Metabolic Causes of Myoglobinuria Paola Tonin, MD, Paulette Lewis, BA, Serenella Servidei, MD," and Salvatore DiMauro, MD ~~

~

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To evaluate the proportion of cases of myoglobinuria that can be ascribed to specific metabolic defects, we have studied eight enzymes-phosphorylase, phosphorylase kinase, phosphofructokinase (PFK), phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGAM), lactate dehydrogenase (LDH), carnitine palmitoyltransferase (CPT), and myoadenylate deaminase (MAD)-in muscle biopsy specimens from 77 consecutive patients with myoglobinuria (documented in 44, suspected in 33). Enzyme defects were found in 36 patients: CPT deficiency in 17, phosphorylase deficiency in 10, phosphorylase kinase deficiency in 4, MAD deficiency in 3, PGK deficiency in 1, and a combined defect of CPT and MAD in 1. Exercise was the main precipitating factor, both in patients with and in those without detectable enzymopathies. Thirty patients had specific enzymopathies without myoglobinuria: 14 had phosphorylase deficiency, 9 had MAD deficiency, 3 had phosphorylase kinase deficiency, 3 had PFK deficiency, and 1 had PGAM deficiency. Systematic biochemical evaluation of muscle biopsy specimens revealed specific enzymopathies in about half of the patients with idiopathic myoglobinuria. The rest may have blocks of metabolic pathways not yet studied routinely, such as beta oxidation, or genetic defects of the sarcolemma, such as Becker's muscular dystrophy. Tonin P, Lewis P, Servidei S, DiMauro S. Metabolic causes of myoglobinuria Ann Neurol 1990;27:181-185 Acute muscle necrosis with myoglobinuria can be due to exogenous or endogenous causes. Exogenous causes include mechanical trauma (Bayswater's syndrome), myotoxic agents (animal poisons, numerous drugs, and alcohol), saltlwarer imbalance, extremes of ambient temperature with hypothermia or fever, and infections. Endogenous causes of what has been called idiopathic myoglobinuria include inherited disorders of muscle metabolism and other genetic diseases, such as malignant hypenhermia and muscular dysrrophy [l}. The number of recognized metabolic defects associated with myoglobinuria has increased in the past 20 years to include, besides myophosphorylase deficiency (McArdle's disease) {23 and phosphofructokinase deficiency (Tarui's disease) {3}, four other defects of glycogen metabolism: phosphorylase kinase C43, phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase { S ] , and 1 defect of lipid metabolism, carnitine palmitoyltransferase {63. However, the proportion of all cases of idiopathic myoglobinuria that can be ascribed to known metabolic myopathies and the relative frequency of the different enzyme defects are difficult to assess because idiopathic myoglobinuria is rare, and only a few laboratories can screen muscle biopsy specimens for all known biochemical causes of myoglobinuria. To answer these questions, we have reviewed the biochemical results obtained in 77 biopsy specimens from patients with idiopathic myoglobinuria referred to us during the past 4 years.

Materials and Methods

From the H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, Columbia University College of Physicians and Surgeons, New York, NY. Received Jun 8, 1989, and in revised form Jul 19. Accepted for publication Jul 20, 1989.

Address correspondence to Dr DiMauro, 4-420 College of Physicians and Surgeons, 630 West 168th St, New York, NY 10032.

Patient Population In the period between January 1, 1985, and December 31, 1988, we received 123 muscle biopsy specimens from patients, aged 15 years or older, with the diagnosis of idiopathic myoglobinuria in whom excessive alcohol intake and drug abuse had been excluded. Forty-six patients were not included in this study because the small size of the muscle sample did not allow complete biochemical investigations. The remaining 77 patients were divided into 2 groups (Table 1). In the first group (44 patients), myoglobinuria was documented during 1 or more attacks by serum creatine kinase values greater than 20,000 units or by detection of myoglobin in serum or urine. In the second group (33 patients), myoglobinuria was suspected by the referring physicians on the basis of clinical features (acute and reversible myalgia and weakness) accompanied by gross discoloration of the urine and usually precipitated by exercise. Eight enzymes were routinely studied: phosphorylase, phosphorylase kinase, phosphofructokinase (PFK), phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGAM), lactate dehydrogenase (LDH), carnitine palmitoyltransferase (CPT), and myoadenylate deaminase (MAD).The following biochemical criteria had to be met for inclusion: Data had to be available for all eight enzymes in patients without detectable enzymopathy, and, in patients with single enzymopathies, at least two other enzymes had to be normal to reassure us about the specificity of the enzyme defect. Seventy-seven patients met these criteria, 60 men and 17 women, ranging in age from 15 to 65 years (mean age, 31 years) (see Table 1).

"Present address: Department of Neurology, Universiti Cattolica del Sacro Cuore, Largo Gemelli 8, 00179 Roma, Italy.

Copyright 0 1990 by the American Neurological Association

181

Table 1. Biochemical Defects in 77 Patients with Myoglobinuria No. of Patients Enzyme Defect

Myoglobinuria Documented

Myoglobinuria Suspected

Sex (WF)

Detected CPT Phosphorylase Phosphorylase kinase PGK MAD CPT + MAD None detected Total

23 13 3 3 1 2

13 4 7 1 0 1 0 20 33

26:lO 13:4 5:5 4:O

CPT

1

21 44

l:o

3:O 0: 1 34:7 60:17

Age (mean)

15-41 (26) 16-63 (36) 18-22 (21) 38 21-35 (27) 53 15-65 (33) 15-65 (31)

= carnitine palmitoyitransferase; PGK = phosphoglycerate kinase; MAD = myoadenylate deaminase.

Table 2. Biochemical Data in 36 Patients with Identifed Enzyme Defects" Patients Enzymeb

Control Subjects (no.)'

Mean

Range

No.

CPT Phosphorylase Phosphorylase kinase PGK MAD

76.08 24.0 4.86 187.2 28.13

4.22 0 0 2.34 1.56

0-10.4 0 0-0.71 2.34 0.90-2.48

18 10 4

f -t

? ? ?

16.39 (65) 7.4 (118) 5.37 (22) 36.6 (21) 3.32 (53)

1

3

"Enzyme activities are expressed as pmol substrate utilizedmidgrn except for CPT (nmol carnitine exchangedmidgrn). bThe patient with combined defects of CPT and MAD has been included in the CPT deficiency group (CPTactivity was 2.5;MAD activity was

2.4). 'Means

?

CPT

carnitine palmitoyltransferase; PGK

=

standard deviation. =

phosphoglycerate kinase; MAD

Biocbemica/ Studies Muscle biopsy samples were frozen in liquid nitrogen, shipped in dry ice, and stored in liquid nitrogen. The occasional sample that thawed en route was excluded. The tissue was homogenized with all-glass homogenizers in 9 volumes of appropriate medium. For all enzyme assays except CPT, homogenates were centrifuged at 10,000 g for 10 minutes and supernatants were used; for CPT determination, whole homogenate was used. Extraction media composition and enzyme assays for phosphorylase 173, phosphorylase kinase {8}, PFK {93, PGK {lo], PGAM f 111, LDH f123, CPT f 137, and MAD { 141 were as described. An enzyme was considered deficient when the activity in the patient's muscle was below 5% of the normal mean (Table 2). Intermediate values for individual enzymes were found in most patients without detectable enzymopathies, but residual activities were in the heterozygote range, making a pathogenic role unlikely.

Results Of the 77 patients with idiopathic myoglobinuria whose biopsy specimens were referred to us for biochemical analysis, specific enzyme defects were found in 36, or 47% of cases (see Tables 1 and 2). The percentage was higher (64%) in patients with documented myoglobinuria than in those with suspected myoglobinuria ( 5 1%). The most common disorder was CPT deficiency (17 182 Annals of Neurology

Vol 27 No 2 February 1990

=

myoadenyiate deaminase.

patients), followed by phosphorylase deficiency (10 patients), phosphorylase kinase deficiency (4 patients), and MAD deficiency (3 patients). Only 1 patient, a man with PGK deficiency, had a defect of terminal glycolysis. There was an overall predominance of men (male/female ratio, 3.5:1), much more evident in patients without enzyme defects (4.8: l) than in those with enzymopathy (2.6:l). One pdtient had a double enzyme defect that involved CPT and MAD (see Table 1). In this patient, the activities of the other enzymes were normal (see Table 2). Whether or not an enzyme defect was found, most patients had had more than 1 episode of myoglobinuria (Table 3). Exercise was the most common precipitating factor in patients with or without documented enzymopathy. Fasting, usually associated with exercise, was recognized as an important precipitating factor in several patients with CPT deficiency and in 1 patient with MAD deficiency but had no evident effect in patients with glycogenoses. Intercurrent infection, possibly associated with vomiting and fasting, was also a more common triggering event in CPT deficiency than in other conditions. Conversely, serum creatine kinase levels between attacks of myoglobinuria were normal in most patients with CPT deficiency but were elevated in patients with glycogenoses. As expected, forearm ischemic exercise test results were abnormal

Table 3. Clinical and Laboratory Features of Patients with Myoglobinuria Enzyme Defect No. of episodes 1 >1 Precipitating factors Exercise Fasting Infections Interictal creatine kinase Increased Normal Unknown Ischemic exerciseb Normal Abnormal Not done Muscle biopsy Increased glycogen' Increased lipid' Nonspecific changes Histochemical defectsd Normal

CPT"

Ph"

PhK"

PGK"

MAD"

None"

3/17 14/17

2/10 8/10

014 414

011

111

013 313

10141 3 1/41

15/17 5/17 5/17

10/10 0110 0/10

314 014 114

I/ 1 011 011

213 113 113

32/37 7/37 8/37

1/16 14/16 1/16

7/10 1/10 2/10

113 213 013

011 I/ 1 o/ 1

112 112 012

15/29 14/29 0129

14/16 0116 2/16

018 618 218

314 014 114

011 I/ 1 011

313 013 013

25/36 4/36 7/36

0117 3/17 2/17

319 019 119 419 119

014 014 214

011 011

214

o/1

013 013 113 213 013

2/36 2/36 6/36 9/36 15/36

12/17

111

"The denominator reflects the number of patients for whom information was available; thus, the denominator may change in different rows of the same column. bRefers to the response of serum lactate. 'Refers to morphological observations. dCould be documented only for Ph and MAD. CPT = carnitine palmitoyltransferase; Ph myoadenylate deaminase.

=

phosphorylase; PhK

(no rise of venous lactate) in all patients with phosphorylase or PGK deficiency who were tested. Normal responses were obtained in all other patients, including those with phosphorylase kinase deficiency. Muscle biopsy specimens (evaluated by the referring physicians) showed glycogen storage in 3 of 9 patients with phosphorylase, but in none of the patients with phosphorylase kinase or PGK deficiency. An increased number of lipid droplets was seen in 3 of 17 patients with CPT deficiency. Myoglobinuria was not an obligatory consequence of the enzyme defects we studied because many of these defects can cause only exercise intolerance, with premature fatigue and cramps, or fixed weakness. Patients with these symptoms were also screened for enzyme defects of glycolysis and lipid metabolism, and we found that 30 patients had specific enzymopathies without myoglobinuria (Table 4): Phosphorylase deficiency accounted for most of these patients (14, or 58% of the group with McArdle's disease), followed by MAD deficiency (9 patients). All 3 patients with PFK deficiency belonged to this group.

Discussion Hereditary disorders of muscle metabolism are among the better known and more extensively studied causes of idiopathic myoglobinuria in adults. They include six enzyme defects of glycogen metabolism and glycolysis:

=

phosphorylase kinase; PGK = phosphoglycerate kinase; MAD

=

Table 4 . Biochemical Defcts in Patients Without Myoglobinuria Sex (No., WF)

Enzyme Defect

No. of Patients

MAD Phosphorylase Phosphorylase kinase PFK PGAM

14 3 3

5:4 6:8 3:O 2: 1

1

0: 1

9

PFK = phosphofructokinase; PGAM MAD = myoadenylate deaminase.

=

phosphoglycerate mutase;

Two of these, phosphorylase deficiency (McArdle's disease) and PFK deficiency (Tarui's disease), have been known since 1959 { 2 } and 1967 {3}, respectively. Three defects of terminal glycolysis (PGK, PGAM, and LDH deficiency) were described in 1980, but only a few additional patients have been reported since then {5, 15, 167. Phosphorylase b kinase deficiency, known to pediatricians as a cause of benign hepatomegaly of infancy {17, 181, has been considered a cause of exercise intolerance and myoglobinuria in only a few cases {4, 19,201. The description of CPT deficiency in 1973 [217 increased the number of patients with an identified biochemical cause of myoglobinuria, and it soon seemed that CPT deficiency would be the most common cause of hereditary myoglobinuria {6]. N o other abnormality of lipid metabolism has been identified as Tonin et al: Metabolic Causes of Myoglobinuria

183

a major cause of myoglobinuria, although acute muscle necrosis occurred in 1 patient with carnitine deficiency 122) and in another with long-chain acyl-coenzyme A dehydrogenase deficiency 1231. In both glycogen and lipid disorders, myoglobinuria has been attributed to a critical shortage of energy needed to insure the integrity of the muscle cell 1241. The discovery of MAD deficiency in 1978 [25} generated controversy about the pathogenic significance of this common genetic defect. Some emphasized the multiple roles of MAD in energy provision (stabilizing the adenylate energy charge, functioning as anaplerotic enzyme for the Krebs cycle, stimulating anaerobic glycolysis), which might explain how MAD deficiency could cause exercise-related aches, pains, and cramps 1261. Others, however, considered the association merely coincidental and probably caused by the relatively high frequency of two independent factors, the clinical syndrome of aches, pains, and cramps (“fading athlete syndrome”) and the genetic lack of MAD 127, 281. One argument used by the skeptics was that an impairment of energy production ought to cause myoglobinuria in at least some patients, while myoglobinuria had never been described in cases of MAD deficiency 1271. Even considering all these biochemical causes, it was cleai that many patients with idiopathic myoglobinuria had no recognized biochemical abnormality. Among the 77 patients whose muscle biopsy specimens were sent to us for biochemical analysis, we found a biochemical defect in about half of the patients with adult-onset myoglobinuria. In children with myoglobinuria, Tein and associates 1291 identified the biochemical defect in only 2 of 35 patients. As was also suggested by the analysis of reported cases 161, we have found that CPT deficiency is the most common, identifiable metabolic cause of myoglobinuria, followed by phosphorylase deficiency. Four patients had phosphorylase kinase deficiency, underscoring the importance of this largely neglected enzyme defect as a cause of myoglobinuria. Three patients had isolated MAD deficiency. In all 3, residual activity was below 10% of normal and it was less than 5% in 2 patients. A decrease of activity below 5% of the normal mean has been required for the definition of primary MAD deficiency 1261. In these patients we cannot exclude a coincidental association of MAD deficiency with one or more still undisclosed genetic causes of myoglobinuria, similar to the association with CPT deficiency that we observed in 1 patient, or the association with phosphorylase deficiency described by Heller and associates 1301. However, MAD deficiency does impair energy production and in at least a few patients may cause myoglobinuria. As is expected for inborn errors of metabolism, most patients with documented enzyme defects had 184 Annals of Neurology

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No 2

February 1990

multiple episodes of myoglobinuria. The distribution of precipitating factors was also predictable; exercise was virtually the sole triggering event in patients with glycogenoses, while fasting and intercurrent infections played an important role in those with CPT deficiency. The venous lactate response to ischemic exercise was impaired in phosphorylase deficiency and in blocks of glycolysis but not in patients with phosphorylase kinase deficiency. This is in agreement with findings in mice genetically lacking muscle phosphorylase kinase 1311. Patients without defined enzymopathies were also likely to have multiple episodes, suggesting that most of them also had inherited but unidentified diseases. These could be metabolic disorders affecting enzymes of glycogen or lipid metabolism that were not investigated by us or, more likely, other metabolic pathways. For instance, myoglobinuria has been described in 4 Italian patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency in whom other biochemical causes had been excluded 132, 331. We did not study G6PD in erythrocytes or muscle of our black patients, but the form of G6PD deficiency prevalent in American blacks is characterized by high residual activity, especially in tissues other than red blood cells 1341. It therefore seems unlikely that this enzyme defect could play an important role in our patients. Other genetic diseases associated with myoglobinuria include malignant hyperthermia and Duchenne’s dystrophy 1351. In malignant hyperthermia, an autosomal dominant condition, myoglobinuria is almost always precipitated by anesthetics and associated with rigidity and hyperthermia, but isolated episodes have been induced by strenuous exercise 111. None of the patients in our series had a family or personal history of anesthetic reactions. General anesthesia has also precipitated myoglobinuria in Duchenne’s dystrophy, and Becker’s dystrophy has been associated with myoglobinuria, usually induced by exercise 1351. Analysis of dystrophin should now be included in studies of patients with myoglobinuria. We found 30 patients with documented enzymopathies but without myoglobinuria. Fourteen (58% of all our patients with McArdle’s disease) had phosphorylase deficiency. Three of our patients had PFK deficiency: 2 had exercise intolerance since childhood, and 1 was a 76year-old man with progressive limb weakness that had started at about age 60. Weakness of late onset without cramps or myoglobinuria has been reported in 2 other patients 136, 371 and PFK deficiency should be considered in the differential diagnosis of late-onset myopathy. As expected, most patients with MAD deficiency had no myoglobinuria. Six of them had residual activity below 5%, compatible with primary MAD deficiency 1261, and 3 had residual activity above 5% but below

15% (secondary cases). All patients complained of exercise-related myalgia and cramps and none had evidence of other neurological disease. Our data show that systematic study of glycogenolysis, glycolysis, and CPT activity will disclose a metabolic cause in about half of the patients with recurrent myoglobinuria. In the others, myoglobinuria could be due to other metabolic diseases, especially defects of beta-oxidation [23}, or to genetic defects that are presumed to affect the sarcolemma, such as Becker’s or Duchenne’s muscular dystrophy or malignant hyperthermia. Supported by Clinical Research Center grants from the National Institute of Neurological Disorders and Stroke (NS11766) and from the Muscular Dystrophy Association. Dr Tonin was supported by a fellowship from the Fidia Research Laboratories, Abano Terme, Italy, and Dr Servidei by a fellowship from the Unione Italiana Lotta alla Distrofia Muscolare (UILDM), Sezione Latiale “Giulia Testore,” Rome, Italy.

15. Tonin P, Shanske S, Brownell AK, et al. Phosphoglycerate kinase (PGK) deficiency: a third case with recurrent myoglobinuria Neurology 1989;39(suppl 1):359-360 16. Meola G, Toscano A, Velicogna M, et al. Muscle phosphoglycerate mutase (PGAM) deficiency in aneural and innervated cultures. Neurology 1989;39(suppl 1):233 (Abstract) 17. Schimke RN, Zakheim RM, Corder RC, Hug G. Glycogen storage disease type IX: benign glycogenosisof liver and hepatic phosphorylase kinase deficiency. J Pediatr 1973;83:1031-1034 18. Lederer B, Van Hoof F, Van den Berghe G, Hers HG. Glycogen phosphorylase and its converter enzymes in haemolysates of normal human subjects and of patients with type VI glycogen storage disease. Biochem J 1975;147:23-35 19. Strugalska-Cynowska M. Disturbances in the activity of phosphorylase b kinase in a case of McArdle myopathy. Folia Histochem Cytobiol 1967;5:151-156 20. Iwamasa T, Fukuda S, Tokumitsu S, et al. Myopathy due to glycogen storage disease. Mol Pathol 1983;38:405-420 2 1. DiMauro S, DiMauro PM. Muscle carnitine palmityltransferase deficiency and myoglobinuria. Science 1973;182:929-93 1 22. Prockop L, Engel WK, Shug AL. Nearly fatal muscle carnitine deficiency with full recovery after replacement therapy. Neurolom 1983:33:1629-163 1 23. Stanley CA. New genetic defects in mitochondrial fatty acid beta-oxidation and carnitine deficiency. Adv Pediatr 1987;34: 59-88 24. DiMauro S, Bresolin N, Papadimitriou A. Fuels for exercise: clues from disorders of glycogen and lipid metabolism. In: Serratrice G et al, eds. Neuromuscular diseases. New York Raven Press, 1984:45-50 25. Fishbein WN, Armbrustmacher VW, Griffin JL. Myoadenylate deaminase deficiency. A new disease of muscle. Science 1978; 200:545-548 26. Sabina RL, Swain JL, Holmes EW. Myoadenylate deaminase deficiency. In: Stanbury J, Wyngaarden J, Fredrickson DS, eds. The metabolic basis of inherited disease. New York: McGraw/ Science, in press 27. Rowland LP, Layzer RB, DiMauro S. Pathophysiology of metabolic muscle disorders. In: Asbury AK, McKhann CM, McDonald WI, eds. Diseases of the nervous system. Philadelphia: Saunders, 1986:197-207 28. Rowland LP. Myoglobinuria, 1984. Can J Neurol Sci 1984;ll: 1-13 29. Tein I, DiMauro S, Spiro AJ, DeVivo DC. Recurrent myoglobinuria of childhood. Ann Neurol 1988;24:310-311 (Abstract) 30. Heller SL, Kaiser KK, Planer GJ, et al. McArdle’s disease with myoadenylate deaminase deficiency:observations in a combined enzyme deficiency. Neurology 1987;37:1039-1042 3 1. Danforth WH, Lyon JB Jr. Glycogenolysis during tetanic contraction of isolated mouse muscles in the presence and absence of phosphorylase a. J Biol Chem 1964;239:4047-4050 32. Bresolin N, Bet L, Moggio M, et al. Muscle G6PD deficiency. Lancet 1987;2:212-2 13 33. Bresolin N, Bet L, Moggio M, et al. A new cause for myoglobinuria: human muscle glucose-6-phosphate dehydrogenase deficiency. Neurology 1988;38(suppl 1):269 (Abstract) 34. Piomelli S . G6PD deficiency and related disorders of the pentose pathway. In: Nathan D, Oski F, eds. Hematology of infancy and childhood. Philadelphia: Saunders, 1987:583-612 35. Hoffman EP, Kunkel LM, Angelini C, et al. Improved diagnosis of Becker muscular dystrophy via dystrophin testing. Neurology 1989;39:1011-1017 36. Hays AP, H d e t M, Delfs J, et al. Muscle phosphofructokinase deficiency: abnormal polysaccharide in a case of late-onset myopathy. Neurology 1981;3 1: 1077- 1086 37. Danon MJ, Servidei S , DiMauro S, Vora S. Late-onset muscle phosphofructokinase deficiency. Neurology 1988;38:956-960 I ,

We wish to thank the many colleagues who have sent us muscle biopsy specimens from their patients with myoglobinuria. We are grateful to Dr Lewis P. Rowland and Audrey S. Penn for their comments and to Ms Mary Tortorelis for typing the manuscript.

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Tonin et al: Metabolic Causes of Myoglobinuria

185

Metabolic causes of myoglobinuria.

To evaluate the proportion of cases of myoglobinuria that can be ascribed to specific metabolic defects, we have studied eight enzymes--phosphorylase,...
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