Diagnosis: Myopathy

The rheumatologist is frequently called upon to evaluate patients with complaints of myalgia, muscle cramping, and fatigue. Because these symptoms may be nonspecific and lack any clear temporal or anatomic pattern, their workup may entail costly and uninformative tests. When similar symptoms emerge during or following physical exertion, a metabolic myopathy should be suspected. Recurrent myoglobinuria, exercise intolerance, and mild fixed proximal muscle weakness are also frequently encountered in metabolic myopathies. Although inflammatory myopathies may present in a similar fashion, such a pattern should prompt a thorough evaluation for an underlying metabolic myopathy. This review will discuss an approach to the diagnosis and treatment of several of the more common metabolic myopathies.

Light micrograph of a neuromuscular junction.

Metabolic Myopathies

The metabolic myopathies are a heterogeneous group of disorders that share the common feature of inadequate production of cellular energy in the muscle. (See Table 1, p. 16, for a summary of metabolic myopathy classification.) They are often categorized into hereditary (primary) disorders, the focus of this review, and acquired (secondary) disorders. A further clinical distinction can be made between those disorders associated with primarily dynamic features (e.g., transient, exercise-induced fatigue, cramping, and rhabdomyolysis) and those disorders associated with primarily static features (fixed weakness).

A detailed review of muscle energy metabolism is beyond the scope of this review, but a brief consideration of the pertinent metabolic pathways is useful to better understand this group of disorders. Under normal circumstances, energy for skeletal muscle function in the form of adenosine triphosphate (ATP) is derived from muscle glycogen, blood glucose, and free fatty acids.¹ Each of these primary energy sources is metabolized through specific biochemical pathways into the final common product, ATP. The majority of fuel for muscle is provided by carbohydrates in the form of glycogen and by lipids in the form of free fatty acids. Through the process of anaerobic glycolysis, glycogen is metabolized to pyruvate inside the muscle cells. Pyruvate is then decarboxylated into acetyl-coenzyme A (acetyl-CoA) inside the mitochondria. Similarly, b-oxidation of free fatty acids (fatty acid oxidation; FAO) inside mitochondria provides another source of acetyl-CoA. Acetyl-CoA then enters the Krebs cycle, generating reduced electron carriers that deliver electrons to the mitochondrial electron transport chain, thus driving the production of energy in the form of ATP. Defects in any one of the steps involved in this complex metabolic pathway can lead to an insufficient supply of ATP and an inability to sustain normal muscle function.