'Energy metabolism' is deranged in wide variety of disorders of the nervous system. This term refers rather loosely to the pathways responsible for the utilization of the major substrates of brain. Primary disorders of energy metabolism are those in which the primary insult affects the cellular machinery required for energy metabolism. A typical example would be a defect in a gene coding for a mitochondrial protein. Biochemically, defects which appear to be hereditary and which lead to disease of the central nervous system have been described in each of the pathways of energy metabolism: glycogenolysis (the break-down of glycogen to glucose); glycolysis (the break down of glucose to pyruvate and lactate); the pyruvate dehydrogenase complex (which oxidizes pyruvate to enter the Krebs tricarboxylic acid cycle); the tricarboxylic acid cycle itself (which completes the oxidation of carbohydrates and other substrates to carbon dioxide); electron transport (which carries out their oxidation to water); the pentose phosphate pathway (an alternative pathway for glucose oxidation); and several 'minor' mitochondrial pathways. Clinically, the spectrum of syndromes associated with primary disorders of energy metabolism is wide. Common manifestations include psychomotor retardation, with associated lactic acidosis and/or hypoglycemia. The laboratory abnormalities may be intermittent. Syndromes which have been culled out include congenital lactic acidosis, Leigh disease, intermittent ataxia, Kearns-Sayre-Shy syndrome (KSS), myoclonus epilepsy with ragged red fibers (MERRF), and mitochondrial myopathy-encephalopathy-lactic acidosis-stroke (MELAS). As with other families of inborn errors, both clinical and biochemical heterogeneity occur. Patients with apparently similar clinical syndromes can turn out to have different inborn errors, and patients with abnormalities of the same gene product can have clinically distinguishable syndromes. Secondary disorders are those in which the derangements of energy metabolism are presumably secondary to some other insult but may still be important for the cellular pathophysiology. These include the metabolic encephalopathies and probably a number of well-known neurodegenerative disorders. In the hereditary ataxias, abnormalities of mitochondrial markers are common but do not correlate consistently with the disorders as conventionally classified; a new classification into axonal ataxias, multiple system degenerations, and ataxic encephalopathies may be easier to relate to the pathophysiology. Abnormalities in mitochondrial markers have been described in brain in Huntington disease and in cultured fibroblasts in Down's syndrome (trisomy 21). In Alzheimer's disease, mitochondrial abnormalities have been found both in biopsied brain and in fibroblasts and other non-neural tissues. Tertiary disorders of energy metabolism are those in which derangements of energy metabolism occur late and are pathophysiologically unimportant. Whether the degenerative disorders are secondary or tertiary disorders of energy metabolism is a matter of controversy. Pathophysiologically, because of the particular dependence of the brain on oxidative metabolism, disorders of oxidative metabolism are likely to lead to clinical disability related to the nervous system. They are likely to present clinically as neurological or psychiatric disease, even if they are due to 'leaky' mutations which impair but do not abolish the function of gene products involved. Impairments of cerebral energy metabolism probably interfere with neuronal functions such as transport and the control of neurotransmitter release before they alter ATP levels, and thus can lead to relatively subtle and selective damage to the central nervous system. Diagnostically, the key laboratory findings in disorders of energy metabolism are abnormalities in blood glucose, pyruvate, or lactate, particularly after a metabolic load. Therapeutically, regimens have been developped which reportedly ameliorate some of these syndromes, but an effective pharmacology of mitochondria has yet to be developed. This review concentrates on primary disorders of energy metabolism and on selected degenerative disorders of the nervous system.
|Number of pages||21|
|State||Published - 1988|