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Myoadenylate deaminase deficiency

Myoadenylate deaminase deficiency (MADD) is a recessive genetic metabolic disorder that affects approximately 1-2% of populations of European descent (making it a not particularly "rare" rare disease). It appears to be considerably rarer in Oriental populations. more...

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Myoadenylate deaminase...
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Myoadenylate deaminase, also called AMP deaminase, is an enzyme that converts adenosine monophosphate (AMP) to inosine monophosphate (IMP), freeing an ammonia molecule in the process. It is a part of the metabolic process that converts sugar, fat, and protein into cellular energy. In order to use energy, a cell converts one of the above fuels into adenosine triphosphate (ATP) via the mitochondria. Cellular processes, especially muscles, then convert the ATP into adenosine diphosphate (ADP), freeing the energy to do work.

In some cases (such as greater than normal energy demand), other enzymes then convert two molecules of ADP into one ATP molecule and one AMP molecule, making more ATP available to supply energy. The resulting AMP molecule is not normally recycled directly, but is converted into IMP by myoadenylate deaminase. If myoadenylate deaminase is deficient, excess AMP builds up in the cell and is eventually transported by the blood to liver to be metabolized or to the kidneys to be excreted.

This failure to deaminate the AMP molecules has three major effects. First, significant amounts of AMP are lost from the cell and the body. Second, ammonia is not freed when the cell does work. Third, the level of IMP in the cell is not maintained.

The first effect -- the loss of AMP -- is mostly significant because AMP contains ribose, a sugar molecule that is also used to make DNA, RNA, and some enzymes. Though the body can manufacture some ribose and obtain more from RNA-rich sources such as beans and red meat, this loss of ribose due to MADD is sometimes sufficient to create a shortage in the body, resulting in symptoms of severe fatigue and muscle pain. This outcome is especially likely if the individual regularly exercises vigorously over a period of weeks or months.

The second effect, the absence of ammonia, is not well understood. It may result in a reduction of the amount of fumarate available to the citric acid cycle, and it may result in lower levels of nitric oxide (a vasodilator) in the body, reducing blood flow and oxygen intake during vigorous exercise.

The third effect, the reduction in IMP, is also not well understood. It may somehow result in a reduction in the amount of lactic acid produced by the muscles.

Symptomatic relief from the effects of MADD may sometimes be achieved by administering ribose orally at a dose of approximately 10 grams per 100 pounds (0.2 g/kg) of body weight per day.


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Exertional myalgia syndrome associated with diminished serum ammonia elevation in ischemic exercise testing
From Military Medicine, 9/1/99 by Riggs, Jack E

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.

Case Report

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.


1. Coleman RA, Stajich JM, Pact VW, Pericak-Vance MA: The ischemic exercise test in normal adults and in patients with weakness and cramps. Muscle Nerve 1986; 9: 216-21.

2. Fishbein WN, Foellmer JW, Davis JI: Medical implications of the lactate and ammonia relationship in anaerobic exercise. Int J Sports Med 1990; 11: S91-100.

3. Fishbein WN: Myoadenylate deaminase deficiency: primary and secondary types. Toxicol Ind Health 1986; 2(2]: 105-18.

4. Sinkeler SPT, Joosten EMG, Wevers RA, Oei TL, Jacobs AEM, Veerkamp JH, Hamel BCJ: Myoadenylate deaminase deficiency: a clinical, genetic. and biochemical study in nine families. Muscle Nerve 1988:11: 312-7.

5. Wagenmakers AJM, Coakley JH, Edwards RHT: Metabolism of branched-chain amino acids and ammonia during exercise: clues from McArdle's disease. Int J Sports Med 1990; 11: S101-13.

6. Graham TE, MacLean DA: Ammonia and amino acid metabolism in human skeletal muscle during exercise. Can J Physiol Pharmacol 1992; 70: 132-41.

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
Provided by ProQuest Information and Learning Company. All rights Reserved

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