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Acta Myologica • 2007; XXVI; p. 35-41
Muscle glycogenoses
Muscle glycogenoses: an overview
S. Di Mauro
Department of Neurology, Columbia University Medical Center, New York, NY
Skeletal muscle is a marvelous motor and much more
versatile than we give it credit for. Suffice it to consider
the different performances of flight muscles in migrating
birds, which cross very long distances non-stop, the cricothyroid muscle in bats, which emits ultrasound signals,
and the leg muscles of a human athlete, who can run the
100-meter dash in less than 10 seconds. Obviously, such
diverse performances require different fuels. At rest, hu-
man muscle utilizes almost exclusively fatty acids, as
indicated by the very low respiratory quotient (around
0.7). At the other end of the spectrum, during extremely
intense exercise, close to vO2max, energy derives mostly
from glycogen through anaerobic glycolysis, a cytosolic
pathway (Fig. 1). During submaximal exercise of high
intensity (70% to 80% vO2max), glycogen is again the
preferred source of energy, which, however, derives from
aerobic glycolysis, providing pyruvate as the anaplerotic
substrate for the mitochondrial Krebs cycle (Fig. 1). During submaximal exercise of moderate intensity (< 50%
vO2max), muscle initially utilizes blood glucose, but – as
the exercise continues beyond a few hours – there is a
gradual shift from the oxidation of glucose, a finite fuel
derived from liver glycogen, to the oxidation of fatty acids,
a virtually inexhaustible fuel derived from fat stores (1).
Two reactions are immediate sources of energy: (i)
the creatine kinase (CK) reaction that breaks phosphocreatine (PCr) down to ATP and creatine in the presence
of ADP through the creatine kinase (CK) reaction (PCr
+ ADP + H+ = ATP + Cr); and (ii) the adenylate kinase
reaction, generating ATP and AMP from the condensation of two molecules of ADP (2ADP = ATP + AMP).
However, by far the largest amount of energy for exercise
derives from oxidative phosphorylation in the mitochondria and a much smaller amount of energy comes from
anaerobic glycolysis, which is crucial only during isometric contraction (when blood supply is virtually cut off).
The still widely held belief that the exercise intolerance
that characterizes many glycogenoses is due to a block
of anaerobic glycolysis is exaggerated and probably due
to the popularity of the forearm ischemic exercise introduced by Brian McArdle in 1951 (2). In truth, the pathophysiology of exercise intolerance in McArdle disease
and similar muscle glycogenoses is mostly due to a block
of aerobic glycolysis.
Disorders of energy supply to muscle, irrespective of
whether the defects involve carbohydrate metabolism, lipid metabolism, or the respiratory chain, result in one of
two syndromes: (i) exercise intolerance, often punctuated
by recurrent and reversible “crises” of muscle breakdown
Figure 1. Selected metabolic pathways in a schematic
rendition of a mitochondrion.
The spirals indicate the sequential reactions of the β-oxidation pathway, resulting in the liberation of acetyl-coenzyme A (CoA) and the reduction of flavoprotein. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine
triphosphate; CACT, carnitine acyl-carnitine translocase;
CoQ, coenzyme Q; CPT, carnitine palmitoyltransferase;
DIC, dicarboxylate carrier; ETF, electron-transfer flavoprotein; ETFDH, electron-transfer flavoprotein dehydrogenase; FAD, flavin adenine dinucleotide; FADH2, reduced
FAD; PDHC, pyruvate dehydrogenase complex; TCA,
tricarboxylic acid; I, complex I; II, complex II; III, complex
III; IV, complex IV; V, complex V.
Address for correspondence: Salvatore Di Mauro, Department of Neurology, Columbia University Medical Center, 630W 168th Street,
New York, NY 10032, USA. Tel. +1 212 3051662. Fax +1 212 3053986. E-mail: [email protected]
35
S. Di Mauro
osmiophilic β-particles shown by electron microscopy
under the sarcolemma and – to a lesser extent – between
myofibrils. For many years, it was unclear what was the
primer of glycogen synthesis, i.e. which enzyme stranded together the first glucosyl units. This starter enzyme
– called glycogenin – is now known (5): the subsequent
growth of glycogen into a spherical polymer is catalyzed
by the sequential and – as we shall see – highly coordinated actions of two enzymes: (i) glycogen synthetase,
which attaches glucosyl units in α-1,4-glucosidic bonds
from UDP-glucose to nascent linear chains of glycogen until a length of approximately 10 glucosyl units is
reached; and (ii) the branching enzyme, which removes a
short linear chain of approximately 4 glucosyl units and
attaches it to a longer chain in an α-1,6-glucosidic bond,
thus starting a new chain.
It is not the purpose of this article to review in detail
the muscle glycogenoses, for which the reader is referred
to recent comprehensive articles (6, 7). However, Figure
3 highlights those enzyme defects that have been associated with muscle glycogenoses within a schematic metabolic pathway of glycogen metabolism, showing by italic
Roman numerals the GSD causing exercise intolerance
and myoglobinuria, and by plain text Roman numerals
those causing fixed weakness. In the rest of this article,
I will consider a few comparative aspects between GSD
V and GSD VII and provide a general framework for the
more specific presentations that will follow.
Starting from the glycogenoses associated with premature fatigue (summarized in Table 1), I will first pay
homage to Brian McArdle, who in 1951, on the strength
of astute clinical reasoning and simple laboratory studies, described the disease that is better known by its eponym than by its biochemical defect (myophosphorylase
deficiency) (2). He studied a young man with exercise
intolerance and cramps. He noted that ischemic exercise
resulted in painful cramps of forearm muscles, and that
no electrical activity was recorded from the shortened
muscles, indicating that they were in a state of contracture. He also noted that oxygen consumption and ventilation were normal at rest but increased excessively with
exercise. Having observed that venous lactate and pyruvate did not increase after exercise, McArdle concluded
that his patient’s disorder was “characterized by a gross
failure of the breakdown of glycogen to lactic acid”. Nor
was the specific involvement of muscle lost on McArdle,
who noted that epinephrine elicited a normal rise of blood
glucose and “shed blood” in vitro accumulated lactate
normally, leading him to conclude that “the disorder of
carbohydrate metabolism affected chiefly if not entirely
the skeletal muscles”.
It is instructive to compare McArdle disease, due to
a block of glycogen breakdown, with Tarui disease (GSD
VII), in which a defect of muscle phosphofructokinase
(PFK) blocks glycolysis. Although, predictably, the clini-
Figure 2. The two major syndromes associated with defects of muscle substrate utilization.
(rhabdomyolysis) and myoglobinuria; or (ii) chronic subacute weakness (Fig. 2). Focusing our attention on the
glycogenoses, all defects associated with the former syndrome involve glycogen breakdown or glycolysis and
are triggered by exercise, whereas the latter syndrome is
associated with defects in a glycogen synthetic enzyme
(brancher), the lysosomal glycogenolytic enzyme (acid
maltase [α-glucosidase]), one glycolytic enzyme (aldolase), and, rather surprisingly, a glycogenolytic enzyme
(debrancher) that works hand-in-hand with myophosphorylase The pathogenesis of weakness in the second group
of glycogenoses is not completely clear. In part, at least,
it relates to the multisystem nature of the enzyme defects.
For example, the profound weakness of infants with glycogen storage disease (GSD) type II is both myogenic
and neurogenic, as autopsy studies have shown massive
glycogen storage in both upper and lower motor neurons
(3, 4), which may also explain the tongue fasciculations
often observed in these babies. Peripheral nerve involvement probably accounts for the distal muscular atrophy
and the “mixed” myogenic and neurogenic EMG pattern
shown by patients with GSD III (debrancher deficiency).
Another explanation often proposed is that muscle glycogen accumulation is much greater in glycogenoses characterized by fixed weakness than in those dominated by
recurrent cramps and myoglobinuria, and this may mechanically disrupt the contractile apparatus. However,
both mechanisms leave unanswered questions: for example, why are adult patients with GSD II weak, although
glycogen accumulation is usually modest and confined to
skeletal muscle?
Glycogen is a highly ramified polymer of glucose in
which linear chains of glucosyl units “stranded” together
by α-1,4-bonds sprout – at regular intervals – side chains
through α-1,6-glucosidic bonds: the resulting highly symmetrical spherical structure of each glycogen molecule
makes it spatially efficient and hydrophilic: these are the
36
Muscle glycogenoses: an overview
Table 1. Main features of the glycogen storage diseases (GSD) associated with exercise intolerance, cramps, and
myoglobinuria.
Enzyme
GSD #
Non-muscle
tissues affected
Isozyme
or subunit
Chromosomal
location
liver
PHKαM
PHKβ
Xq12-13
16q12-13
M
11q13
R49X
(Caucasian)
∆5
(Ashkenazi)
Phosphorylase b kinase
GSD VIII
Phosphorylase
GSD V
PFK
GSD VII
RBS
PFK-M
1cen-q32
PGK
GSD IX
RBC
CNS
PGK-1
Xq13
PGAM-M
7p13-12.3
LDH-A
11p15.4
β
17pter-q11
PGAM
GDS X
LDH
GSD XI
Smooth muscle
skin
β-enolase
GSD XIII
cal pictures are very similar and dominated by undue
fatigue, cramps, and recurrent myoglobinuria, there are
interesting clinical, laboratory, and pathological differences (Table 2).
Clinically, McArdle disease is a pure myopathy
because the lack of the muscle isozyme, which is also
expressed in heart and brain, is amply compensated in
these tissues by the much more abundant expression of
the brain isozyme. In contrast, the genetic defect of the
muscle subunit of PFK (PFK-M) results in a partial defect
of PFK activity in erythrocytes, manifesting as compensated hemolytic anemia. Thus, hyperbilirubinemia and
increased reticulocytes help in differential diagnosis.
More importantly, the “second wind” phenomenon,
described by patients as the ability to resume exercising
if they take a brief rest at the first appearance of undue
fatigue, distinguishes GSD V from GSD VII, despite
some reports to the contrary. In fact, Vissing and Haller
have based a novel diagnostic test on the “second wind”
phenomenon (8). Cycle exercise at a moderate, constant
workload resulted in “second wind” (measured as decreased heart rate 7 to 15 minutes into exercise) in all 25
patients with McArdle but in none of 17 normal controls
or 25 patients with other metabolic myopathies.
Yet another distinguishing feature described by Haller
and Vissing is the opposite effect of glucose administration in the two diseases. Patients with McArdle disease
benefit from glucose administration or from a sucrose
load before exercise (9) because their metabolic block,
which is far upstream in carbohydrate metabolism, impairs glycogen but not glucose utilization (Fig. 3). In contrast, meals rich in carbohydrate exacerbate the exercise
intolerance of patients with phosphofructokinase (PFK)
deficiency for two reasons: (i) due to the metabolic block
downstream in glycolysis, their muscle cannot utilize either glycogen or glucose; (ii) glucose decreases the blood
concentration of the alternative fuels FFA and ketones, a
situation dubbed the “out of wind” phenomenon (10).
In 1980, while studying two patients with PFK deficiency, we noted, much to our surprise, that their muscle
biopsies showed, in addition to deposits of normal-looking glycogen, pockets of an abnormal polysaccharide
with the histochemical and ultrastructural features of
polyglucosan (11): the polysaccharide was intensely
PAS-positive but only partially digested by diastase and,
in the electron microscope, consisted of finely granular
and fibrillar material, similar to the amylopectin-like storage material of GSD IV (branching enzyme deficiency).
Based on experiments in E. coli (12), we reasoned that
the high concentration of glucose 6 phosphate (G6P)
resulting from the metabolic block would activate gly-
Table 2. Comparative clinical and laboratory features of
McArdle disease (GSD V) and Tarui disease (GSD VII).
GSD V
GSD VII
Other tissues
involved
None
RBC
Glucose
administration
beneficial
detrimental
(“out of wind”)
Second wind
Polysaccharide
stored
+
-
Glycogen
Glycogen +
polyglucosan
Common
mutations
37
S. Di Mauro
The pathogenesis of rhabdomyolysis and myoglobinuria in McArdle disease, as in other glycogenoses, remains unclear. There is no doubt that the block of aerobic
glycolysis or, sometimes, anaerobic glycolysis during intense exercise results in an “energy crisis”. However, neither old biochemical determinations in muscle biopsies
taken during an exercise-induced contracture (15) nor
more recent 31P magnetic resonance spectroscopic studies during controlled exercise (1, 16) have ever revealed
a critical decrease of ATP. This has led to the conclusion
that probably the decrease of ATP is compartmentalized
to ATP pools coupled to Na+ K+ ATPases or to Ca++ ATPases, a concept supported by the finding that sarcolemmal
sodium pumps are decreased in McArdle muscle (17).
This finding also explains the muscle inexcitability after
repeated nerve stimulation observed many years ago in
McArdle patients.
Over 40 mutations have been identified all along the
gene (PYGM) encoding myophosphorylase. While by far
the most common mutation in Caucasian patients is the
R49X (Arg49Stop) mutation, it is important to keep in
mind that the frequency of different mutations varies in
different ethnic groups. For example, the R49X mutation
has never been described in Japan, where a single codon
deletion 708/709 seems to prevail (18). To complicate
things further, it was documented that an apparently innocent polymorphism in the PYGM gene impaired cDNA
splicing and was, in fact, pathogenic (19). This phenomenon, aptly dubbed “echo of silence” by Mankodi and
Ashizawa (20), has to be taken into account in McArdle
patients without clearly pathogenic mutations.
Genotype:phenotype correlations are not easily discernible, as patients with the same genotype (e.g. homozygous for the commonest mutation, R49X) may have
very different clinical manifestations, varying from relatively mild exercise-related discomfort to almost crippling
myalgia and recurrent myoglobinuria. Although these
differences can be due in part to different lifestyles or dietary regimens, genetic must play a role. For example,
rare cases of genetic “double trouble”, such as the coexistence in the same individual of homozygous mutations
in PYGM and in the gene for adenylate deaminase, may
explain more severe phenotypes (21, 22). Perhaps more
importantly, screening for insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) in 47
patients showed a good correlation between clinical severity and number of ACE genes harboring deletion (22).
I will briefly consider only one other glycogenosis
causing exercise intolerance and myoglobinuria, phosphoglycerate mutase (PGAM) deficiency (GSD X), in
part for sentimental reasons, as my group discovered
this enzyme defect in 1981 (23). Nine of the 13 patients
identified thus far have been African American, and
they all harbor one common nonsense mutation (W78X)
either in homozygosity or in heterozygosity (Table
Figure 3. Scheme of muscle glycogen metabolism and
glycolysis designating the glycogen storage diseases
(GSD) affecting muscle with Roman numerals. Numerals in
italics indicate GSD causing exercise intolerance, cramps
and myoglobinuria. Numerals in plain text indicate GSD
causing fixed weakness. The numerals denote defects in
the following enzymes: II, acid maltase; III, debrancher;
IV, brancher; V, myophosphorylase; VII, phosphofructokinase (PFK); VIII, phosphorylase b kinase (PHK); IX, phosphoglycerate kinase (PGK); X, phosphoglycerate mutase
(PGAM); XI, lactate dehydrogenase (LDH); XII, aldolase
A; XIII, β-enolase. Abbreviations: c-AMP, cyclic adenosine monophosphate; ADP, adenosine diphosphate; ATP,
adenosine triphosphate; PLD, phosphorylase-limit dextrin; UDPG, uridine-diphosphate glucose.
cogen synthetase abnormally and alter the normal ratio
of glycogen synthetase (GS) to branching enzyme (BE)
to the advantage of GS, thus favoring the synthesis of
polysaccharide with excessively long and poorly ramified
chains (polyglucosan). In a serendipitous but spectacular
experiment, Raben et al. verified this mechanism when
they overexpressed GS in the muscle of transgenic mice
lacking acid maltase and observed massive accumulation
of polyglucosan (13). The crucial role of the GS/BE ratio
in the synthesis of normal glycogen has been confirmed
in other conditions, such as cardiac glycogenoses due to
defects in AMP-dependent protein kinase (AMPK) (14)
and, possibly, in Lafora disease (this issue).
38
Muscle glycogenoses: an overview
Table 3. Main features of 14 patients with GSD X (PGAM deficiency).
Sex/Age
Ethnicity
Clinical
Biopsy
Gene defect
M/52
Afr..Amer.
Ex, Cr, Mg
ND
F/17
Afr. Amer.
Ex, Cr, Mg
W78X
M/24
Afr. Amer.
Ex, Cr, Mg
Tub. Aggr.
W78X
F/17
Afr. Amer.
Ex, Cr
W78X
M/30
Afr. Amer.
Ex, Cr, Mg
W78X/E89A
F/34
Afr. Amer.
Ex, Cr, Mg
W78X
F/36
Afr. Amer.
Ex, Cr, Mg
M/25
Afr. Amer.
Ex, Cr, Mg
Tub. Aggr.
W78X
Tub. Aggr.
W78X
M/20
Afr. Amer.
Ex, Cr, Mg
M/23
Italian
Ex, Cr, Mg
R90W
F/31
Italian
Ex
R90W
M/25
Pakistani
Ex, Cr, Mg
M/55
Japanese
Ex, Cr
G97A*
M/22
Japanese
Ex, Cr
G97A*
3). However, the disease is not confined to this ethnic
group, and different mutations have been identified in
Italian (24), Japanese (25), and most recently, Pakistani
and Ashkenazi Jewish patients (Naini et al, unpublished
observations).
There are two curious aspects of PGAM deficiency. The first is the frequency of manifesting heterozygotes, which is counterintuitive considering that PGAM
is the glycolytic enzyme with the highest activity (26).
W78X
Tub. Aggr.
R180X
The second peculiarity is that this enzyme defect is
frequently associated with tubular aggregates (27). In
isolation, these abnormal structures have been seen in
patients with exercise intolerance, myalgia, or weakness, but they have also been associated with various
disorders (including hypokalemic periodic paralysis
and myotonia congenita) or with exposure to drugs or
toxins (28). In frozen sections, they react strongly with
the Gomori trichrome (mimicking ragged-red fibers)
Table 4. Main features of the glycogen storage diseases (GSD) associated with fixed weakness.
Enzyme
GSD #
Non-muscle
tissues affected
Isozyme or
Subunit
Chromosomal
location
Common mutations
α-glucosidase
GSD IV
heart
CNS
liver
17q23-q25
IVS1-13t > g (Caucasian)
∆18 9 (Dutch)
R854X (African-American)
Debrancher
GSD III
liver
heart
1p21
4455delT
(North African Jews)
Brancher
GSD IV
liver
heart
brain (APBD)
3p12
Y329S (APBD)
Aldolase
GSD XII
RBC
TPI
GSD XIV
RBC
brain
Lafora disease
brain
nerve
muscle
Ald A
16q22-24
12p13
laforin
39
6q
S. Di Mauro
and with the NADH-tetrazolium reductase. Ultrastructurally, however, these predominantly subsarcolemmal
aggregates do not contain mitochondria, but tubules derived from the sarcoplasmic reticulum (SR), especially
from the terminal cisternae near the junctions between
the SR and the transverse tubules. Bundles of tubules,
which are 50 to 80 nm in diameter and have a double
membrane, often form hexagonal arrays. While there is
no doubt about their origin from the SR, little is known
about what triggers the formation of tubular aggregates,
except that they seem to occur in response to abnormalities of excitation-contraction coupling and intracellular
Ca++ flux regulation (28). Tubular aggregates have been
described in four patients with PGAM deficiency and we
have recently encountered a fifth patient in collaboration
with Dr. Ashok Verma of the University of Miami. Thus,
tubular aggregates seem to occur in PGAM deficiency
more often than can be explained by chance, which may
provide some clues as to their pathogenesis.
I will not consider in any detail the group of glycogenoses characterized by fixed weakness, which are
listed in Table 4, because acid maltase deficiency (GSD
II), branching enzyme deficiency (GSD IV), AMPK deficiency (a GSD still without a Roman numeral attribution), and Lafora disease (a glycogenosis sui generis, also
without a Roman numeral label) each are discussed in
separate chapters. I will only make a few considerations
on debrancher deficiency (GSD III).
The debrancher is a bifunctional enzyme, with two
catalytic activities, oligo-1,4-1,4-glucantransferase and
amylo-1,6-glucosidase. After phosphorylase has shortened the peripheral chains of glycogen to about four glycosyl units (this partially chewed up glycogen is called
phosphorylase-limit dextrin [PLD]), the debrancher enzyme removes the residual “twigs” in two steps. First, a
maltotriosyl unit is transferred from a donor to an acceptor chain (transferase activity), leaving behind a single
glucosyl unit, which is then hydrolyzed by the amylo1,6-glucosidase. The enzyme is encoded by a single-copy
gene (AGL) on chromosome 1p21 (29).
Clinical presentations of debrancher deficiency vary
depending on which tissues are affected and which enzymatic function is deficient (30). In the most common
clinical variant (IIIa), the enzyme defect is generalized
but liver and muscle are predominantly affected. In the
rare variant IIIb, only liver is affected. The even less frequent variants IIIc and IIId are characterized by the selective defect of the glucosidase activity (IIIc) or of the
transferase activity (IIId).
Patients with the IIIa variant typically present in
childhood with hepatomegaly, growth retardation, hypoglycemia, and occasional seizures related to hypoglycemia. Symptoms tend to resolve spontaneously around
puberty. Myopathy often appears in adult life, long after
liver symptoms have subsided. Adult-onset myopathies
have been distinguished into two groups, distal and generalized (31). Patients with distal myopathy develop atrophy of leg and intrinsic hand muscles, often suggesting
the diagnosis of motor neuron disease or peripheral neuropathy (32). The course is slowly progressive and the
myopathy is rarely crippling. Patients with generalized
myopathy are more severely affected and often suffer
from respiratory distress (31, 33).
Although debrancher works in parallel with myophosphorylase, the symptoms of debrancher deficiency
are very different from those of McArdle disease and
cramps and myoglobinuria are exceedingly rare. One reason for this discrepancy may be that in McArdle disease
glycogen cannot be broken down at all, whereas in GSD
III, the most peripheral portions of normal glycogen can
be utilized, as shown by lactate production in vitro (Fig.
4). However, for this minor “spare fuel” to work in vivo,
one has to postulate a constant recycling of the peripheral chains between glycogen and PLD, while most of
the stored glycogen in GSD III appears to be in the form
of PLD.
A more important explanation for the fixed, and
mostly distal, weakness is the simultaneous involvement
of muscle and nerve, as clearly documented both electrophysiologically and by nerve biopsy (34, 35).
Although the glycogenoses have been studied for almost one century (29), this Symposium documents how
new enzyme defects are still being discovered, clinical
variants of known defects are being described, pathogenetic mechanisms are incompletely understood, molecular studies have not provided clear genotype/phenotype
relationships, and therapy is still woefully inadequate.
Clearly, much remains to be done.
Figure 4. Comparative lactate production through anaerobic glycolysis in vitro by muscle homogenates from normal controls, 3 patients with debrancher deficiency (P1,
P2, P3) and one patient with McArdle disease.
Acknowledgements
Part of this work has been supported by a grant from
the Muscular Dystrophy Association.
40
Muscle glycogenoses: an overview
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