Metabolic myopathies (MM) are rare inherited primary muscle disorders that are mainly due to abnormalities of muscle energy metabolism resulting in skeletal muscle dysfunction. These diseases include disorders of fatty acid oxidation, glyco(geno)lytic muscle disorders and mitochondrial respiratory chain (MRC) disease. Clinically these disorders present with a range of symptoms including infantile hypotonia, myalgia/exercise tolerance, chronic or acute muscle weakness, cramps/spasms/stiffness or episodic acute rhabdomyolysis. The precipitant may be fasting, infection, general anaesthesia, heat/cold or most commonly, exercise. However, the differential diagnosis includes a wide range of both acquired and inherited conditions and these include exposure to drugs/toxins, inflammatory myopathies, dystrophies and channelopathies. Streamlining of existing diagnostic protocols has now become a realistic prospect given the availability of second-generation sequencing. A diagnostic pathway using a 'rhabdomyolysis' gene panel at an early stage of the diagnostic process is proposed. Following detailed clinical evaluation and first-line investigations, some patients will be identified as candidates for McArdle disease/glycogen storage disease type V or MRC disease and these will be referred directly to the specialised services. However, for the majority of patients, second-line investigation is best undertaken through next-generation sequencing using a 'rhabdomyolysis' gene panel. Following molecular analysis and careful evaluation of the findings, some patients will receive a clear diagnosis. Further functional or specific targeted testing may be required in other patients to evaluate the significance of uncertain/equivocal findings. For patients with no clear diagnosis, further investigations will be required through a specialist centre.
1. The increase in activation coefficient (stimulated: basal activity) of erythrocyte NAD(P)H 2 :glutathione oxidoreductase ( EC 16.4.2) and reduction in hepatic flavin concentration which occurred in riboflavin-deficient weanling rats were not markedly or consistently affected by differences in the concentration of lipid in the diet nor by differences in the total proportion of saturated or polyunsaturated fatty acids in the dietary lipid. 2. Their gain in body-weight was, however, reduced when the dietary lipid concentration was increased from 30 to 200 g/kg and liver: body-weight and hepatic triglyceride content were correspondingly increased, suggesting a functionally-deleterious effect of high fat intake in the deficient animals. This was especially severe when the diets contained cottonseed oil, which appeared to be toxic for the deficient animals. 3. Comparisons between fatty acid profiles of hepatic phospholipids of deficient, pair-fed and ad lib. -fed control animals indicated that the increase in proportion of 18:2 ω6 and the decrease in proportion of 20:4 ω6 observed in deficient animals were due specifically to riboflavin deficiency, whereas certain other changes were probably caused by inanition. The changes in 18:2ω6 and 20:4 ω6 were observed at both low and high levels of lipid intake and at both low and high levels of dietary lipid polyunsaturation. Similar changes in fatty acid profiles were observed in renal, erythrocyte membrane, and plasma phospholipids, but were not seen in cardiac phospholipids. 4. A consistent increase in proportion of 18:2 ω6 was also observed in the hepatic triglycerides, together with a decrease in proportion of 16:0. 5. It is concluded that acute riboflavin deficiency affects lipid metabolism in a characteristic manner, probably by interfering with β-oxidation of fatty acids, but that diets of high lipid content do not significantly increase the extent of flavin depletion.
Multiple acyl-CoA dehydrogenation deficiency is a disorder of fatty acid and amino acid oxidation caused by defects of electron transfer flavoprotein (ETF) or its dehydrogenase (ETFDH). A clear relationship between genotype and phenotype makes genotyping of patients important not only diagnostically but also for prognosis and for assessment of treatment. In the present study, we show that a predicted benign ETFDH missense variation (c.158A>G/p.Lys53Arg) in exon 2 causes exon skipping and degradation of ETFDH protein in patient samples. Using splicing reporter minigenes and RNA pull-down of nuclear proteins, we show that the c.158A>G variation increases the strength of a preexisting exonic splicing silencer (ESS) motif UAGGGA. This ESS motif binds splice inhibitory hnRNP A1, hnRNP A2/B1, and hnRNP H proteins. Binding of these inhibitory proteins prevents binding of the positive splicing regulatory SRSF1 and SRSF5 proteins to nearby and overlapping exonic splicing enhancer elements and this causes exon skipping. We further suggest that binding of hnRNP proteins to UAGGGA is increased by triggering synergistic hnRNP H binding to GGG triplets located upstream and downsteam of the UAGGGA motif. A number of disease-causing exonic elements that induce exon skipping in other genes have a similar architecture as the one in ETFDH exon 2.
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