Metabolic Myopathies: Update 2009

Abstract

Metabolic myopathies are inborn errors of metabolism that result in impaired energy production due to defects in glycogen, lipid, mitochondrial, and possibly adenine nucleotide metabolism. Fatty acid oxidation defects (FAOD), glycogen storage disease, and mitochondrial myopathies represent the 3 main groups of disorders, and some consider myoadenylate deaminase (AMPD1 deficiency) to be a metabolic myopathy. Clinically, a variety of neuromuscular presentations are seen at different ages of life. Newborns and infants commonly present with hypotonia and multisystem involvement (liver and brain), whereas onset later in life usually presents with exercise intolerance with or without progressive muscle weakness and myoglobinuria. In general, the glycogen storage diseases result in high-intensity exercise intolerance, whereas the FAODs and the mitochondrial myopathies manifest predominately during endurance-type activity or under fasted or other metabolically stressful conditions. The clinical examination is often normal, and testing requires various combinations of exercise stress testing, serum creatine kinase activity and lactate concentration determination, urine organic acids, muscle biopsy, neuroimaging, and specific genetic testing for the diagnosis of a specific metabolic myopathy. Prenatal screening is available in many countries for several of the FAODs through liquid chromatography-tandem mass spectrometry. Early identification of these conditions with lifestyle measures, nutritional intervention, and cofactor treatment is important to prevent or delay the onset of muscle weakness and to avoid potential life-threatening complications such as rhabdomyolysis with resultant renal failure or hepatic failure. This article will review the key clinical features, diagnostic tests, and treatment recommendations for the more common metabolic myopathies, with an emphasis on mitochondrial myopathies.

Fatty Acid Oxidation Disorders in a Chinese Population in Taiwan

“…Impaired transfer of electrons affects multiple dehydrogenation reactions and is thus termed multiple acylCoA dehydrogenase (MAD) deficiency. FAO disorders can present with life-threatening symptoms, such as hypoketotic hypoglycemia, Reye-like syndrome in infants (Brivet et al 1999;Baruteau et al 2009;Spiekerkoetter 2010), acute encephalopathy (Gregersen et al 2001;Spiekerkoetter 2010), cardiomyopathy (Bonnet et al 1999;Spiekerkoetter et al 2009a), myolysis (Spiekerkoetter et al 2009a;van Adel and Tarnopolsky 2009), and liver dysfunction (Clayton 2003). Currently more than 15 distinct FAO disorders have been elucidated based on enzymatic and/or molecular analyses (Gregersen et al 2008).…”

Clinical and biochemical improvement of very long-chain acyl-CoA dehydrogenase deficiency in pregnancy

“…5,6 Mitochondrial b-oxidation deficiencies such as VLCAD deficiency present as a wide spectrum of phenotypes that are more pronounced during periods of metabolic stress, such as exercise, fasting and other intercurrent illnesses. 2,3 These variants reflect the variable tissue-specific energy requirements, gene expression, and perhaps complex epigenetic interactions in a developing organism. For example, in its most severe forms, the VLCAD deficiencies present with neonatal cardiomyopathy and hypoglycemia.…”

“…Regardless of the variant, management should include the administration of high-carbohydrate, low longchain fat diet, with medium-chain triglyceride supplementation and replenishment of carnitine deficits. [1][2][3][4] Very little is known about the course of VLCAD deficiency during pregnancy. To our knowledge (Ovid and PubMed, 1966 to the present), only few cases have been reported in the literature 1,7 providing scattered details on the perinatal management in this condition.…”

“…They are released from lipids and enter the mitochondrial outer membrane through transporter proteins, where they are converted into fatty acyl-CoA esters by a long-chain acyl-CoA synthetase. [1][2][3] After conjugation with carnitine, the long-chain acyl-CoA esters are converted to acylcarnitine esters, which are then transported into the mitochondrial matrix. After their import, acylcarnitine esters are converted back to acyl-CoA esters and subsequently enter FA boxidation.…”

“…2 Inherited defects in mitochondrial b-oxidation comprise a group of at least 20 disorders characterized by enzyme or transporter deficiencies along this pathway. [1][2][3][4] Membrane-associated very long-chain acyl-CoA dehydrogenase (VLCAD), encoded by ACADVL on 17p13.1, is an enzyme that interacts in the earliest steps of the sequential 2-carbon shortening of FA in the b-oxidation spiral. The enzymatic deficiency has an autosomal recessive inheritance pattern, with an estimated incidence ranging from 1:31 500 to 1:125 000 live births.…”