Glycogenosis type II and Pompe’s disease
Background Histopathology & Immunohistochemistry Differential Diagnosis Reference
BACKGROUND AND CLINICAL INFORMATION:
Summary of glycogenosis Classificaiton of glycogenoses by enzyme deficiency
Summary Clinical variants
Glycogen storage disease or glycogenosis type II is
in fact a lysosomal storage disease due to the deficiency of the monomeric a-1,4-glucosidase which is a lysosomal acid maltase. It can present
as an infantile variant (also know as Pompe’s disease), juvenile, and adult
variant. In general, the earlier the onset the poorer the prognosis and
Pompe’s disease is inevitably fatal. Clinically, it may mimic spinal muscular
atrophy (SMA), limb-girdle dystrophy, and other myopathies such as inflammatory
myopathies. The infantile onset form but not the juvenile or adult onset form is
associated with cardiomyopathy and characteristic EKG findings. Histologically,
the affected fibers contain numerous vacuoles that contain PAS(+), PASD(-)
material and acid phosphatase. The muscle spindles are always affected. There is
also an entity with clinical features of Pompe’s disease but has normal acid
maltase, these entities has been recently termed pseudo-Pompe’s disease [It
seems like one of these pseudo-Pompe’s disease is Danon’s disease. The
nosology still has to be clarified [Nishino
I et al., 2000; Danon
MJ et al., 1981; Hart
ZH et al., 1987; Valeros
et al., 1997].
Incidence: According to one study in the Netherlands, the
overall incidence is 1
in 40000. The incidence is 1 in 138 000 for infantile GSD II and 1 in 57 000 for
adult GSD II [Ausems
et al., 1999].
Biochemistry: The a-1,4-glucosidase
is a lysosomal enzyme that undergoes extensive post-translational modification
as it moves from the rough endoplasmic reticulum to lysosomes.
Genetics: The gene is located on chromosome 17(q21-23).
Infantile form (Pompe’s disease):
Course: This is usually fatal within the two years of life
as a result of cardiorespiratory failure.
Onset: The babies may be floppy at birth or have a short
period of normal development, usually a few weeks, before onset of symptoms.
CK: CK is mildly elevated (in the range of hundreds).
Macroglossia is typical. The
babies fail to thrive. There is also poor motor development
and respiratory problems. Deep
tendon reflex is abolished because of involvement of the anterior horn cell;
this feature and the severity of the hypotonia often suggest spinal muscular
atrophy. Several features separate them from SMA. First, the
diaphragm in Pompe’s disease is affected. Second, unlike SMA that the facial
muscles are spared, facial weakness may be seen in Pompe’s disease. In
addition, Pompe’s disease has life-threatening cardiomegaly; there is also
hepatomegaly and protrusion of the tongue.
EKG: Characteristic EKG with gigantic QRS complexes and
a very short P-R interval.
Juvenile form: Onset
usually occurs during the first decade with respiratory difficulties and
proximal weakness. It may resembe the limb-girdle dystrophy clinically. In
contrast to the infantile form, cardiomegaly does not occur. Patients tend to
scumb to respiratory disease in the twenties and thirties.
Adult form: The
onset is variable and may occur between the second to the sixth decade. There is
painless weakness that develops insidiously in limb girdles and proximal limb
muscles resembling limb-girdle dystrophy. The lower limbs are affected more
severely than the upper limbs. The respiratory muscles may be disproportionately
weak. CK is only mildly elevated. Some cases may be fatal because of respiratory
HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY:
Infantile form Adult form
General: The pathologic changes in infantile are far more
severe than that in the adult form.
Skin biopsy: Prominent vacuolar glycogen storage in eccrine
addition to widespread pathologic changes in the muscle, the heart and the
nervous system are also severely affected. There is glycogen storage in neurons
(especially lower motor neurons, the reason why Pompe’s disease may have
clinical features similar to SMA), astrocytes, oligodendroglial, and Schwann
Muscle histopathology: There
is marked vacuolar myopathy and many vacuolar spaces are up to 60 mm in diameter. The pattern of the muscle is
Muscle histochemistry: The
vacuoles contains large amount of PAS(+), PASD(-) and acid phosphatase
indicating that glycogen accumulation is accumulation of lyosomal proliferation.
In addition to typical glycogen, the infantile cases often contain a
metachromatic substance that I also positive with alcian blue at pH 1.7.
Combined PAS-alcian blue stain will reveal accumulation of predominantly purple
but also some red and some blue substances. In one case report, inclusion bodies
with tetrazolium salt reduction similar to those in reducing body myopathy have also been described.
Acid maltase activity: The
activity of acid maltase is zero or close to zero in infantile cases. This
reaction, however, is not helpful for diagnosis because the activity of acid
maltase in normal muscle is minimal or non-reactive.
Semithin sections: The
vacuoles are well demonstrated and some fibers are reduced to a bag of vacuoles.
Electron microscopy: The
vacuoles have a single limiting membrane. They may be filled with glycogen or
may be empty due to leakage of glycogen; they may also contain lipofuscin
granules. Cytoplasmic glycogen particles not delimited by a membrane can also be
The degree of pathologic changes varies with different muscle and also reflects
the clinical severity. The vastus medialis is the often the most fruitful target
to be biopsied but it also show significant variation. In less severely
affected, there is no or minimal glycogen storage.
Most of the vacuolated fibers are type I fibers.
In contrast to many myopathies, the muscle spindles are always conspicuously
involved irrespective of the degree of pathologic changes in the surrounding
There is a rare form of glycogenosis with normal acid maltase activity [Danon et al., 1981; Valeros et al., 1997REFERENCES: Head
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