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Muscle contraction is dependent on the high-energy molecule adenosine triphosphate (ATP), and deficiency of ATP synthesis leads to premature muscle fatigue and weakness. Carbohydrate metabolism, fatty acid oxidation, and the oxidative phosphorylation are all important in the generation of ATP from metabolic fuels, and defects in all three pathways result in metabolic myopathies. Although this chapter is primarily concerned with the muscle symptoms of these metabolic disorders, it is important to remember that many of them also affect other tissues and organs, particularly when the final common pathway of energy metabolism is involved—mitochondrial oxidative phosphorylation.


Glycogen storage disorders (the glycogenoses) are a group of rare inherited metabolic diseases caused by abnormal synthesis or breakdown of glycogen. Most involve cytoplasmic enzymes, except α-glucosidase (acid maltase) deficiency, which involves the lysosomal glycogen degradation pathway. Most glycogen storage disorders are autosomal recessive; phosphorylase b kinase may be either autosomal or X-linked recessive, and phosphoglycerate kinase deficiency is X-linked recessive.

The glycogen storage disorders generally manifest clinically in one of two ways: either with exercise intolerance, muscle cramps, and intermittent rhabdomyolysis or with slowly progressive proximal weakness (Table 88-1). Unusual manifestations include insidious neuromuscular ventilatory failure observed in some adults with α-glucosidase deficiency. Although the biochemical and genetic bases are well established for most of these disorders, the reasons for the phenotypical variability are unknown, and both environmental and epistatic genetic factors play roles (such as the interaction between phosphofructokinase deficiency and adenosine monophosphate deaminase/myoadenylate kinase).

The Glycolytic Pathway

Glycolysis provides energy for high-intensity muscle activity when oxygen availability limits aerobic respiration (Fig. 88-1). Muscle phosphorylase (also called myophosphorylase) initiates the liberation of glucose from muscle glycogen stores. Phosphofructokinase catalyzes the rate-limiting step in glycolysis. Under anaerobic conditions, glycolysis ultimately results in the conversion of pyruvate to lactate. This generates only a fraction of the ATP that would be produced if the glucose were fully oxidized to carbon dioxide and water by aerobic metabolism. The accumulation of lactate and of the major components of ATP hydrolysis (inorganic phosphate, adenosine diphosphate, and adenosine monophosphate) play an important role in causing muscle fatigue.

For a full description of the metabolic pathways, see Matthews and van Holder.1

Clinical Features, Diagnosis, and Management

Myophosphorylase Deficiency (McArdle’s Disease, Type V Glycogenosis)

Myophosphorylase deficiency typically manifests in late childhood or the early teenage years with muscle pain and weakness in the early stages of moderate exertion. Mild symptoms are rapidly relieved by rest, but after prolonged exercise, the symptoms may persist for days, accompanied by reversible painful contractures. Some patients are able to work through the initial symptoms and find that prolonged exercise becomes possible (the so-called “second wind” phenomenon), because of the mobilization of fatty acids as a fuel. By gradually “warming up” with light exercise, some patients reduce the intensity of their symptoms and increase exercise tolerance, presumably through the same mechanism. Myoglobinuria is common (often microscopic), and rhabdomyolysis may occur, even as a presenting feature.

The serum creatine kinase level is usually elevated between acute attacks but rises dramatically immediately after an episode of muscle pain. Electromyography may reveal nonspecific myopathic features, but the appearance is often normal. Forearm exercise testing characteristically reveals a high or even supranormal ammonia response, with a minimal or no increase in venous blood lactate levels during or immediately after exercise. This test is not without risk, inasmuch as it may provoke rhabdomyolysis or a forearm compartment syndrome. Skeletal muscle histochemistry study demonstrates glycogen storage and the absence of phosphorylase activity. Muscle phosphorylase deficiency can be confirmed biochemically (levels usually <5% of normal), but this is rarely necessary. In the majority of patients of European descent, molecular genetic analysis reveals the R49X mutation (>70%) in the PYGM gene,10 which is either homozygous or compound heterozygous, with another mutation in the coding region of the gene. Different common mutations are found in other populations.11

Most patients adapt their lifestyles to avoid precipitating factors. There is evidence that an oral sucrose load before activity can increase exercise tolerance, but this may not be practical in every circumstance.12 Myoglobinuria and rhabdomyolysis should be treated aggressively by increasing the fluid intake. Careful monitoring of the serum creatine kinase and phosphate levels is essential. Intravenous fluids, furosemide, and hemodialysis are sometimes required.

β-Enolase Deficiency (Type XIII Glycogenosis)

This enzyme defect has also been described in a single patient, a man with adult-onset exercise intolerance and chronically increased serum creatine kinase.17a The patient was a compound heterozygote for mutations in the ENO3 gene, which encodes β-enolase, the isoform expressed predominantly in skeletal muscle.


Since the first description of carnitine palmitoyltransferase (CPT) deficiency in 1973,18 there has been a steady increase in both the number of different fatty acid oxidation disorders recognized and the number of affected patients identified. Defects involving many of the different enzymes and transport proteins involved in fatty acid oxidation have been described.19

The clinical features in these patients are diverse and depend on the nature and severity of the biochemical defect. However, the most prevalent symptoms are related to neuromuscular, cardiac, and hepatic involvement.

Fatty Acid Oxidation

Mitochondrial fatty acid β-oxidation is especially important in conditions of fasting and exercise.20 The switch from predominantly carbohydrate metabolism in early exercise to fatty acid oxidation depends on several factors, including the intensity of exercise and the relative fitness of the individual.

When glycogen reserves are depleted, triglycerides are mobilized from lipid stores, and free fatty acids are released at the endothelial walls of the capillaries by the action of lipoprotein lipase. The free fatty acids are then transported across the muscle plasma membrane by tissue-specific fatty acid transporters. Also transported across the plasma membrane is carnitine, which is crucial for the transport of long-chain fatty acid into mitochondria. The muscle carnitine transporter “pumps” carnitine from blood up a tissue gradient, so that the level of muscle carnitine is approximately 50 times greater than that in blood.

At the outer mitochondrial membrane, fatty acids are converted into their acyl-coenzyme A (CoA) esters by the ATP-dependent acyl-CoA synthetases (Fig. 88-2). These acyl-CoA esters are then converted into acylcarnitine and free CoA by CPT-I at the outer mitochondrial membrane. The resulting acylcarnitine is then transported across the inner mitochondrial membrane by the carnitine:acylcarnitine translocase in exchange for free carnitine. Once inside the mitochondrial matrix, the acyl-CoA ester is reformed by CPT-II, and carnitine is released for further exchange by the carnitine:acylcarnitine translocase.

The β-oxidation of fatty acids involves the concerted action of a series of four chain length–specific reactions, which remove a molecule of acetyl-CoA (C2) per cycle from the original fatty acid molecule. The fatty acid therefore is eventually completely broken down to acetyl-CoA, which is the main substrate of the citric acid cycle. The first reaction is catalyzed by the acyl-CoA dehydrogenases, a family of flavin adenine dinucleotide–requiring oxidoreductases. The electrons generated by this process are transferred via electron-transfer flavoprotein (ETF) and ETF ubiquinone oxidoreductase to the respiratory chain. Very-long-chain acyl-CoA dehydrogenase (VLCAD) is responsible for reducing acyl-CoA esters of chain length C12 to C18. Medium-chain acyl-CoA dehydrogenase (MCAD) is responsible for the acyl-CoA esters of chain length C6 to C10, and short-chain acyl-CoA dehydrogenase for C4 to C6 substrates. Long-chain acyl-CoA dehydrogenase has substrate specificity intermediate between VLCAD and MCAD; this is the least characterized of the enzymes, and its deficiencies have not yet been described.

The second reaction of β-oxidation involves the hydration of the double bond in the 2,3 position to produce the L-hydroxyacyl-CoA ester. Two enzymes catalyze this reaction. The long-chain enoyl-CoA hydratase is responsible for hydrating the long-chain esters and is part of a membrane-bound trifunctional protein (TFP), which includes the subsequent enzyme in the sequence: long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) and then the final stage, long-chain 3-ketothiolase activity. The second hydratase, short-chain enoyl-CoA hydratase, is responsible for the hydration of short- and medium-chain enoyl-CoA esters.

The third reaction of β-oxidation involves the reduction of the l-3-hydroxyacyl-CoA to a 3-ketoacyl-CoA ester. In this reaction, nicotinamide adenine dinucleotide is converted to its reduced form, which is subsequently oxidized at complex I of the respiratory chain. LCHAD is part of the TFP and is responsible for the oxidation of long-chain substrates, whereas a short-chain 3-hydroxyacyl-CoA dehydrogenase has broad specificity and is responsible for the medium- and short-chain substrates.

The final step of β-oxidation involves the thiolytic cleavage of the 3-ketoacyl-CoA ester into acetyl-CoA and an acyl-CoA that is two carbon units shorter. The enzyme responsible for the thiolysis of long chain species is the long-chain 3-ketothiolase activity, which is part of the TFP. There are also a medium-chain thiolase and a short-chain thiolase, which are active for the medium- and short-chain 3-ketoacyl-CoA esters.

Clinical Features of Mitochondrial Fatty Acid Oxidation Disorders

Many of the different enzyme deficiencies have similar clinical features. Muscle involvement is frequent, which reflects the importance of fatty acid oxidation for normal muscle function. In some patients, this is reflected by exercise-induced muscle pain and rhabdomyolysis. The pain is characteristically caused by prolonged exercise and may occur after the exercise has been completed. In some patients, physiological fasting or fasting secondary to infection or illness can induce an episode. The rhabdomyolysis can be severe and lead to renal failure.

In some patients, there is no pain but marked proximal weakness, severe enough to lead to respiratory compromise. In other patients, there is cardiac involvement and, sometimes, liver involvement. In severe cases, the manifestation is in early childhood and associated with metabolic changes such as hypoglycemia and even sudden death.