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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Diseases of Carbohydrate and Fatty Acid Metabolism in Muscle

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One class of glycogen or lipid metabolic disorders in muscle is manifest as acute, recurrent, reversible dysfunction

These disorders occur with exercise intolerance and myoglobinuria, with or without cramps. Among the glyogenoses, this is characteristic of deficiencies in phosphorylase, phosphofructokinase (PFK), aldolase, phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGM) and lactate dehydrogenase (LDH). Among the disorders of lipid metabolism, this is characteristic of deficiencies in very-long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein (TP), carnitine palmitoyltransferase II (CPT II) and short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD). Figures 42-1 and 42-2 schematically illustrate the pathways of glycogen and fatty acid metabolism.

Figure 42-1. Schematic representation of glycogen metabolism and glycolysis.

Figure 42-1

Schematic representation of glycogen metabolism and glycolysis. Roman numerals indicate the sites of identified enzyme defects: I, glucose-6-phosphatase; II, acid maltase; III, debrancher enzyme; IV, brancher enzyme; V, muscle phosphorylase; VI, liver (more...)

Figure 42-2. Schematic representation of fatty acid oxidation.

Figure 42-2

Schematic representation of fatty acid oxidation. This metabolic pathway is divided into the carnitine cycle Image dclboxa.jpg, the inner mitochondrial membrane system Image dclboxb.jpg, and the mitochondrial matrix system Image dclboxc.jpg. The carnitine cycle includes the plasma membrane transporter, (more...)

Phosphorylase deficiency (McArdle's disease, glycogenosis type V) is an autosomal recessive myopathy caused by a genetic defect of the muscle isoenzyme of glycogen phosphorylase (Fig. 42-1). Intolerance of strenuous exercise is present from childhood, but usually onset is in adolescence, with cramps after exercise [1,5]. Myoglobinuria occurs in about one-half of patients. If they avoid intense exercise, most patients can live normal lives; however, about one-third of them develop some degree of fixed weakness, usually as a late-onset manifestation of the disease. In a few patients, weakness rather than exercise-related cramps and myoglobinuria characterizes the clinical picture.

In patients with myoglobinuria, renal insufficiency is a possible life-threatening complication. Physical examination between episodes of myoglobinuria may be completely normal or show some degree of weakness and, occasionally, wasting of some muscle groups.

Even between episodes, most patients have increased serum creatine kinase (CK); forearm ischemic exercise causes no rise of venous lactate concentration. This is a useful but nonspecific test in McArdle's disease. The electromyogram (EMG) at rest shows nonspecific myopathic features in about one-half of patients.

Muscle biopsy demonstrates subsarcolemmal blebs that contain periodic acid-Schiff (PAS)-positive material, a marker for glycogen. The histochemical stain for phosphorylase is negative, except in regenerating fibers. Biochemical documentation of the enzyme defect requires muscle biopsy because the defect is not expressed in more easily accessible tissues, such as leukocytes, erythrocytes and cultured fibroblasts. The gene encoding muscle phosphorylase has been assigned to chromosome 11, and a dozen distinct mutations have been identified in patients [5]. By far the most common among these is a nonsense mutation in codon 49 (mut-49). This allows diagnosis of 90% of patients through molecular analysis of genomic DNA isolated from blood, thus making muscle biopsy unnecessary in most cases [5].

Phosphofructokinase deficiency (Tarui's disease, glycogenosis type VII) is an autosomal recessive myopathy caused by a genetic defect of the muscle (M) subunit of the rate-limiting enzyme of glycolysis, PFK (Fig. 42-1). Presenting symptoms are cramps after intense exercise, followed by myoglobinuria in some patients. A few patients may have mild jaundice, reflecting excessive hemolysis, or typical symptoms and signs of gout. In patients with typical presentation, fixed weakness appears to be less common than in phosphorylase deficiency. However, in PFK deficiency, as in phosphorylase deficiency, a few patients have only weakness, without cramps or myoglobinuria. In addition to renal insufficiency due to myoglobinuria, other possible complications include renal colic due to urate stones and gouty arthritis [1].

Physical examination may show slight jaundice. Neurological examination is normal. Serum CK is variably increased in most patients. Forearm ischemic exercise causes no rise of venous lactate concentration. Serum bilirubin is elevated in most patients, and the number of reticulocytes is increased. Serum uric acid is also increased in most patients. The EMG is usually normal. Muscle biopsy shows focal, mostly subsarcolemmal, accumulation of glycogen. In some patients, a small portion of the glycogen is abnormal. By histochemical analysis, it is shown to be diastase-resistant; by electron microscopy, it appears finely granular and filamentous in structure. The enzyme defect can be demonstrated by a specific histochemical reaction for PFK. Although a partial defect of PFK activity is manifest in erythrocytes from patients, firm diagnosis usually requires biochemical studies of muscle. The gene encoding PFK-M is on chromosome 1, and several mutations have been identified in patients of different ethnic origins. Recognition of a specific mutation in genomic DNA from blood cells can eliminate the need for a muscle biopsy in suspected PFK-deficient patients [1].

The first patient with muscle aldolase deficiency was identified in 1996: this young boy suffered from a hemolytic trait but also complained of exercise intolerance and experienced several episodes of myoglobinuria during febrile illnesses [1].

Phosphoglycerate kinase deficiency is an X-linked recessive disease (type IX, Fig. 42-1). The most common clinical presentation includes hemolytic anemia with or without CNS involvement (see below). Thus far, only three patients have been described with a purely myopathic syndrome, characterized by exercise-induced cramps and myoglobinuria. Between episodes of myoglobinuria, physical and neurological examinations were normal. Forearm ischemic exercise caused contracture and no rise of venous lactate concentration.

Because the enzyme defect is expressed in all tissues except sperm, diagnosis can be made by biochemical studies of muscle, erythrocytes, leukocytes and cultured fibroblasts. Two distinct mutations have been identified in patients with myopathy [1].

Phosphoglycerate mutase deficiency is an autosomal recessive myopathy caused by a genetic defect of the muscle subunit of the enzyme PGM (type X, Fig. 42-1). Ten patients with this enzyme deficiency have been identified thus far.

The clinical picture includes cramps and recurrent myoglobinuria following intense exercise. Aside from episodes of myoglobinuria, none of the patients was weak. Forearm ischemic exercise caused a 1.5- to 2.0-fold increase in venous lactate concentration, an abnormally low but not absent response. Muscle biopsy showed normal or only moderately increased glycogen concentration. Because other accessible tissues, such as erythrocytes, leukocytes and cultured fibroblasts, express a different isoenzyme, the diagnosis of PGM-M subunit deficiency must be established by biochemical studies of muscle. Three different mutations have been identified in the PGM-M gene, which is located on chromosome 7 [1].

Lactate dehydrogenase deficiency is an autosomal recessive myopathy caused by a genetic defect of the muscle subunit, which is encoded by a gene on chromosome 11 (type XI, Fig. 42-1). Thus far, six Japanese families and three Caucasian patients with this disease have been described. The clinical picture is characterized by cramps and myoglobinuria after intense exercise.

Forearm ischemic exercise showed a subnormal rise of lactate concentration, contrasting with an increased rise of pyruvate. The diagnosis can be established by electrophoretic studies of LDH in serum, erythrocytes and leukocytes, showing lack of subunit M-containing isoenzymes. Nevertheless, it should be confirmed by biochemical studies of muscle or by molecular analysis of genomic DNA as five different mutations have been documented in patients [1].

Carnitine palmitoyltransferase deficiency is an autosomal recessive myopathy caused by a genetic defect of the mitochondrial enzyme CPT (Fig. 42-2). The disease is prevalent in men (male:female ratio, 5.5:1) and appears to be the most common cause of recurrent myoglobinuria in adults [4].

Clinical manifestations are limited to attacks of myoglobinuria, not preceded by contractures and usually precipitated by prolonged exercise, of several hours duration; prolonged fasting; or a combination of the two conditions. Less common precipitating factors include intercurrent infection, emotional stress and cold exposure, but some episodes of myoglobinuria occur without any apparent cause. Most patients have two or more attacks, probably because the lack of muscle cramps deprives them of a warning signal of impending myoglobinuria.

For unknown reasons, some women seem to have milder symptoms, such as myalgia, after prolonged exercise, without pigmenturia. This has been observed in sisters of men with recurrent myoglobinuria. The only serious complication is renal failure following myoglobinuria.

Physical and neurological examinations are completely normal. Prolonged fasting at rest, which should be conducted under close medical observation, causes a sharp rise of serum CK in about one-half of patients. Also, in about one-half of patients, ketone bodies fail to increase normally after prolonged fasting. Forearm ischemic exercise causes a normal increase of venous lactate concentration. Aside from episodes of myoglobinuria, the serum CK concentration and EMG are normal. A muscle biopsy specimen may appear completely normal or show variable, but usually moderate, accumulation of lipid droplets. Most patients with CPT deficiency benefit from a high-carbohydrate, low-fat diet, and the therapeutic response may serve as an indirect diagnostic clue. Because the enzyme defect appears to be generalized, tissues other than muscle, such as mixed leukocytes or isolated lymphocytes or platelets, can be used to demonstrate CPT deficiency; but the diagnosis should be confirmed in muscle.

The myopathic form of CPT deficiency is due to a defect of CPT II. The gene for CPT II has been localized to chromosome 1, and several mutations have been identified in patients [4]. As in the case of McArdle's disease (see above), one mutation, a serine-to-leucine substitution at codon 113, is far more common than the others and can be screened for in genomic DNA from blood cells, thus potentially avoiding muscle biopsy.

Very-long-chain acyl-CoA dehydrogenase and trifunctional protein are the two inner membrane-bound enzymes of fatty acid β-oxidation. Genetic defects of either can mimic the clinical presentation of CPT II deficiency by causing recurrent myoglobinuria in otherwise apparently healthy young adults. As in CPT II deficiency, precipitating factors include prolonged exercise, prolonged fasting, cold exposure, intercurrent illnesses or emotional stress [4].

Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency has been described in three patients. It is associated with additional defects of β-oxidation, which have been associated with limb weakness and attacks of myoglobinuria, and it is potentially fatal.

A second class of disorders of glucose and fatty acid metabolism causes progressive weakness

These disorders are associated with acid maltase, debrancher enzyme and brancher enzyme deficiencies among the glycogenoses. These are also associated with carnitine deficiency, some defects of β oxidation and other biochemically undefined lipid-storage myopathies among the disorders of lipid metabolism. Figures 42-1 and 42-2 schematically illustrate the pathways of glycogen and fatty acid metabolism.

Acid maltase deficiency (AMD) (glycogenosis type II) is an autosomal recessive disease caused by a genetic defect of the lysosomal enzyme acid maltase, an α-1,4- and α-1,6-glucosidase capable of digesting glycogen completely to glucose (Fig. 42-1). Two major clinical syndromes are caused by AMD. The first is Pompe's disease, which is a severe, generalized and invariably fatal disease of infancy; the second is a less severe neuromuscular disorder beginning in childhood or in adult life (see Chap. 41).

Infantile, generalized cardiomegalic AMD, or Pompe's disease, usually becomes manifest in the first weeks or months of life, with failure to thrive, poor suck, generalized hypotonia and weakness, also termed floppy infant syndrome. Macroglossia is common, as is hepatomegaly, which, however, is rarely severe. There is massive cardiomegaly, with congestive heart failure. Weak respiratory muscles make these infants susceptible to pulmonary infection; death usually occurs before the age of 1 year and invariably before the age of 2 years [1].

The childhood- and adult-onset forms of AMD cause signs and symptoms that are limited to the musculature, with progressive weakness of truncal muscles and of proximal, more than distal, limb muscles, usually sparing facial and extraocular muscles. In the childhood form, onset is in infancy or childhood and progression tends to be rapid. In the adult form, onset usually is in the third or fourth decade but occasionally even later and the course is slower [1].

The clinical picture in male children can closely resemble Duchenne-type muscular dystrophy; in adults, it mimics limb-girdle dystrophy or polymyositis. The early and severe involvement of respiratory muscles in most patients with AMD is a distinctive clinical clue. Respiratory failure and pulmonary infection are the most common causes of death.

Serum CK is consistently increased in all forms of AMD. Forearm ischemic exercise causes a normal rise of venous lactate concentration in patients with childhood or adult AMD. The electrocardiogram (ECG) is altered in Pompe's disease, with a short P-R interval, giant QRS complexes and left ventricular or biventricular hypertrophy, but is usually normal in the later-onset forms. The EMG shows myopathic features and fibrillation potentials, bizarre high-frequency discharges and myotonic discharges.

Muscle biopsy shows vacuolar myopathy of very severe degree affecting all fibers in Pompe's disease but of varying degree and distribution in childhood and adult AMD. In adult AMD, biopsy specimens from unaffected muscles may appear normal by light microscopy. The vacuoles contain PAS-positive material, a marker for glycogen. Electron microscopy shows abundant glycogen, both within membranous sacs, presumably lysosomes, and free in the cytoplasm.

The enzyme defect is expressed in all tissues, and the diagnosis can be made by biochemical analysis of urine, lymphocytes (mixed leukocytes do not give reliable results) or cultured skin fibroblasts. Fibroblasts cultured from amniotic fluid can be used for prenatal diagnosis of Pompe's disease. The gene encoding acid maltase is on chromosome 17, and numerous mutations have been identified in patients with both forms of AMD, confirming that infantile and late-onset AMD are allelic disorders. Predictably, more severe mutations are associated with Pompe's disease; however, many patients are compound heterozygotes, and there is no strict genotype/phenotype correlation [1].

Debrancher enzyme deficiency (glycogenosis type III, Cori's disease, Forbe's disease) is an autosomal recessive disease (Fig. 42-1). In its more common presentation, debrancher enzyme deficiency causes liver dysfunction in childhood, with hepatomegaly, growth retardation, fasting hypoglycemia and seizures [1]. Myopathy has been described in about 20 patients [1]. In most, onset of weakness was in the third or fourth decade. Wasting of distal leg muscles and intrinsic hand muscles is common, and the association of late-onset weakness and distal wasting often suggests the diagnosis of motor neuron disease or peripheral neuropathy. The course is slowly progressive. In a smaller number of patients, onset of weakness is in childhood, with diffuse weakness and wasting. The association of hepatomegaly and growth retardation facilitates the diagnosis.

There is no glycemic response to glucagon or epinephrine (Fig. 42-1), whereas a galactose load causes a normal glycemic response. Forearm ischemic exercise produces a blunted venous lactate rise or no response. Serum CK activity is variably, often markedly, increased. The ECG shows left ventricular or biventricular hypertrophy in most patients, and the EMG may show myopathic features alone or associated with fibrillations, positive sharp waves and myotonic discharges. This “mixed” EMG pattern in patients with weakness and distal wasting often reinforces the erroneous diagnosis of motoneuron disease. Motor nerve conduction velocities are moderately decreased in one-fourth of patients, suggesting a polyneuropathy.

Muscle biopsy shows severe vacuolar myopathy with glycogen storage. On electron microscopy, the vacuoles correspond to pools of glycogen free in the cytoplasm.

In most patients, the enzyme defect is generalized, and it has been demonstrated in erythrocytes, leukocytes and cultured fibroblasts. In patients with myopathy, the diagnosis is securely established by measurement of debrancher enzyme activity in muscle biopsy specimens or by studies of iodine adsorption spectra of glycogen isolated from muscle; there is a shift in the spectrum toward lower wavelengths, indicating that the polysaccharide has abnormally short peripheral branches. The gene for the debrancher enzyme has been assigned to chromosome 1, and the first mutations have been identified in patients [1].

Branching enzyme deficiency (glycogenosis type IV; Andersen's disease) is an autosomal recessive disease of infancy or early childhood, typically causing liver dysfunction with hepatosplenomegaly, progressive cirrhosis and chronic hepatic failure (Fig. 42-1). Death usually occurs in childhood. Although muscle wasting and hypotonia are mentioned in several reports, only three patients have had severe hypotonia, wasting, contractures and hyporeflexia, suggesting the diagnosis of spinal muscular atrophy [1].

There are no diagnostic laboratory tests. A muscle biopsy specimen may be normal or show focal accumulations of abnormal glycogen, which is intensely PAS-positive and partially resistant to diastase digestion. With the electron microscope, the abnormal glycogen is found to have a finely granular and filamentous structure. The gene that encodes the branching enzyme has recently been cloned and assigned to chromosome 3 [1].

Carnitine deficiency is a clinically useful term describing a diversity of biochemical disorders affecting fatty acid oxidation. Carnitine deficiency may be tissue-specific or generalized.

Tissue-specific carnitine deficiency has previously been termed myopathic carnitine deficiency because patients have generalized limb weakness, starting in childhood. Limb, trunk and facial musculature may be involved. The course is slowly progressive, but weakness may fluctuate in severity. Laboratory investigations show normal or near-normal serum carnitine concentrations and variably increased serum CK values. The EMG shows myopathic features with or without spontaneous activity at rest. Muscle biopsy reveals severe triglyceride storage, best seen with the oil red O stain in frozen sections. This condition is transmitted as an autosomal recessive trait. Originally, it was thought that the primary biochemical defect involved the active transport of carnitine from blood into muscle. However, no such defect has ever been documented [6]. Rather, an increasing number of patients have a tissue-specific defect involving the short-chain isoform of acyl-CoA dehydrogenase (SCAD). As such, the muscle carnitine deficiency is secondary to a primary enzyme defect.

Generalized carnitine deficiency, in its primary form and inherited as an autosomal recessive trait, is due to a defect of the specific high-affinity, low-concentration, carrier-mediated carnitine-uptake mechanism. The defect has been documented in cultured fibroblasts and muscle cultures, but the same uptake system is probably shared by heart and kidney, thus explaining the cardiomyopathy and the excessive “leakage” of carnitine into the urine. Oral l-carnitine supplementation results in dramatic improvement in cardiac function [4,6].

Systemic carnitine deficiency was first described in 1975 and is thought to represent a defect in the de novo biosynthesis of carnitine [4,6]. However, no such defect has been documented. Patients with systemic carnitine deficiency have a generalized decrease in the tissue and plasma concentrations of carnitine and an excessive urinary excretion of carnitine. Many of the patients originally reported to have systemic carnitine deficiency have been reinvestigated and found to have a primary enzyme defect, such as medium-chain acyl-CoA dehydrogenase deficiency (MCAD). This deficiency is the prototype of a defect in β oxidation that produces secondary carnitine deficiency. β-Oxidation defects also are associated with dicarboxylic aciduria. This finding is particularly prominent during a metabolic crisis and may be rather inconspicuous between attacks. The differential diagnosis of systemic carnitine deficiency and dicarboxylic aciduria includes other defects of β oxidation, such as deficiencies of the long-chain isoform of acyl-CoA dehydrogenase (LCAD), SCAD, electron transfer flavoprotein (ETF) and ETF oxidoreductase [4], the long- and short-chain isoforms of 3-hydroxyacyl CoA dehydrogenase (LCHAD, SCHAD), β-ketothiolase, and the newly described TP enzyme that includes the catalytic activities of enoyl hydratase, LCHAD and β-ketothiolase. Cardiac involvement is particularly prominent in conditions that involve the metabolism of long-chain fatty acids. Other genetically determined biochemical defects involving organic acid metabolism and respiratory chain function may produce secondary carnitine deficiency. Carnitine deficiency also may result from acquired diseases, such as chronic renal failure treated by hemodialysis, renal Fanconi's syndrome, chronic hepatic disease with cirrhosis and cachexia, kwashiorkor and total parenteral nutrition in premature infants [6]. The mechanisms of carnitine depletion in these diverse conditions include excessive renal loss and excessive accumulation of acyl-CoA thioesters. These potentially toxic compounds are esterified to acylcarnitines and excreted in the urine, resulting in an excessive loss of carnitine.

The genetically determined defect of membrane carnitine transport is the only known condition that fulfills the criteria for primary carnitine deficiency [4,6,7]. This condition, like the other conditions involving the carnitine cycle, is not associated with dicarboxylic aciduria. It is transmitted as an autosomal recessive trait and produces a life-threatening cardiomyopathy in infancy or early childhood, which is effectively treated with carnitine supplementation. The untreated patient also manifests systemic features of hypotonia, failure to thrive and alterations of consciousness, including coma. Carnitine concentrations are extremely low in plasma and body tissues, and the excretion of carnitine in the urine is extremely high. The excessive urinary carnitine losses are caused by a defect in renal tubular uptake of filtered carnitine, resulting from the primary defect of the plasma membrane carnitine transporter. This condition can be documented by carnitine-uptake studies in cultured skin fibroblasts from patients. Uptake studies in parents give intermediate values, consistent with a heterozygous state.

A few patients have been described with a defect involving the carnitine—acylcarnitine translocase system, which facilitates the movement of long-chain acylcarnitine esters across the inner membrane of the mitochondrion (Fig. 42-2). These patients have extremely low carnitine concentrations and minimal dicarboxylic aciduria [4,6].

Carnitine concentrations are normal to high in patients with a primary defect of CPT I. Patients with CPT II have normal carnitine concentrations. Two clinical syndromes have emerged in relationship to CPT II. The more common syndrome, as discussed previously, involves recurrent myoglobinuria provoked by fasting or intercurrent infection and later is associated with fixed limb weakness. The less common syndrome involves infants and produces hypoketotic hypoglycemic coma with a Reye-like clinical signature. All cases thought to be recurrent Reye's syndrome should be investigated for defects involving fatty acid oxidation. Low serum carnitine concentrations and increased urinary dicarboxylic acids implicate a biochemical defect of β oxidation. Low serum carnitine concentrations and normal urinary dicarboxylic acids implicate a defect of the membrane carnitine transporter or the mitochondrial inner membrane carnitine—acylcarnitine translocase system. Normal to high serum carnitine concentrations and no dicarboxylic aciduria suggests a defect of CPT I or CPT II.

Oral administration of l-carnitine is life-saving in patients with the genetically determined defect of the plasma membrane carnitine transporter [4,6,7]. It also is recommended as a supplement in all patients who have documented carnitine deficiency, even though clear evidence of benefit is lacking. Medium-chain triglyceride supplementation has proven beneficial in CPT I deficiency and should be beneficial also in the other defects of the carnitine cycle. Medium-chain fatty acids cross the plasma membrane and the mitochondrial membranes directly and are esterified to the thioesters in the mitochondrial matrix (Fig. 42-2). A ketonemic response to medium-chain triglycerides documents the biological integrity of β oxidation and implicates a biochemical defect of the carnitine cycle or of β oxidation involving the metabolism of the longer-chain fatty acids.

The impairment of energy production from carbohydrate, which is the common consequence of these defects, should result in similar, exercise-related signs and symptoms

Except for debrancher deficiency, this is the case [1]. Of the nine glycolytic enzyme defects described above, six affect glycogen breakdown or glycolysis: phosphorylase, debrancher, PFK, aldolase, PGK, PGM, LDH deficiencies. Patients with phosphorylase, PFK, aldolase, PGK, PGM, or LDH deficiency have exercise intolerance manifested by premature fatigue, cramps and myoglobinuria. As predicted by the crucial role of glycogen as a fuel source, these patients are more prone to experience cramps and myoglobinuria when they engage in isometric exercise, such as lifting weights, or in intense dynamic exercise, such as walking uphill. Energy for these types of exercise derives mainly from anaerobic or aerobic glycolysis. The block of glycogen utilization leads to a shortage of pyruvate and, therefore, of acetyl CoA (Fig. 42-3), the pivotal substrate of the Krebs cycle, and to a decreased mitochondrial energy output. Moderate exercise typically causes premature fatigue and myalgia, but these symptoms usually resolve after brief rest or slowing of pace; thereafter, patients find that they can resume or continue exercise without problems. This second-wind phenomenon seems to be due to early mobilization of fatty acids and to increased blood flow to exercising muscles.

Figure 42-3. Schematic representation of mitochondrial metabolism.

Figure 42-3

Schematic representation of mitochondrial metabolism. Respiratory chain complexes or components encoded exclusively by the nuclear genome are light orange. Complexes containing some subunits encoded by the nuclear genome and others encoded by mitochondrial (more...)

Conversely, patients with fatty-acid oxidation defects experience myalgia and myoglobinuria after prolonged, though not necessarily high-intensity, exercise. Fasting exacerbates these complaints. Thus, myoglobinuria occurs in CPT deficiency under metabolic conditions that favor oxidation of fatty acids in normal muscle [4,8]. This observation suggests that impaired cellular energetics are the common cause of myoglobinuria in diverse metabolic myopathies. However, biochemical proof of energy depletion is still necessary. No abnormal decrease of ATP concentration has yet been measured in muscle of patients with McArdle's disease during fatigue, which is defined as failure to maintain the required or expected force, or during ischemic exercise-induced contracture. It cannot be excluded, however, that contracture as well as necrosis may involve only a relatively small percentage of fibers. Measurements of ATP and phosphocreatine in whole muscle might fail to detect loss of high-energy phosphate compounds in selected fibers. Additionally, ATP deficiency may affect a specific subcellular compartment.

The cause of weakness is also poorly understood. Chronic impairment of energy provision is unlikely because two of the three glycogenoses causing weakness involve a glycogen-synthesizing enzyme, branching enzyme deficiency, and a lysosomal glycogenolytic enzyme, acid maltase deficiency (Chap. 41), neither of which is directly involved in energy production [1].

A more likely explanation is that weakness may be due to a net loss of muscle fibers because regeneration cannot keep pace with the rate of degeneration. With fewer functioning fibers, the muscle cannot exert full force. EMG reinforces this interpretation: motor unit potentials are of smaller amplitude and briefer duration than normal due to loss of muscle fibers from a motor unit. Fibrillations are attributed to areas of focal necrosis of muscle fiber, isolating areas of the cell from the neuromuscular junction in a form of “microdenervation.” Muscle fiber degeneration may be due to excessive storage of glycogen, as in acid maltase and debrancher enzyme deficiencies, or lipid droplets, as in carnitine deficiency. In agreement with this hypothesis is the observation that in at least two of the glycogenoses causing weakness, infantile acid maltase deficiency and debrancher enzyme deficiency, glycogen storage is much more severe than in the glycogenoses causing cramps and myoglobinuria. Similarly, lipid storage is much more severe in carnitine deficiency than in CPT deficiency [4,6,7].

An additional cause of weakness may be involvement of the anterior horn cells of the spinal cord, which is very conspicuous in infantile acid maltase deficiency. All three glycogenoses causing weakness are in fact due to generalized enzyme defects, but histological signs of denervation are not evident.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28177

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