A muscle biopsy
performed elsewhere
showed nonspecific
findings. Stains for
muscle glycogen,
lipid, and
ultrastructural
examination of
muscle tissue were
not performed.
The above studies
illustrate several
points. Patient 1
represents the
classic infantile
presentation of
Pompe disease.
Patient 2
illustrates the
insidious
progression of
pelvic girdle
weakness, typical of
the late-onset
presentation of
Pompe disease, which
characteristically
occurs in early to
mid adulthood. The
caveat against
always attributing
elevations of ALT
and AST to liver
disease is
illustrated by this
case. These enzymes
are also present in
muscle, and testing
with both a
liver-specific
enzyme such as gamma
glutamyl transferase
(GGT) and the
muscle-specific
enzyme CK is
stressed. Patient 3
illustrates the
early onset of
respiratory
insufficiency that
is typical in
patients with
late-onset Pompe
disease.
Characteristic
Symptoms
Pompe disease is
a rare and often
unrecognized
disease. Advances in
diagnosis and
therapy of Pompe
disease demand a
greater awareness of
this disease. The
pathophysiology of
disease in all
patients a
deficiency of
lysosomal acid
alpha-glucosidase
(GAA). GAA is
essential for the
degradation of
lysosomal glycogen.
Deficiency in this
enzyme causes
accumulation and
distension of
lysosomes with
myofibrillary
replacement and
eventual lysosomal
rupture and muscle
destruction.[1]
This
autosomal-recessive
disorder has been
associated with more
than 200 mutations
of the GAA gene
located on
chromosome 17q.
Unlike other
glycogen storage
diseases that result
in increased
cytosolic glycogen,
Pompe disease
results in lysosomal
accumulation of
glycogen. Additional
mechanisms for
cellular injury
result from impaired
activity in
autophagic pathways,
leading to excessive
storage of glycogen
in cardiac and
skeletal muscle.[2]
Pompe disease is
a clinical spectrum.
As with many genetic
disorders, the
earlier the onset of
symptoms the more
severe the clinical
phenotype. The
amount of residual
GAA correlates with
the severity of the
clinical
presentation. The
classic infantile
onset is associated
with minimal (< 1%)
or no residual GAA
activity: Later
onset, less severe
clinical phenotypes
are associated with
measurable GAA
activity. However,
one cannot predict
the clinical
phenotype by
measuring enzyme
activity in either
muscle or fibroblast
cultures. Similarly,
the
genotype-phenotype
correlations have
not been precisely
defined.
The variation in
age of onset, extent
of organ
involvement, and
rate of disease
progression has
resulted in a
complex and
confusing
classification of
this disease. All
patients with Pompe
disease share the
same basic problem:
insidious
accumulation of
glycogen in target
tissues - most
prominently cardiac
and skeletal muscle.
Pompe disease is
therefore best
viewed as a disease
spectrum of a unique
pathogenesis and
identical primary
and downstream
targets for
potential therapies.
The overall
incidence of Pompe
disease is
approximately 1 in
40,000.[3]
The infantile-onset
form affects less
than 1 in 100,000
live births.
Late-onset disease
occurs in
approximately 1 in
57,000 older
children and adults.
Pompe disease
conforms to a
classic
autosomal-recessive
pattern of
inheritance. Because
of the huge number
of mutations
affecting the GAA
gene, virtually all
patients represent
compound
heterozygotes
(affected by 2
different mutations
in sister alleles).
Defects include
missense and
nonsense and splice
site mutations and
small and large
deletions and
insertions. Some
mutations are more
common in general
populations or in
certain ethnic
groups, but many are
private mutations
identified in
individual patients.
There is an
especially high
incidence of
specific nul
mutations in
Taiwanese and
African American
children that
essentially "kill"
the GAA gene.
The most
devastating form of
Pompe disease is the
classic
infantile-onset
presentation
illustrated by
patient 1. These
infants have
profound and rapidly
progressive muscle
weakness manifest by
paralytic hypotonia,
severe head lag, and
the phenotypic
picture of a
severely floppy baby
(Figure 1). Motor
development is
invariably severely
delayed. In more
than 90% of
patients, marked
cardiomegaly is
identified -- often
by means of x-ray
studies at the time
of symptomatic
presentation because
of either
cardiomyopathy or
respiratory
infection (Figure
2).
Figure 1.
Hypotonia and
head lag. Note
nasogastric
feeding tube.
