A 36-year-old man with chronic severe exertional myalgias had a normal serum lactate elevation and diminished serum ammonia elevation on an ischemic forearm exercise test (IFET). The IFET is commonly performed in the evaluation of patients with complaints of exertional myalgias, cramps, and rhabdomyolysis. The finding of a normal serum lactate elevation and a diminished serum ammonia elevation after ischemic exercise is usually considered indicative of myoadenylate deaminase deficiency. However, myoadenylate deaminase activity was normal in this man's muscle biopsy specimen. This case suggests that a diminished serum ammonia elevation in the IFET is not always indicative of myoadenylate deaminase deficiency, a disorder of ammonia production. A diminished serum ammonia elevation in the IFET could also reflect an impairment of net ammonia efflux from muscle into blood.
he ischemic forearm exercise test (IFET) has been used as the standard screening test for defects in muscle glycolysis since the 1950s.1 Such patients often present with episodes of rhabdomyolysis and typically do not produce an elevation of serum lactate on the IFET. With attempts to standardize the IFFY, serum ammonia began to be measured as well to ensure that a failure of lactate elevation represented a "true" metabolic abnormality rather than poor effort.2 It was soon discovered that some patients with exertional myalgias and cramps do not produce an elevation of serum ammonia on the IFET.3,4 This diminished elevation of serum ammonia on the IFET was demonstrated to be caused by myoadenylate deaminase deficiency (MADD).2,3 The case of a man with severe exertional myalgias, diminished elevation of serum ammonia on the IFET, but histochemically normal myoadenylate deaminase (MAD) activity is reported.
A 36-year-old man was referred for evaluation of severe exertional myalgias. The patient recalled that even as a very young child he had severe pains in his legs associated with activity. During adolescence, his exertional myalgias decreased and he was able to increase his activity level. Beginning in his 20s, the exertional myalgias again became quite symptomatic, particularly in the upper extremities. Although these myalgias markedly decreased his level of physical activity, he did not note the loss of any specific motor function. He was found to have chronic mild elevations of serum creatine kinase (244-864 units/L; normal range, 24-195 units/L) and aldolase (8.4-8.5 IU/L; normal range, 2.0-7.4 IU/L). One year before his neuromuscular evaluation, the patient was found to have a 2-cm pituitary tumor on cranial computed tomography. He underwent a subtotal surgical resection of the pituitary tumor, which proved to be an adenoma. Because of low serum testosterone and growth hormone levels, the patient was treated with testosterone cypionate intramuscular injections (200 mg every 2 weeks) and somatropin intramuscular injections (36 IU every day). These hormone treatments had no effect on his muscle symptoms. Thyroid function studies were normal. Electromyographic studies demonstrated no evidence of myopathic motor unit potentials. An electrocardiogram was normal. An outside IFET demonstrated a normal increase in serum lactate at 2 minutes after exercise but no corresponding increase in serum ammonia.
On physical examination, the patient had normal muscle bulk, strength, and tone. His muscle stretch reflexes were normal. The remainder of his neurological examination was normal. A left biceps muscle biopsy demonstrated mild type 2 myofiber hypertrophy and increased internal nuclei in both type 1 and type 2 myofibers (Fig. 1). No abnormal deposits of periodic acid-- Schiff-positive material or lipid were present. No ragged red fibers or tubular aggregates were present. Myophosphorylase and MAD (Fig. 2) reactions were normal. A negative MAD reaction (Fig. 3) in a muscle biopsy specimen from a patient with MADD is shown for comparative purposes.
Because the histochemical muscle MAD reaction was normal, a second IFET was performed. An indwelling intravenous catheter was inserted into the right antecubital vein. Baseline serum lactate and ammonia levels were determined. A blood pressure cuff was placed around the right upper arm and inflated to 170 mm Hg (systolic blood pressure was 124 mm Hg). The patient then tightly squeezed a hand dynamometer at the rate of one squeeze per second for 60 seconds (he actually performed 59 squeezes with a total accumulated force of 1,858 kg). The blood pressure cuff was then deflated and removed. Serum lactate and ammonia were then determined at 1, 3, 6, and 10 minutes after ischemic exercise. Venous lactate levels at baseline and at 1, 3, 6, and 10 minutes after ischemic exercise were 1.5, 4.2, 3.9, 3.0, and 2.1 mm/L, respectively (Fig. 4). Venous ammonia levels at baseline and at 1, 3, 6, and 10 minutes after ischemic exercise were 37, 44, 45, 41, and 38 (mu)m/L, respectively (Fig. 4). Normal individuals should increase lactate by at least 20 mg/dl (or 2.2 mm/L) and ammonia by at least 100 (mu)g/dl (or 60 (mu)m/L) during the IFET.1 This patient's maximal increase of lactate on the IFET was normal at 2.7 mm/L, but his increase of ammonia was markedly diminished at only 8 (mu)m/L. Alternatively, a normal individual's increase in ammonia during an IFET should be 1% to 3% of the increase in lactate.2 A relative increase of ammonia compared with lactate of less than 0.4% is usually considered indicative of MADD.2 This patient's relative increase of ammonia compared with lactate was less than 0.3% (8 (mu)m/L ammonia compared with 2,700 (mu)m/L lactate, as shown in Fig. 4). Thus, the results of the second IFET confirmed a normal serum lactate elevation and a diminished serum ammonia elevation after ischemic exercise.
In skeletal muscle, the enzyme MAD catalyzes the deamination of adenosine monophosphate to produce inosine monophosphate and ammonia.5 This reaction is the main source of skeletal muscle ammonia production during the IFET. More than 97% of the ammonia produced in skeletal muscle is in the form of the ammonium ion (NH^sup +^^sub 4^).6 The cell membrane, however, may not be readily permeable to the ammonium ion. If that is the case, ammonia may enter venous blood via an indirect route in the IFET. One possible mechanism is the reaction of ammonia with glutamate via glutamine synthetase to form glutamine.5 Glutamine then effluxes from muscle. Glutaminase activity is very high in endothelial cells.5 Consequently, as glutamine enters the vasculature, it may be broken down to glutamate and ammonia. Glutamate would then be free to reenter muscle, and ammonia would be effectively released into venous blood draining skeletal muscle. A defect in this glutamate metabolic pathway would produce a deficiency in the ammonia elevation in the IFET despite the normal intramuscular production of ammonia by MAD. In effect, a diminished serum ammonia elevation in the IFET, as was documented in this patient, could reflect an impairment of "net" ammonia efflux from muscle into blood.2
Examples of diminished elevation of serum ammonia on the IFET and histochemically normal MAD activity have been reported.1,2 In one report, five of seven patients who failed to increase serum ammonia on the IFET despite a normal increase in serum lactate had normal MAD activity in muscle biopsy specimens.1 Such examples, as with this patient, clearly demonstrate the necessity for muscle biopsy with assessment of MAD activity to make a definitive diagnosis of MADD.2
*West Virginia University School of Medicine, Morgantown, WV.
^Marshall University School of Medicine, Huntington, WV. The opinions and assertions contained herein are those of the authors and do not necessarily reflect those of the Navy Medical Department or the Department of Defense.
This manuscript was received for review in September 1998. The revised manuscript was accepted for publication in December 1998.
Reprint & Copyright by Association of Military Surgeons of U.S.,1999.
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Guarantor: CAPT Jack E. Riggs, MC USNR
Contributors: CAPT Jack E. Riggs, MC USNR*; Sydney S. Schochet, Jr., MD*; Ralph W. Webb, MD^
Copyright Association of Military Surgeons of the United States Sep 1999
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