Respiratory chain disorders

Metabolic Myopathies Glycogen Storage Disease Disorders of Lipid Metabolism Respiratory Chain Disorders Mitochondrial DNA Abnormalities Myotonias, Periodic Paralyses, and Malignant Hyperpyrexia Myotonias... 

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 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). 

L8. Leonard, I. V., and Schapira, A. V. H., Mitochondrial respiratory chain disorders II Neurode-generative disorders and nuclear gene defects. Lancet 355, 389-394 (2000). 

Several classes of inborn errors of metabolism in addition to inborn errors of urea synthesis can cause neonatal hyperammonemia. These include organic acidurias, fatty acid oxidation defects, amino acidopathies, and mitochondrial respiratory chain disorders. All of these disorders have a number of features in common. Labor and delivery tend to be normal, and there are no predisposing risk factors. Clinical features present after 24 h of life and are progressive. They are inherited, and thus a family history of previously affected children or neonatal deaths may be present. While most are inherited in an autosomally recessive manner, ornithine tran-scarbamoylase (OTC) deficiency is X linked, and a family history of affected males in the maternal pedigree is not uncommon. 

Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thor-burn DR. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 2002 59 1406-1411. 

Leonard JV, Schapira AH. Mitochondrial respiratory chain disorders I mitochondrial DNA defects. Lancet 2000 355 299-304. 

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. 

Finsterer J, Jarius C, Eichberger H, Jaksch M. Phenotype variability in 130 adult patients with respiratory chain disorders. J Inherit Metab Dis 2001 24 560-76. 

Montenez JP, Van Bambeke F, Piret J, Brasseur R, Tulkens PM, Mingeot-Leclercq MP (1999) Interactions of macrolide antibiotics (erythromycin A, roxithromycin, erythromycylamine [Dmthromycin] and azithromycin) with phospholipids computer-aided conformation analysis and studies on acellular and cell culture models. Toxicol Appl Pharmacol 156 129-140 Morgan MY, Reshef R, Shah RR, Oates NS, Smith RL, Sherlock S (1984) Impaired oxidation of debrisoquine in patients with perhexiline liver injury. Gut 10 1057-1064 Morris AAM (1999) Mitochondrial respiratory chain disorders and the liver. Liver 19 357-368 Morris AAM, Taanman JW, Blake J, Cooper JM, Lake BD, Malone M, Love S, Clayton PT, Leonard JV, Schapira AHV (1998) Liver failure associated with mitochondrial DNA depletion. J Hepatol 28 556—563... 

In recent years we have increasingly encountered patients whose clinical and biochemical presentations both suggest a fatty acid oxidation disorder but who do not meet the criteria for any of the recognised P-oxidation defects. These patients may have mild to moderate reductions in fibroblast oxidation of both [9,10- Iflmyristate and [9,10- HJpalmitate, often into the VLCAD and TCHAD ranges, but show only a moderate reduction in oxidation of [9,10- H]oleate (Fig. 5). A number of such patients have presented with hepatic and/or skeletal muscle symptomatology but have subsequently proved to have a definite or probable mitochondrial respiratory chain disorder. 

Muscle hypotonia is a trait demonstrated by many children bom with an inherited metabolic disease. Floppy baby syndrome, typical for such disorders as Prader-Willi syndrome and severe motor neuron diseases, may be also present in inborn lactic acidosis, some respiratory chain disorders, nonketotic hyperglycemia, molybdenum cofactor deficiency, sulfite oxidase deficiency, peroxisomal disorders, glycosylation disorders, and Pompe disease [1,2]. 

Respiratory-chain disorders (with mitochondrial myopathy) Lactic Various, including cytochromes b, aa, cytochrome c oxidase, NADH-coenzyme Q reductase 15.6... 

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