Myopathies due to enzyme deficiencies

Abstract

After the discovery in 1959 of myophosphorylase deficiency, at least 15 myopathies due to deficiency of enzymes involved in energy substrate utilization have been described. In this review two main categories of enzymopathies, glycogenosis and mitochondrial disorders, are discussed. Clinically, the patients with these categories of enzyme defects present two major syndromes: acute recurrent muscle impairment, generally related to exercise, associated with cramps and/or myoglobinuria; progressive muscular weakness and wasting eventually associated with signs of affected organs other than skeletal muscle. Defects of glycogen breakdown and of the first step of glycolysis are more frequently associated with acute exercise intolerance, such as in myophosphorylase and phosphofructokinase deficiencies, but may be associated with progressive muscle weakness and wasting, such as in acid maltase and debrancher enzyme deficiency. Clinical heterogeneity is common in these disorders, but a biochemical explanation for their different clinical expression is still lacking. Defects of the second step of glycolysis, phosphoglycerate kinase, phosphoglycerate mutase and lactate dehydrogenase deficiencies, have been discovered recently and are associated with exercise intolerance. The reason for muscle weakness and atrophy in glycogenosis is still unclear, although it has been suggested that excessive protein catabolism occurs in myophosphorylase, debrancher and acid maltase deficiencies. Myopathies due to deficiencies of mitochondrial enzymes are less well defined, as a group, than the glycogenoses. They are currently considered to fall into three main groups: defects of substrate utilization, such as carnitine palmitoyltransferase deficiency; defects of respiratory chain complexes, such as cytochrome-c-oxidase deficiency and defects of phosphorylation-respiration coupling, such as Luft's disease. Again, severe and benign exercise intolerance or progressive life-threatening myopathic syndromes may be the clinical expression of these disorders. Detailed biochemical and morphological studies of muscle biopsies are needed in these patients to obtain a definite diagnosis and prognosis, and to decide on eventual treatment.

Nerve‐muscle involvement in a large family with mitochondrial cytopathy: Electrophysiological studies

“…Aiiother possibility could be large macro M U P d u e to recording artefacts. Tremoy, giving a tendency to synchronicity between motor units resulting in large niacro aniplitucles, could be excluded as a cause for two reasons: (1) no signs of tremor were seen in the firing pattern of the motor units arid (2) no signs of synchronicity were seen in the analysis where a specia1 algorithm was used for its detection.…”

Deficiency of the reduced nicotinamide adenine dinucleotide dehydrogenase component of complex I of mitochondrial electron transport. Fatal infantile lactic acidosis and hypermetabolism with skeletal-cardiac myopathy and encephalopathy.

“…A broad categorization of known genetic defects causing lactic acidosis includes deficiencies of enzymes specifically required for utilization of pyruvate and deficiencies of oxidation or electron transport affecting not only pyruvate but also other substrates such as fatty acids and amino acids. In recent years several defects of components of the mitochondrial electron transport chain have been described (1)(2)(3). Biochemical characterization of this group ofgenetic disorders remains at an early stage.…”

Mitochondria as a Biosensor for Drug-induced Toxicity – Is It Really Relevant?

“…Statins are generally safe and well tolerated, but the major side effect, which occurs in about 1% of patients, is skeletal myopathy (Davidson, 2001). Interestingly, many congenital myopathies are associated with defects in mitochondrial enzymes (Cornelio & Di Donato, 1985;Wallace, 2000) and bio-accumulation of statins by fast twitch skeletal muscle cells can increase the risk of mitochondriallyinduced rhabdomyolysis (Westwood, Bigley et al, 2005). Several reports describe acute effects of statins on skeletal muscle mitochondria.…”