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Myoadenylate deaminase deficiency and forearm ischemic exercise testing.

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661
MYOADENYLATE DEAMINASE DEFICIENCY AND
FOREARM ISCHEMIC EXERCISE TESTING
PETER A. VALEN, DENNY A. NAKAYAMA, JUDITH VEUM, A. R. SULAIMAN, and
ROBERT L . WORTMANN
Myoadenylate deaminase (MADA) deficiency has
been associated with symptoms of postexertional aches,
cramps, weakness, and skeletal muscle dysfunction.
Measurement of plasma lactate and ammonia concentrations after forearm ischemic exercise has been suggested as a screening test for this disorder. We performed forearm ischemic tests on 3 patients with
histochemically defined MADA deficiency and 13
healthy control subjects, in a standardized fashion. Our
results demonstrated that subject effort and/or performance during the exercise portion of testing is a critical
variable. In addition to lactate and ammonia, plasma
purine compounds (adenosine, inosine, and hypoxanthine) were measured. The finding of decreased purine
release after exercise in MADA-deficient patients compared with that in normal individuals increases the
specificity of the test and supports the hypothesis that
disordered purine metabolism occurs in MADA deficiency.
Myoadenylate deaminase (MADA) (EC 3.5.4.6)
catalyzes the deamination of AMP to IMP in skeletal
muscle and plays an important role in the purine
From the Section of Rheumatology, Department of Medicine, and the Department of Neurology, Medical College of Wisconsin and Clement J. Zablocki Veterans Administration Medical
Center, Milwaukee, Wisconsin.
Supported in part by a grant from The Arthritis Foundation,
Wisconsin Chapter.
Peter A. Valen, MD; Denny A. Nakayama, MD; Judith
Veum, BA; A. R. Sulaiman, MBBS, FRCP(C); Robert L.
Wortmann, MD
Address reprint requests to Robert L. Wortmann, MD,
Rheumatology Division-IOCN, Medical College of Wisconsin,
Clement J. Zablocki Veterans Administration Medical Center, Milwaukee, WI 53295.
Submitted for publication October 29, 1986; accepted in
revised form December 12. 1986.
Arthritis and Rheumatism, Vol. 30, No. 6 (June 1987)
nucleotide cycle (Figure 1) (1). A deficiency of MADA
activity, perhaps the most common cause of metabolic
myopathy , has been reported in association with skeletal muscle dysfunction (2). Although the clinical
picture is variable, most MADA-deficient subjects
experience easy fatigue, cramps, and postexertional
myalgias (2-4). The precise relationship between the
enzyme deficiency and these symptoms is not clear.
Sabina et a1 have observed that significant alterations
in purine nucleotide content of skeletal muscle occur
with exercise in MADA-deficient individuals, both in
vitro and in vivo ( 5 ) .
Although tissue analysis is required to secure
the diagnosis of MADA deficiency, several methods
have been suggested as screening. tests. These involve
sequential measurements of blood lactate and ammonia concentrations in conjunction with vigorous forearm exercise. A normal response to the exercise is a
several-fold increase in both lactate and ammonia
concentrations (5,6). In MADA-deficient subjects, lactate concentrations increase, but little or no change is
observed in ammonia levels (2,5-8). Such a response
has been reported in all MADA-deficient subjects
described to date, but there have been many falsepositive results in normal subjects (7,9). In addition,
diminished generation of adenosine, inosine, and
hypoxanthine after exercise has been observed in
MADA-deficient subjects compared with that seen in
normal subjects (6,8). Methods previously described
for such screening vary greatly in duration of exercise,
whether exercise is performed under ischemic or
nonischemic conditions, and even whether blood is
sampled from the exercised or nonexercised arm.
To establish the limitations of the test, we
performed a forearm ishemic exercise test in 3 patients
662
VALEN ET AL
ATP
7
s
ADP
FUMARATE
ADENYLOSUCCINATE
GTP
+
31’
7 1 7 $ 3
AMP
ADENOSINE
IMP
.
*
INOSINE
NH3
1
r
HYPOXANTHINE
Figure 1. Purine nucleotide cycle. Abbreviated scheme of purine
nucleotide catabolism in skeletal muscle. Enzymes 1, 2 , and 3
constitute the purine nucleotide cycle. I = myoadenylate
deaminase; 2 = adenylosuccinate synthetase; 3 = adenylosuccinate
lyase; 4 = S’nucleotidase; 5 = adenosine deaminase; 6 = purine
nucleoside phosphorylase; 7 = myokinase.
with histochemically defined MADA deficiency a n d in
13 healthy volunteers, in a standardized fashion. Our
results demonstrate that subject performance during
exercise is a critical variable. In addition, we observed
d e c r e a s e d concentrations of plasma purine compounds (adenosine, inosine, a n d hypoxanthine) after
exercise in subjects with MADA deficiency compared
with control subjects, despite similar levels of performance during exercise. These findings indicate that t h e
measurement of plasma purines after exercise increases t h e specificity of the test a n d support t h e
hypothesis that disordered purine metabolism occurs
in MADA deficiency.
PATIENTS AND METHODS
Patients and controls. Three MADA-deficient subjects were identified by histochemical analysis (10) of muscle
biopsy specimens submitted to the Neurohistochemistry
Laboratory at Clement J. Zablocki Veterans Administration
Medical Center and the Medical College of Wisconsin.
Control subjects were 13 healthy volunteers, ages 25-41.
These studies were approved by the Human Research Review Committee of the Clement J. Zablocki Veterans Administration Medical Center and Medical College of Wisconsin. All subjects gave informed consent.
Patient 1. Patient 1, a 49-year-old woman, began
noting muscle “aches and tightness” in her legs at age 46. At
the evaluation, she was most troubled by sore leg muscles
after minimal or moderate exercise, such as climbing stairs.
She had no history of Raynaud’s phenomenon, rash, arthritis, or sensorimotor symptoms. There was no family history
of rheumatic or neuromuscular disorders. She had a history
of significant alcohol intake, but had imbibed no alcohol for
the past 5 years. She smoked 1 pack of cigarettes per day.
She was using no medications. Results of her physical
examination were unremarkable except for bilateral aphakia,
mild temporal muscle wasting, and slightly decreased pinprick sensation in the feet, in a stocking distribution. A left
sural nerve biopsy revealed minimal-to-mild demyelinative
neuropathy. Biopsy of the left gastrocnemius muscle revealed small foci of perivascular mononuclear cell infiltrates
and evidence of chronic denervation and reinnervation.
Myosin ATPase revealed good fiber type differentiation with
moderate preponderance of type I fibers. Occasional fibers
revealed minimally increased, periodic acid-Schiff staining.
Phosphorylase and oil-red 0 stains were unremarkable.
Myoadenylate deaminase staining was absent.
Patient 2. Patient 2 was a 37-year-old woman whose
muscular symptoms began at age 34 and included bilateral
leg aches and weakness beginning 15-30 minutes after activities such as, or equivalent to, bowling 3 games. On occasion
the weakness was so severe that she was unable to stand. On
days following particularly strenous activity, such as hauling
firewood, she would experience severe persistent muscular
aches and weakness. Her symptoms were confined to the
lower extremities. Medical history and a review of her
symptoms were unremarkable. Family history revealed 1
sister with multiple sclerosis and 7 other healthy siblings.
There was no other family history of neuromuscular disorders. Physical examination revealed no thyroid enlargement.
Complete blood count, electrolytes, thyroid function,
creatinine phosphokinase levels, and electromyogram findings were within normal limits. A biopsy of the right
quadriceps muscle showed normal results, except for the
absence of myoadenylate deaminase staining.
Patient 3 . Patient 3, a 35-year-old man, reported the
insidious onset, at age 34, of mild, lower extremity weakness
and muscle cramps. In time, symptoms became more severe
and temporally related to exertion. Two episodes of severe
calf cramping caused him to seek medical attention. Several
of his episodes were accompanied by a “hot” feeling and
increased perspiration in the involved areas. He noted
intermittent ankle swelling, but denied experiencing other
symptoms. He had an episode of diarrhea (with positive
cultures for Campylobacter and Giardia) about the time his
symptoms began. His medical history included hyperthyroidism treated with propylthiouracil. His mother had
Guillain-BarrC syndrome with persistent lower extremity
weakness, but there was no additional family history of
neuromuscular disorders. Physical examination results were
normal except for a slightly enlarged nontender thyroid. A
biopsy of the right quadriceps muscle revealed a mild
interstitial mononuclear cell infiltration with axonal degeneration of intramuscular nerves, suggestive of denervation
atrophy. Enzyme stains were normal except for deficient
myoadenylate deaminase activity.
Methods. The following method was used for exercise testing. An intravenous line was established in an
antecubital vein without using a tourniquet. Baseline blood
samples were drawn, and the line was maintained with
heparinized saline. A blood pressure cuff was placed around
the upper arm proximal to the intravenous line and was
663
MADA DEFICIENCY
Figure 2. Apparatus used to quantitate subject’s effort during exercise testing. The subject squeezed a grip
dynamometer with attached strain gauge (left) connected to strip recorder. Exercise was quantitated by
summing the areas of curves generated by each grip. Areas were measured using a planimeter (right).
inflated to, and maintained at, 10-20 mm of mercury above
systolic pressure for 90 seconds. While the cuff was inflated,
subjects exercised their forearms by squeezing a grip dynamometer as forcefully as possible, at a rate of 1 grip every 2
seconds. The dynamometer was attached to a strain gauge
and strip recorder so that the amplitude and duration of each
grip was recorded (Figure 2). Exercise continued until the
patient was exhausted or for a maximum of 90 seconds.
Blood samples were collected through the intravenous line at
1, 3, 5, and 10 minutes after the cuff was deflated.
A subset of normal subjects repeated the test at least
1 week later; they were asked to exercise at the above rate,
but at what they considered to be 50%-75%
of maximum
effort. Subject performance was quantitated by summing the
areas under the deflection curves generated with each
squeeze using a Dietzgen Model D 1806 compensating polar
planimeter. The grip apparatus was calibrated before each
test and the summed areas, which reflected subject exercise
effort or performance, were expressed in Standardized
Planimeter Units (SPU).
After the line was cleared of heparinized saline, 10-cc
venous samples were collected in a plastic syringe and
divided equally into tubes containing lithium heparin and 250
pl of either 0.87% NaCl (tube A) or 0.1 mM EHNA (an
adenosine deaminase inhibitor) and 0.2 mM dipyridamole (as
inhibitor of bidirectional nucleoside transport) in 0.87%
NaCl (tube B). Tubes were kept on ice and centrifuged
within 10 minutes of collection. Plasma from tubes A was
immediately analyzed for lactate and ammonia on a Dupont
Automated Clinical Analyzer using American Chemical Association analytical test packs (Dupont, Wilmington, DE).
Plasma from tubes B was stored at -70°C for subsequent
determination of purine nucleosides and bases.
Prior to purine determinations, samples were
ultrafiltered with Amicon CV-25 cones (Amicon, Lexington,
MA). Hypoxanthine, inosine, and adenosine were quantitated on a Varian 5200 high performance liquid chromatography instrument, with a Varian Micropak MCH-10 reversephase column, using the method described by Hartwick et a1
(1 l), with modifications (12).
RESULTS
Subject performance was critical to the quantity
of lactate, ammonia, and purine compounds generated
after forearm ischemic exercise. Figure 3 shows results of lactate and ammonia measurements obtained
after 3 separate trials of forearm ischemic exercise in a
normal individual. As the level of effort was decreased, these compounds were generated to a lesser
degree, such that at 58% of maximum effort, the
patterns of lactate and ammonia were indistinguishable from the typical results for a MADA-deficient
subject.
VALEN ET AL
TRIAL I - 100% EFFORT
TRIAL II - 91% EFFORT
8-
-
4-
d
/&--
/
--- ------
P--+-----,-_
----a
o- ' /,
1
l21
3
5
10
TRIAL 111 - 58% EFFORT
1
3
5
10
MADD PATIENT
121
MINUTES POST-EXERCISE
Figure 3. Forearm ischemic exercise test results for a normal individual exercising at different levels of
intensity on 3 separate occasions (the Standardized Planimeter Units generated by maximum performance is
called 100% effort, and subsequent performance is expressed as a percentage of that) and results from a
myoadenylate deaminase-deficient (MADD) patient exercising at maximum effort.
3.6 -
36
ma
a
a
28
2.8 -
20
2.0
12
12-
a
04
:1
0
r=O71
I
2
36
1
1
I
I
1
0.4
1
4
6
8
10 12 14
LACTATE RISE (rnEq/l)
1
-0
0
'
'
a
A
d
0
A
I
a
a
l
l
r = 034
I
l
I
1
1
I
18
PURINE RISE (Hx. INO. AO) IN DM
. a
28
20
12
a
'
A
A
r = 0.63
04
J
I
I
I
I
3
20
40
60
80
I
I
l
i
100 120 140 160
AMMONIA RISE (prnol/L )
Figure 4. Maximum levels of lactate, ammonia, and total purines (Hx = hypoxanthine, I N 0 = inosine, A 0
= adenosine) versus maximum performance for control subjects, control subjects exercising with
submaximal effort, and myoadenylate deaminase-deficient (MADD) patients. SPU = Standardized
Planimeter Units. = control subjects; A = control subjects exercising submaximally; 0 = MADD subjects.
MADA DEFICIENCY
665
Concentrations utilized for subsequent analyses
were the maximum values obtained at a single time
point and were consistently found in the 1- or 3-minute
sample for lactate and ammonia, and the 10-minute
samples for purines. Correlation coefficients for performance versus lactate, ammonia, and total purines
(adenosine plus inosine plus hypoxanthine) were 0.71,
0.63, and 0.35, respectively (Figure 4).
Measurements of peak plasma lactate and ammonia concentrations within 10 minutes of forearm
ischemic exercise proved to be effective in differentiating normal subjects from MADA-deficient subjects,
if all individuals performed the exercise with maximum effort (Figure 5). In normal subjects, lactate
concentrations were increased to 6.4 mEq/liter (range
4.0-10.5) from a baseline of 1.0 mEqAiter (range
1.0-1.8), and ammonia was increased to 105 pmoles/
liter (range 42-160) from a baseline of 18 pmoles/liter
(range 14-61). MADA-deficient subjects had lactate
levels that were increased over baseline, although to a
lesser degree than was seen in normal subjects, but
their ammonia concentrations were not increased.
Performance levels for these tests ranged from 1.5-3.3
SPU for control subjects and were 1.1, 2.1, and 2.3
SPU for the 3 MADA-deficient subjects.
In 7 of 9 normal subjects who were retested at
submaximal exercise levels (range 0.62.1 SPU), lactate and ammonia generation patterns were indistinguishable from those of MADA-deficient subjects.
Samples for purine analysis were collected in
-
220 200 180 160 140120 -
11
10 -
987-
5
4321-
-
,
-
o
:
:
0
AA
A
A
A
0
loo8060-
40200-,
the presence of EHNA and dipyridamole, and centrifuged rapidly after collection to eliminate the in vitro
changes in concentration that we observed in preliminary studies (data not shown) and that have been
reported by others (13). Mean (+SD) baseline values
for normal subjects were: hypoxanthine 0.52 2 0.47
p M , inosine 0.54
1.27 p M , and adenosine 4.14 -+
1.71 p M . Respective baseline values in MADAdeficient subjects were 1.38 ? 0.01 p M , 2.04 2 2.21
p M , and 3.09 i 0.78 p M .
With exercise at maximum effort, hypoxanthine
concentrations in normal individuals were increased
by an average of 17.7 pM (range 6.0-32.3); the
MADA-deficient patients had hypoxanthine concentrations that were 0, 3.5, and 6.8 p M above baseline.
With submaximum efforts, the increase in hypoxanthine concentration obtained in 4 of 6 normal
subjects fell into the MADA-deficient range (Figure 5).
No overlap between control subjects and MADAdeficient subjects was observed when maximum total
purines (hypoxanthine plus inosine plus adenosine)
were compared (Figure 5).
*
DISCUSSION
Muscle weakness and muscle aches are frequently encountered symptoms in medical practice.
Possible causes of these symptoms may include
psychoneurosis, muscular dystrophy, metabolic myopathy, or inflammatory myositis. At times, no spe-
44 40 3632 0
28 24.)
20 1612-
0
7
i
8
A
A
0.
44
40 36 -
32-
AA
A
t
A
8-
0
AA
I
&L
0
0
4-
O
-
28 24 20 16 12-
u
?!&
0
8-
0
4A
0
0- u r n
A
d
0
Figure 5. Maximum rises in lactate, ammonia, total purine, and hypoxanthine in control subjects exercising
maximally (Max), control subjects exercising submaximally (Submax), and myoadenylate deaminasedeficient (MADD) patients.
VALEN ET AL
cific diagnosis can be made. Recent observations of a
group of patients with mild muscle weakness and
postexercise cramping have suggested a possible role
for disordered purine metabolism in the pathogenesis
of their symptoms. Fishbein et a1 described 5 patients
who had mild muscle weakness and cramping after
exercise, and demonstrated diminished myoadenylate
deaminase activity, defined histochemically , on muscle biopsy specimens (2). Further investigations have
shown that myoadenylate deaminase deficiency is not
rare and it may be the most common cause of metabolic myopathy . Using the histochemical staining assay ( 2 4 , approximately 2% of muscle biopsy specimens in large series have been shown to be deficient in
this enzyme.
Myoadenylate deaminase is a distinct isoenzyme of adenylate deaminase found only in skeletal
muscle. It is present in both type I and type I1 fibers,
with higher levels seen in the latter. MADA-deficient
patients who have been tested have normal levels of
adenylate deaminase in their lymphocytes, neutrophils, and red blood cells (2). Family members of some
MADA-deficient subjects have been shown to have
lowered levels of enzyme activity as well, suggesting
the presence of a carrier state (14).
MADA deficiency has been described in association with many other disorders, including periodic
paralysis, influenza-like illness, Kugelberg-Welander
syndrome, amyotrophic lateral sclerosis, spinal muscular atrophy, facial and limb girdle myopathy,
poly myositis, dermatomyositis, systemic lupus erythematosus, systemic sclerosis, diabetes, hyperthyroidism, and gout (3,4,7,15,16). However, many patients with this deficiency have no other rheumatic or
neuromuscular disorder that could explain their symptoms. Fishbein recently reviewed 58 cases of MADA
deficiency (14). In 28 of the patients, there was no
other neuromuscular disease. These patients tended to
have the lowest levels of MADA activity and normal
levels of creatine kinase and adenylate kinase, compared with the 30 patients who had additional
neuromuscular diagnoses, higher residual MADA activities, and decreased activities of creatine kinase and
adenylate kinase. It is possible, therefore, that MADA
deficiency can occur in a primary form, perhaps inherited in an autosomal recessive pattern, and a secondary form, related to nonspecific pathologic muscle
damage from a variety of neuromuscular disorders.
The exact relationship between MADA deficiency and muscular symptoms remains unclear. The
normal response to muscular work is an increase in
plasma lactate, ammonia, and the ATP degradation
product, hypoxanthine (6,8,17), These increases probably result from normal MADA activity and normal
functioning of the purine nucleotide cycle (Figure 1).
Although the precise function of MADA is not completely understood, it is important in the regeneration
of ATP during muscular activity and recovery (17).
MADA catalyzes the conversion of AMP to IMP with
the release of ammonia (1). In the absence of MADA
activity, there would be less generation of ammonia
during muscle activity. This would explain the lack of
rise in ammonia after exercise in MADA-deficient
subjects, and might also account for the smaller than
normal increases in lactate observed in these individuals, since ammonia stimulates glycolysis by activating phosphofi-uctokinase (18).
Our results indicate that measurement of
venous lactate and ammonia concentrations following
forearm ischemic exercise is an effective means of
screening for MADA deficiency and that submaximal
exercise performance, whether due to weakness, pain,
or poor effort, can be responsible for false-positive
results. Measurements of lactate after exercise have
been used for many years to test for abnormalities of
glycogen metabolism. Munsat standardized a forearm
ischemic exercise test for that purpose (19). Using a
grip dynamometer, reliable results were obtained if the
subject produced a workload of 4-7 kg/meter. Initially,
we tried to standardize ammonia generation with
work, but found no correlation. Satisfactory results
were obtained only when duration of work was added
to the measurement. We have termed this combined
measure “performance” and expressed it in Standardized Planimeter Units. The conclusion from Munsat’s
study and ours is that valid results depend upon the
vigor of the exercise effort. Thus, failure to generate
lactate or ammonia after exercise does not indicate
abnormality of lactate generation or MADA deficiency
unless an adequate exercise effort is documented. In
addition, an abnormal result should be followed by a
muscle biopsy for confirmation of the putative enzyme
deficiency.
Our results also confirm that measurements of
hypoxanthine and other ATP degradation products
increase the specificity of exercise testing for MADA
deficiency. Patterson et a1 observed decreased ammonia and hypoxanthine generation (6), and Sinkeler et al
recently reported diminished changes in plasma
adenosine, inosine, and hypoxanthine concentrations
in MADA-deficient subjects after ischemic and
nonischemic exercise (8). Our results are similar,
MADA DEFICIENCY
although the rise in hypoxanthine observed in 1 normal
subject (who happened to be the individual who performed at the lowest exercise level) fell into the range
observed for the MADA-deficient subjects. Calculation of the total level of adenosine plus inosine plus
hypoxanthine allowed separation of that subject from
the MADA-deficient subjects.
The findings of low levels of purines released
after exercise in MADA-deficient subjects also support the hypothesis that disordered purine metabolism
occurs when MADA activity is absent. Sabina et a1
observed delayed ATP regeneration after exercise in
MADA-deficient subjects compared with that in normal subjects (5,20). In the absence of MADA activity,
AMP is not converted to IMP. AMP, a product of the
adenylate kinase reaction, can inhibit that enzyme and
thus can interfere with one of the “backup” systems
for maintaining ATP concentrations. In addition, without MADA activity, the purine nucleotide cycle is
blocked, which leads to decreased fumarate generation. Fumarate, an important component of the
tricarboxylic acid cycle, is released in the conversion
of adenylsuccinate to AMP (1). Thus, the result of
absent MADA activity would be a decreased capacity
to regenerate ATP by oxidative metabolism during
periods of recovery from muscle activity or during
increased steady-state work (21,22).
The rise in hypoxanthine after exercise in normal subjects is a result of the degradation of IMP, and
probably reflects the rate of flux of ATP breakdown
products through the purine nucleotide cycle. The
absence of MADA activity allows prediction of low
levels of inosine and hypoxanthine in MADA-deficient
individuals. It was also possible, however, that
adenosine concentrations might increase in those subjects, but this was not observed. One possibility is that
adenosine is produced when MADA activity is absent,
but is retained intracellularly ; however, this was not
observed in the muscle biopsy specimens studied ‘by
Sabina et a1 (20). Alternatively, adenosine might be
released, but be taken up by endothelial cells, causing
vasodilation (23). This could lead to warmth and
perhaps erythema after exercise, events reported by
one of our subjects. A third possibility is that the
absence of MADA activity severely limits normal ATP
regeneration and that total ATP turnover is limited,
such that smaller amounts of the degradation products
are formed. Further study is needed to determine
which of these mechanisms occur in patients who have
MADA deficiency.
667
ACKNOWLEDGMENTS
The authors thank Ken Gulbrandson for his technical
assistance and Ruth Ann Loosen for secretarial assistance in
the preparation of this manuscript.
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668
14. Fishbein WN: Myoadenylate deaminase deficiency: inherited and acquired forms. Biochem Med 33:15&169,
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15. Mercelis R, Martin JJ, Dehaene I, deBarsy T, van den
Berghe G: Myoadenylate deaminase deficiency in a
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16. Gertler PA, Jacobs RP: Myoadenylate deaminase deficiency in a patient with progressive systemic sclerosis.
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17. Sutton JR, Toews CJ, Ward GR, Fox IH: Purine metabolism during strenuous muscular exercise in man. Mefabolism 29:25&260, 1980
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