Pompe's Disease

Electromyographic, Electron Microscopic,

and Cardiovascular Aspects

Joseph M. Bordiuk, MD; Marianne J. Legato, MD;

Robert E. Lovelace, MD; and Sidney Blumenthal, MD, New York

GENERALIZED glycogen storage disease Fig 1.\p=m-\Electromyographicfindings in Pompe's Dis-

A indicates spontaneous fibrillation in right later¬
(Pompe's disease or type II glycogenosis) is ease.
al gastrocnemius muscle; B, spontaneous positive sharp
a fatal disease characterized during life by waves and fibrillation in right lateral gastrocnemius
marked generalized muscular hypotonia, muscle; C, postcontraction myotonia in right lateral
gastrocnemius muscle (Vol Cont, voluntary contraction);
plus central nervous system and myocardial D, insertlonal myotonia in left deltoid muscle; E, vol¬
dysfunction. The disease process is due to, untary contraction in left deltoid muscle, short, reduced
or at least associated with an absence of duration, low amplitude ("myopathie") potentials;
and
F, calibration.
alpha 1-4 glucosidase (acid maltase), appar-
ently inherited as an autosomal recessive
gene.1,2 No effective therapy has been de-
vised, although attempts have been made to
administer acid maltase to affected infants.3
This paper presents electromyographic,
electron microscopic, and cardiovascular
data from one patient with generalized gly-
cogenosis. Electromyographic changes in an
appropriate clinical setting are strongly
suggestive of this disease.
Report of a Case
The patient was anadopted white male child
whose family history was unknown. He ap-
peared to be anormal infant until age31/2
months, at mche began to feed poorly.
whitihe
A chest roentgenogram obtained at this time
Submitted for publication Dec 17, 1969; accepted
Jan 12, 1970. E ·—

/W'Jl·
From the departments of pediatrics (Drs. Bordiuk, 100

Legato, and Blumenthal) and neurology (Dr. Love- -

Calibration 200 /iv
lace) (the Neurological Clinical Research Center),
College of Physicians and Surgeons, Columbia Uni-
versity, and the Department of Medicine, Roosevelt
Hospital, New York.
Reprint requests to The Neurological Institute,
710 W 168th St, New York 10032 (Dr. Lovelace).

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 Fig 2.—Myocardial tissue obtained at postmortem examination approximately four hours after
death. Mitochondria (M) have undergone characteristic postmortem changes and show swelling,
vacuolation, and cristal degeneration. Orderly rows of sarcomeres (S) usually seen in human myo¬
cardial cell are not present; pools of glycogen (G) have replaced significant percentage of sar-
commeric units (black line, 1.5/i) (x 10,500).

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 demonstrated cardiomegaly, and he was re¬
ferred for cardiac evaluation.
Physical examination revealed a flaccid, mild¬
ly cyanotic infant, lying in bed in a frog leg
position and exhibiting minimal spontaneous
motion. Muscle mass appeared adequate. The
tongue was large and protruding.
The heart was enlarged to palpation. Cardiac
rate was 120 beats per minute, and heart tones
were of good quality. A grade 2/6 short, rough
systolic murmur was best heard at the second
and third left intercostal spaces, along the ster¬
nal border. Peripheral pulses were normal. The
liver edge was soft and extended 4 cm below
the right costal margin.
Neurologic examination revealed markedly
decreased muscular tone without atrophy. Deep
tendon reflexes were absent. There were no
muscular fasciculations.
Laboratory data included elevated serum glu¬
tamic oxaloacetic transaminase of 820 Sigma
Frankel unit, elevated serum glutamic pyruvic
transaminase of 250 Sigma Frankel units, and
increased red blood cell glycogen of 131/ig/gm
of hemoglobin.
Chest roentgenogram demonstrated diffuse
cardiomegaly and pulmonary congestion. The
electrocardiogram revealed sinus arrhythmia
with a short p-r interval (p-r 0.09 second
=
with rate =
120). The QRS complex measured
0.06 seconds. Diffuse increased QRS voltage
and wave abnormalities were present. The
tracing was interpreted as being compatible
with biventricular enlargement and diffuse my-
ocardial disease. The vectorcardiogram was in¬
terpreted in a similar manner.
The clinical impression was generalized gly-
cogenosis.
Cardiac catheterization was performed before
the patient was digitalized. There was mild
right ventricular outflow tract obstruction
without associated involvement of the left ven¬
tricular outflow tract. These findings were not
altered by an infusion of isoproterenol hydro¬
chloride. Angiography demonstrated infundibu¬
lar pulmonary stenosis and excellent right to
left ventricular systolic emptying.
Electromyographic studies revealed a picture
of grossly increased insertional activity with
varying discharges of positive waves (Fig 1).
These often fired in crescendo and decrescendo
patterns similar to myotonia. The motor unit
potentials under voluntary control were of low
voltage, reduced duration, and often complex
and fragmented. Right posterior tibial nerve
conduction was normal (35.5 meters per sec¬
ond), indicating that the disorder was not in
the peripheral nerve. The electromyographic
study, with the associated clinical picture, was
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suggestive of generalized glycogenosis.
The diagnosis was confirmed by analysis of
muscle obtained from the gastrocnemius mus¬
cle. The gross muscle appeared normal. Light
microscopic examination revealed marked en¬
largement of muscle fibers due to cytoplasmic
vacuolization. The vacuoles were PAS positive,
and diastase digested sections contained no
PAS positive material, suggesting that the ma¬
terial was glycogen. The glycogen content was
16% wet weight (normal 1% to 1.5%), and
alpha 1-4 glucosidase was absent. Muscle phos¬
phorylase, with and without adenosine mono-
phosphate, was within normal limits (46.4µ 1
of phosphorus per minute per gram wet weight
and 218/imol of phosphorus per minute per
gram wet weight). Phosphoglucomutase was
also normal, being 29.5µ 1 of phosphorus per
minute per gram wet weight.
Several days following admission to the hos¬
pital, tachycardia and gallop rhythm developed.
Administration of digitalis, diuretics, oxygen,
and antibiotics was without benefit. The clinical
course was progressively downhill, wth the ad¬
vent of pneumonia, and the patient died at
the age of 6 months.
Postmortem examination was performed ap¬
proximately four hours after death. Light mi¬
croscopy, using PAS stain, demonstrated mas¬
sive glycogen deposition in heart, skeletal
muscle, liver, kidney, nerve cells of the medulla,
spinal cord, astrocytes, oligodendroglia and
ependymal cells, peripheral nerves, and histio-
cytes.
The electron microscopic studies of myo-
cardial and hepatic tissue (Fig 2 to 4) illus¬
trate swelling, vacuolation, and cristal degener¬
ation of mitochondria, with replacement of a
significant percent of the sarcomeric units by
glycogen and replacement of the body of the
polyhedral liver parenchymal cells by glycogen.
Comment
Generalized glycogenosis is associated
with a deficiency of alpha 1-4 glucosidase
(acid maltase).4 This enzyme is thought to
be localized to lysosomes and, in its absence,
excessive amounts of normal glycogen are
accumulated in tissue cells.5 It has been
suggested that free cytoplasmic glycogen
may be normally degraded by glycogenolytic
enzymes, but that glycogen accumulating in
deficient lysosomes may be stored, thus dis¬
rupting normal cellular functions.56 What¬
ever the mechanism, muscular and organ
dysfunction result from excessive accumula-
 Fig 3.—Higher power view of single myocardial cell reveals greatly reduced sarcommeric
volume due to replacement of intracellular structures with massive pools of glycogen (G). Sar¬
commeric units left are fragmented and deformed (arrows). Actual amount of tissue available
for forceful, orderly, or coordinated contraction is consequently greatly reduced. (N indicates
nucleus) (black line, 1.5µ) (X 20,500).

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 tions of normal glycogen, and the character¬ cardial cells suggests a mechanism for this
istic clinical picture results. abnormal function. The ultrastructure of the
Newborn patients with generalized glyco¬ normal myocardium undergoes certain char¬
genosis have been entirely asymptomatic, acteristic changes which occur within three
but have usually had evidence of cardiomeg¬ hours after death. The most dramatic
aly. In less advanced cases, either cardiac change is mitochondrial degeneration with
or skeletal muscular dysfunction may give cristal deterioration, swelling, and vacuola-
rise to the presenting complaint. It is usual, tion.9 Sarcomeres show a thickening of
however, for both cardiac and skeletal symp¬ bands and loss of definition of the actin
toms to become clinically apparent by the and myosin filaments. Chromatin clumping
age of 2 months. is conspicuous by this time in the cell nucle¬
Abnormal accumulations of glycogen in us and is most prominent at the interior of
muscle appear to result in characteristic the nuclear membrane. However, the general
changes in the electromyogram.7·8 These organization of the cell is not disturbed, and
changes consist either of spontaneous, bi¬ certain conclusions regarding the mechanism
zarre high frequency discharges which are of impaired myocardial function in glycogen
complex motor unit potentials repeated at storage disease can therefore be made from
constant rate and amplitude, or of streams the studies in our patient.
of positive waves with varying frequency It is apparent that the orderly rows of
and amplitude, resulting in decrescendo- sarcomeres (the contractile unit of the cell)
crescendo patterns indistinguishable from within the individual myocardial cells are
true myotonia. The motor unit potentials disrupted, fragmented, and almost complete¬
under voluntary control are of low voltage, ly replaced by large pools of glycogen gran¬
reduced duration, and are often complex ules which significantly reduce the actual
and fragmented, consistent with a primary volume of the myofibril's contractile appara¬
muscular disorder. Thus, the finding of such tus. In some instances, the cell has become
an electromyographic picture in an infant, virtually emptied of sarcomeres, becoming
in the absence of muscle atrophy, strongly essentially a mass of glycogen granules con¬
suggests the presence of generalized glyco¬ tained by a cell membrane. The nucleus and
genosis. Infantile spinal muscular atrophy in mitochondria are apparently entirely free of
the Werdnig-Hoffmann syndrome usually invasion by glycogen, but no conclusion may
does not give such repetitive discharges of be drawn regarding possible associated mito¬
positive waves and is associated with ex¬ chondrial lesions, due to early postmortem
treme atrophy. Congenital myopathies or changes.
polymyositis dermatomyositis syndrome rare¬ It is apparent that the primary reason for
ly present with recognizable severity at congestive failure in this patient is replace¬
this age. The electromyogram may therefore ment of the entire content of the myocardial
be a useful diagnostic tool early in the dis¬ cell (except for its nucleus and probably
ease, prior to development of the character¬ mitochondria) by glycogen. The contractile
istic clinical picture. Its greatest usefulness apparatus and sarcoplasmic reticulum are
may well be in the evaluation of the very obliterated.
young infant in whom there has been a Primary myocardial dysfunction leads to
family history of generalized glycogenosis. hypertrophy and, in several cases, such
We have recently seen one such child in hypertrophy has produced outlet obstruc¬
Whom the electromyogram performed at 1 tion.10·11 The minor pulmonary gradient
month of age was identical with that report¬ demonstrated in our patient was probably
ed above, establishing the diagnosis before not hemodynamically significant and did
biochemical values were available. Also, as not increase with inotropic stimulation, as
treatment for this disorder is developed, the would obstruction due to infundibular or
electromyogram may be used to document subaortic hypertrophy. Endocardial fibro-
change during therapy. elastosis is being recorded with increasing
Abnormal myocardial performance is a frequency in generalized glycogenosis, the
striking feature of generalized glycogenosis. endocardial change being a secondary
Electron microscopic examination of myo- phenomenon.12 Our patient had a normal

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 Fig 4.—Liver obtained at postmortem examination which reveals replacement of
virtually entire body of polyhedral liver parenchymal cell by glycogen. Membrane (M)
Indicated by arrows (x 10,500).

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endocardium at postmortem examination.
The clinical course of our patient, with un¬
remitting heart failure, was due to myo¬
cardial failure, secondary to intracellular
glycogen accumulation.
Summary
A case of generalized glycogenesis is pre¬
sented with specific reference to the electro¬
myographic, electron microscopic, and cardiac
physiologic changes. The electron micro-
scopic and cardiovascular studies documented
that cardiac failure was due to primary myo¬
cardial dysfunction, resulting from massive
replacements of the content of the myocardial
cells by glycogen.
The electromyogram demonstrated the
myotonic patterns associated with general¬
ized glycogenosis. Taken in clinical context,
the electromyogram may be considered diag¬
nostic of this disease.
This investigation was supported by Public Health
Service research giants NB 3359 and HE 05389-08.

References
1. Mekanik G, Smith RL, MacLeod EM: Enzyme
patterns in glycogen storage disease type II
(Pompe's disease). Metabolism 15:641-648, 1966.
2. Spach M, Martin A, Sidbury JB Jr, et al:
Clinical pathologic conference. Amer Heart
72:265-273, 1966.
3. Lauer RM, Mascarinas T, Racela AS, et al:
Administration of a mixture of fungal glucosidases
to a patient with type II glycogenosis (Pompe's
disease). Pediatrics 42:672-676, 1968.
4. Hers HG: Alpha-glucosidase deficiency in gen-
eralized glycogen storage disease (Pompe's disease).
Biochem J 86:11-16, 1963.
5. Baudhein P, Hers HG, Loeb H: An electron
microscopic and biochemical study of type II glyco-
genosis. Lab Invest 13:1139-1152, 1964.
6. Nitowsky H, Grunfeld A: Lysosomal-glucosi-
dase in type II glycogenosis: Activity in leukocytes
and cell cultures in relation to genotype. J Lab Clin
Med 69:472-484, 1967.
7. Swaiman KF, Kennedy WR, Sauls HS: Late
infantile acid maltase deficiency. Arch Neurol
18:642-648, 1968.
8. Gutman L, Hogan R, Schmidt R: Electromyo-
J
graphy and histology of Pompe's disease. Bull Amer
Assoc Electromyography Electrodiagnosis 14:13, 1967.
9. James TN, Sharf L, Fine G, et al: Compara-
tive ultrastructure of the sinus node in man and
dog. Circulation 34:139-163, 1966.
10. Ehlers KH, Haggstrom JWC, Lukas DS, et al:
Glycogen storage disease of the myocardium with
obstruction to left ventricular outflow. Circulation
25:96-109, 1962.
11. Hohn A, Lowe C, Sokal J, et al: Cardiac
problems in the glycogenoses with specific reference
to Pompe's disease. Pediatrics 35:313-321, 1965.
12. Dincsoy MY, Dincsoy HP, Kessler AD, et al:
Generalized glycogenosis and associated endocardial
fibroelastosis. J Pediat 67:728-739, 1965.

EXAMINATIONS

Examinations are not things that happen in school. They are a recurring feature of
life, whether in the form of decisive interviews to pass, of important letters to write, or
life-and-death diagnoses to make, or meetings to address, or girls to propose to. In most
of these classes you cannot bring your notes with you and must not leave your wits be¬
hind. The habit of passing examinations is therefore one to acquire early and to keep
exercising even when there is a possibility of getting around it.—BARZUN: Teacher in
America.

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