Overview
Background
Metabolic myopathies refer to a group of hereditary muscle disorders caused by specific enzymatic defects due to defective genes. Metabolic myopathies are heterogeneous conditions that have common abnormalities of muscle energy metabolism that result in skeletal muscle dysfunction. Most recognized metabolic myopathies are considered primary inborn errors of metabolism and are associated with known or postulated enzymatic defects that affect the ability of muscle fibers to maintain adequate energy and adenosine triphosphate (ATP) concentrations. Traditionally, these diseases are grouped into abnormalities of glycogen, lipid, purine, or mitochondrial metabolism.
Metabolic myopathies are rare but potentially treatable disorders. They are sometimes misdiagnosed as muscular dystrophies or inflammatory myopathies. Metabolic myopathies are the most clearly defined and etiologically understood muscle disorders because their fundamental biochemical defects are known through recent molecular biology and biochemistry developments. Also, many of the genetic defects have been characterized, and genetic counseling is now possible.
Metabolic myopathies are important disorders since they mimic other more commonly encountered neurologic diseases. The diagnosis depends on a high index of suspicion and involves correlating certain clinical manifestations to specific metabolic defects. Finally, understanding these muscle disorders enables a better understanding of the dynamics of muscle and body metabolism.
Pathophysiology
Understanding energy metabolism in exercising muscles is a prerequisite to the study of metabolic myopathies. Muscle contraction depends on the chemical energy of ATP and several biochemical processes within the muscle cell maintain a supply of ATP to support muscle contraction.
The 3 major pathways that supply ATP to meet the energy demands of exercising muscle are as follows:
Glycogen metabolism: Aerobic exercise is essential for intermittent or submaximal contraction. Anaerobic exercise may be substituted for high-intensity muscular activity, particularly when blood flow is reduced and oxygen availability is limited.
Lipid metabolism: Lipid is an important source of energy in sustained submaximal exercise (i.e., exercise lasting longer than 40 min).
Phosphocreatine stores: These stores, consumed in the purine nucleotide cycle, are vital for very high-intensity exercise of short duration, as other stores are depleted early.
The pathophysiological principles of metabolic myopathies may be simplified into a logical biochemical cascade. For example, presume that a series of reactions proceed forward (from substrate A to H) through stepwise enzymatic reactions (i.e., enzymes 1-7) as follows:
A -(1) – B -(2)- C -(3)- D -(4)- E -(5)- F -(6)- G -(7)- H
If enzyme 3 is absent (or deficient), some possible results may be as follows:
Accumulation of substrate C
Absence (or decrease) in the subsequent substrates (i.e., D, E, ….)
Potential disruption in the feedback or rate-limiting effect of one or more of the absent (or deficient) substrate products
Potential defect in the transportation of substrate into its target destination
Frequency
The exact incidence and prevalence of metabolic myopathies are uncertain. They are relatively rare and are much less common than most muscular dystrophies. However, increased awareness and improved diagnostic capabilities have resulted in an increased number of metabolic myopathies diagnosed. Additionally, the presence of an abnormal allele in some patients, such as with myoadenylate deaminase deficiency, may not result in a specific muscular disorder.
Acid maltase deficiency (Pompe disease) is seen in approximately 1 in 40,000 people. McArdle disease affects approximately 1 of 100,000 people. Carnitine palmitoyltransferase deficiency is the most commonly identified metabolic cause of recurrent myoglobulinemia in adults and has been reported in more than 150 patients. Other forms of metabolic myopathies are much less common. Approximately 2% of the population is homozygous for mutant alleles of myoadenylate deaminase, although not all have clinical symptoms.
Mortality and morbidity
Mortality and morbidity rates vary depending on the specific disorder and the extent of enzymatic deficiency (i.e., complete or partial).
The mortality rate is high in infantile acid maltase deficiency (Pompe disease). Invariably, the disease is progressive, leading to death within 1–2 years.
The juvenile form of acid maltase deficiency is less severe, and most children die by the end of the second decade of life from respiratory complications.
In contrast, patients with the adult form of acid maltase deficiency often present with slowly progressive limb-girdle weakness, but some develop early respiratory failure secondary to the involvement of intercostal muscles. The mortality rate of the adult form of acid maltase deficiency is much lower and the morbidity much less severe than those of the other two forms because of a partial deficiency of the enzyme.
Age
Metabolic myopathies have a wide age range of symptom onset. However, most patients present early in life (i.e., infancy, childhood, or young adulthood).