The investigation and management of metabolic myopathies.

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.

Implications of impaired ketogenesis in fatty acid oxidation disorders.

Long-chain fatty acids are important sources of respiratory fuel for many tissues and during fasting the rate of hepatic production of ketone bodies is markedly increased. Many extra hepatic tissues utilize ketone bodies in the fasted state with the advantage that glucose is "spared" for more vital tissues like the brain. This glucose sparing effect of ketones is especially important in infants where there is a high proportional glucose utilization in cerebral tissue. The first reported inherited defect affecting fatty acid oxidation was described in 1973 and to date about 15 separate disorders have been described. Although individually rare, cumulatively fatty acid oxidation defects are relatively common, have major consequences for affected individuals and their families, and carry significant health care implications. The major biochemical consequence of fatty acid oxidation defects is an inability of extra hepatic tissues to utilize fatty acids as an energy source with absent or limited hepatic capacity to generate ketones. Clinically patients usually present in infancy with acute life-threatening hypoketotic hypoglycaemia, liver disease, hyperammonaemia and cerebral oedema, with or without cardiac involvement, usually following a period of catabolic stress. Chronically there may be muscle involvement with hypotonia or exercise intolerance with or without cardiomyopathy. Treatment is generally by the avoidance of fasting, frequent carbohydrate rich feeds and for long-chain defects, the replacement of long-chain dietary fats with medium-chain formulae. Novel approaches to treatment include the use of d,l-3-hydoxybutyrate or heptanoate as an alternative energy source.