Glycogenosis type II and Pompe’s disease

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Background   Histopathology & Immunohistochemistry  Differential Diagnosis  Reference

BACKGROUND AND CLINICAL INFORMATION: Head  

Summary of glycogenosis     Classificaiton of glycogenoses by enzyme deficiency

Summary    Clinical variants   

Summary: 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).

Clinical variants:

 ·         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).

Clinical features: 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 failure.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head  

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 secretary cells.

Infantile form: 

·         General: In 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 cells.

·         Muscle histopathology: There is marked vacuolar myopathy and many vacuolar spaces are up to 60 mm in diameter. The pattern of the muscle is completely distorted.

·         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 seen.

 Adult form:

·         General: 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.

·         Fiber typing: Most of the vacuolated fibers are type I fibers.

·         Muscle spindle: In contrast to many myopathies, the muscle spindles are always conspicuously involved irrespective of the degree of pathologic changes in the surrounding muscle.

DIFFERENTIAL DIAGNOSIS: Head  

There is a rare form of glycogenosis with normal acid maltase activity [Danon et al., 1981; Valeros et al., 1997

Danon MJ, Oh SJ, DiMauro S, Manaligod JR, Eastwood A, Naidu S, Schliselfeld LH. Lysosomal glycogen storage disease with normal acid maltase. Neurology. 1981 Jan;31(1):51-7.

Reuser AJ, Kroos MA, Hermans MM, Bijvoet AG, Verbeet MP, Van Diggelen OP, Kleijer WJ, Van der Ploeg AT. Glycogenosis type II (acid maltase deficiency). Muscle Nerve. 1995;3:S61-9. Review.

Ausems MG, Verbiest J, Hermans MP, Kroos MA, Beemer FA, Wokke JH, Sandkuijl LA, Reuser AJ, van der Ploeg AT. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet. 1999 Sep;7(6):713-6.

Poenaru L. Approach to gene therapy of glycogenosis type II (Pompe disease). Mol Genet Metab. 2000 Jul;70(3):163-9. Review.