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Chapter 29: Metabolic Myopathies

INTRODUCTION

The inherited metabolic myopathies are traditionally classified by their underlying biochemical abnormalities as disorders of (1) carbohydrate, (2) lipid, and (3) adenine nucleotide metabolism. A fourth possible category includes the mitochondrial encephalomyopathies. As mitochondrial disorders do not cause defects in a specific biochemical pathway, they are discussed in a separate chapter. The immediate source of energy for muscles comes from the hydrolysis of adenosine triphosphate (ATP). At rest, the major substrate for muscle in terms of ATP production comes from the metabolism of long-chain fatty acids. Therefore, any disorder impairing β-oxidation of long-chain fatty acids in the mitochondria can lead to a myopathy. During exercise, ATP is derived from the metabolism of carbohydrates, fatty acids, and ketones. Early in the course of exercise (e.g., up to 45 minutes), energy is derived mainly from free glucose or glucose made available via glycogenolysis. Subsequently, there is a shift toward the metabolism of fatty acids such that after a few hours 70% of energy is derived from lipid breakdown.

Metabolic myopathies can also be viewed as static or dynamic disorders. The static myopathies are defined by the presence of fixed or progressive weakness. On the other hand, the dynamic myopathies are associated with exercise intolerance (i.e., exertional myalgias, cramps, and myoglobinuria) as the dominant clinical features. Some metabolic defects are associated with both a dynamic and a static myopathy.

DISORDERS OF CARBOHYDRATE METABOLISM

Carbohydrates are stored in liver and muscle as glycogen, a highly branched polymer of glucose. Normal synthesis and breakdown of glycogen is essential to maintain adequate glucose concentration in muscle that can be further metabolized and provide energy in the form of ATP. There are 16+ recognized glycogen storage diseases (GSDs), also called glycogenoses (Table 29-1). This is somewhat a misnomer because some of these glycogenoses do not result in the accumulation of glycogen in tissues.

TABLE 29-1.DISORDERS OF CARBOHYDRATE METABOLISM
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TABLE 29-1.DISORDERS OF CARBOHYDRATE METABOLISM
Disorder Enzyme Defect Inheritance Clinical Features
Type 0 Glycogen synthase 1 Autosomal recessive Childhood onset weakness, hypertrophic cardiomyopathy
Type I (von Gierke disease) Glucose-6-phosphate Autosomal recessive No neuromuscular signs or symptoms
Type II (Pompe disease) Acid maltase (α-1,4-glucosidase) Autosomal recessive

Infancy: hypotonia, cardiomyopathy, respiratory failure, generalized weakness

Childhood–adult: progressive weakness, respiratory failure
Type III (Cori–Forbes disease) Debranching enzyme (amylo-1,6-glucosidase) Autosomal recessive

Infancy: hypotonia, generalized weakness

Childhood/adult: proximal or distal weakness, spasticity, dementia, incontinence
Type IV (Anderson disease) Branching enzyme (amylo-1,4–1,6-transglucosidase) Autosomal recessive

Infancy: hypotonia, generalized weakness

Childhood/adult: proximal or distal weakness
Type V (McArdle disease) Myophosphorylase Autosomal recessive

Infancy: rare weakness

Childhood/adult: Exercise intolerance, rare weakness
Type VI Liver phosphorylase Autosomal recessive No muscle involvement
Type VII (Tarui disease) Phosphofructokinase Autosomal recessive Childhood: exercise intolerance, rare weakness
Type IXB aPhosphorylase b kinase B subunit Autosomal recessive Infancy to adult: exercise intolerance, rare weakness
Type IXD aPhosphorylase ...

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