Disorders of muscle lipid metabolism may involve intramyocellular triglyceride degradation, carnitine uptake, long-chain fatty acids mitochondrial transport or fatty acid b-oxidation. Many patients with lipidosis at muscle biopsy remain without diagnosis despite thorough investigations. This low rate of diagnosis could be explained by the physiological and inter-individual variability of lipid accumulation within muscle fibres, other unknown metabolic diseases and secondary increase of lipid in muscle without primary enzymatic defect.
In our lab we carry out the study of both Multiple acyl-CoA dehydrogenase deficiency (MAD) and carnitine palmitoyl transferase II deficiency.
MAD deficiency, also known as glutaric aciduria type II (GAII), results in abnormal fatty acid, amino acid and choline metabolism. Molecular defects have been disclosed in two electron transfer flavoproteins which transfer electrons from acyl-CoA dehydrogenases to the respiratory chain: ETF (Electron Transfer Flavoprotein, coded by ETFA and ETFB genes) and ETFQO (ETF-ubiQuinone Oxidoreductase coded by ETFDH gene). MAD deficiency has a wide range of clinical presentations, the most severely affected patients show congenital anomalies such as cystic renal dysplasia while milder cases present in childhood with hypoglycaemia, encephalopathy, muscle weakness or cardiomyopathy. Less severely affected patients display progressive muscle weakness or rhabdomyolysis episodes at adult age, and some of these patients show a dramatic response to riboflavin treatment. It has been recently demonstrated that riboflavin-responsive MAD deficiency is often associated with mutations in ETFDH gene.
CPT II was the first inherited defect of fatty acids oxidation to be identified. Three different clinical phenotypes are associated with a defect in CPT II according to the age of onset, but muscular symptoms occur mainly in the juvenile-adult onset form. The myopathic form is probably the most frequent cause of recurrent myoglobinuria in young adults. Episodes of myalgias and rhabdomyolysis are triggered by prolonged exercise, infections, fasting, cold or emotional stress. A mildly increased lipid content in muscle biopsy is observed in 20% of cases.
A prevalent mutation (c.338C > T, p.Ser113Leu) in the CPT2 gene has been identified in more than 60% of mutant alleles in the myopathic form.