism can be affected (see below). 

DiDonato, S. (2000) Disorders related to mitochondrial membranes Pathology of the respiratory chain and neurodegeneration. J. Inher. Metab. Dis. 23, 247-263. 

Senior, B. and Jungas, R.L. (1974), A disorder resulting from an enzymatic defect of the respiratory chain. Pediatr. Res., 8,438 (Abstract). 

EMA aciduria maybe associated with several other inherited and acquired conditions, including (1) glutaric acidemia type II (some cases are actually labeled to have ethylmalonic adipic aciduria),(2) disorders of the intramitochon-drial flavin adenine dinucleotide pathway, (3) mitochondrial respiratory chain disorders, and (4) ethylmalonic encephalopathy. Jamaican vomiting sickness (due to ingestion of unripe ackee fruit containing the poison hypoglycin A) and ifosfamide treatment represent two additional causes of ethylmalonic aciduria. 

A slowly progressive congenital neuromuscular disorder was reported in which the respiratory chain-linked energy transfer at a level common to all three energy coupling sites of respiratory chain was defective.52 Uncouplers of mitochondrial oxidative phosphorylation (2,4-dinitrophenol and carbonylcyanide-m-chlorophenylhydrazone) (5) produced mitochondrial myopathy in rats.53... 

The answer is a. (Murray, pp 627-661. Scriver, pp 3897-3964. Sack, pp 121-138. Wilson, pp 287-320.) Vitamins A, D, E, and K are all fat-soluble. The physical characteristics of fat-soluble vitamins derive from the hydrophobic nature of the aliphatic chains composing them. The other vitamins listed are water-soluble, efficiently administered orally, and rapidly absorbed from the intestine. Fat-soluble vitamins must be administered intramuscularly or as oral emulsions (mixtures of oil and water). In intestinal disorders such as chronic diarrhea or malabsorption due to deficient digestive enzymes, fat-soluble vitamins are poorly absorbed and can become deficient. Supplementation of fat-soluble vitamins is thus routine in disorders like cystic fibrosis (219700), a cause of respiratory and intestinal disease that is the likely diagnosis in this child. 

The concentration and associated ratio of the ketone bodies, aceto-acetate and 3-hydroxybutyrate, may also be helpful [15, 18, 19]. Ketosis and keto-aciduria are observed in certain patients with a mitochondrial disorder. A non-physiological increase of ketone bodies postprandially may be another indicator of a mitochondrial defect (Saudubray et al). Increased 3-hydroxybutyrate/acetoacetate ratio may suggest a defect in the respiratory chain in liver tissue. 

Defects of complex II. These have not been fully characterized in the few reported patients, and the diagnosis has often been based solely on a decrease of succinate-cytochrome c reductase activity (Fig. 42-3). However, partial complex II deficiency was documented in muscle and cultured fibroblasts from two sisters with clinical and neuroradiological evidence of Leigh s syndrome, and molecular genetic analysis showed that both patients were homozygous for a point mutation in the flavoprotein subunit of the complex [17]. This was the first documentation of a molecular defect in the nuclear genome associated with a respiratory chain disorder. 

Articaine has been implicated in an episode of weakness of the limb muscles, fatigue, and anorexia in a patient with a rare respiratory chain disorder due to a genetic defect in mitochondrial DNA (Kearn-Sayre Syndrome). 

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