Metabolic and Mitochondrial Myopathies

McArdle disease, an autosomal recessive myophosphorylase deficiency leading to glycolytic defects, is the common glycogen storage disease (GSD). Other glycolytic defects—phosphofructokinase, phosphoglycerate mutase, and lactic dehydrogenase deficiencies—produce similar clinical pictures. Children experience easy fatigability and mild weakness. In adolescence, with more vigorous activity, painful muscle cramps develop. Muscle necrosis and myoglobinuria occur frequently. Individuals avoid intense activity, preferring less demanding sustained exercise, such as walking. A prominent second-wind phenomenon with renewed strength, attributed to fatty acid mobilization and increased muscle blood flow, occurs after 8 to 10 minutes exercise when the patient is no longer glycogen dependent. Between attacks, patients are well, leading reasonably normal lives. Mild, permanent weakness occurs in 25%.

Diagnostically, creatine kinase (CK) is elevated in 90% of resting patients. Venous lactate fails to rise during forearm ischemic exercise tests (FIET) because McArdle patients do not metabolize glycogen. In contrast, peak venous lactate levels normally occur within 3 to 5 minutes after exercise, reaching three to five times preexercise levels. Electromyography (EMG) is usually normal between attacks but may show mild myopathic potentials in chronic patients having permanent weakness. Muscle biopsy demonstrates subsarcolemmal glycogen accumulations and completely absent phosphorylase activity. Patients are encouraged to prevent attacks and muscle injury by avoiding high-intensity activity and ingesting glucose before activities.

Pompe disease (PD), acid maltase (α-1,4-glucosidase) deficiency, is a rapidly fatal infantile autosomal recessive GSD disorder secondary to an alpha-glucosidase gene mutation. Skeletal muscle glycogen accumulation occurs in heart and nervous system, leading to severe hypotonia, weakness, and respiratory and heart failure. Milder, later-onset (childhood and adult) forms occur. Usually symptoms begin in the third to fourth decades, with slowly progressive proximal limb, trunk, and respiratory muscle weakness leading to respiratory failure.

Serum CK is elevated. Infantile electrocardiograms are abnormal. EMG discloses myopathic motor unit potentials, fibrillations, complex repetitive potentials, and myotonia. Muscle biopsy reveals a vacuolar myopathy. Electron microscopy demonstrates glycogen granule clusters within cytoplasm and vacuoles. Dried blood spot enzyme analysis provides screening; diagnosis is confirmed by enzyme assay. PD is now treatable with intravenous recombinant human alpha-glucosidase.

Carnitine palmitoyl transferase deficiency (CPTd) is an autosomal recessive, male-predominant, lipid metabolism disorder wherein muscle cells suffer energy deficits. CPT, an enzyme permitting fatty acid transport into mitochondria, provides muscle cell energy via beta oxidation. Its primary hallmark is recurrent myoglobinuria provoked by prolonged exercise or fasting. Unlike glycolytic disorders, painful cramps do not occur during exercise; thus patients lack warning signals of impending muscle injury. Severe muscle pain, swelling, and tenderness occur during episodes of acute muscle weakness.

CK, normal at rest, rises sharply during attacks. In contrast to McArdle GSD, CPTd venous lactate rises normally during FIET forearm exercise testing. Muscle biopsy is normal except with previous myoglobinuric episodes, wherein scattered necrotic and regenerating fibers appear. Prolonged fasting (30-72 hours) leads to significant serum CK increase and delayed or decreased ketone body production. Muscle CPT biochemical assay or genetic testing provides definitive diagnosis.

Frequent meals with a low-fat, carbohydrate-rich diet may improve exercise tolerance. These patients should receive intravenous glucose before and during general anesthesia because prolonged fasting may provoke an attack.

Mitochondrial myopathies are genetically determined metabolic muscle dysfunction disorders caused by mitochondrial genome mutations. This circular, double-stranded molecule, consisting of 16,569 base pairs and coding for 22 transfer ribonucleic acids (RNAs), 2 ribosomal RNAs, and 13 polypeptides contributing to various respiratory chain complexes, is the site of oxidation-reduction reactions generating adenosine triphosphate (ATP), the energy currency of the cell. These patients’ mitochondria fail to produce sufficient energy for harmonious muscle metabolism function, leading to muscle weakness.

Ocular muscle weakness, notably ptosis and ophthalmoparesis, are characteristic clinical features that advance slowly, referred to as chronic progressive ophthalmoplegia (CPEO). Cardinal morphologic features include muscle fibers having prominent subsarcolemmal mitochondria accumulations appearing red on modified trichrome stain, designated “ragged red” fibers. Kearns-Sayre syndrome is a severe mitochondrial myopathy related to mitochondrial deoxyribonucleic acid (DNA) deletion manifesting as a multisystem disorder having retinitis pigmentosa, heart block, elevated cerebrospinal fluid protein (sometimes including ataxia), short stature, endocrinopathy, and cognitive impairment.

Two mitochondrial disorders, designated mitochondrial encephalomyopathies involving muscle and central nervous syndrome, are caused by transfer ribonucleic acid (tRNA) mitochondrial mutations. Myoclonus epilepsy with ragged-red fibers (MERRF) is characterized by mitochondrial myopathy, myoclonus, ataxia, weakness, and seizures. Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) has childhood onset, intermittent vomiting, proximal weakness, and recurrent strokelike episodes.

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