Clinical variability in Pompe’s disease

In 1932 the Dutch pathologist J.C. Pompe described for the first time an infant with a combination of clinical and pathological signs later indicated with the eponym ‘Pompe’s disease’. Based on descriptions of similar patients in the following years it appeared to be a uniform entity. Feeding difficulties, failure to thrive, attacks of dyspnoea, peri-oral cyanosis particularly during feeding, and/or weakness with hypotonia in the first months of life are the presenting symptoms. The infant looks severely ill, has a greyish-pale colour and is dyspnoeic. The tongue may be enlarged. Crying is weak and the baby is hypo-active. The liver and especially the heart are enlarged. The legs assume a ‘frog-like’ position. The muscles feel firm. Most patients die in their first year of life from cardiorespiratory failure. On post-mortem examination Pompe found massive accumulation of glycogen in heart and skeletal muscles and other tissues. His was the second form of glycogen storage (the first form being that described by Von Gierke). Therefore Pompe’s disease has been given the name of glycogen storage disease type 2 (GSD II).

In 1955 De Duve and his co-workers introduced the concept of lysosomes, being intracellular organelles, rich in hydrolytic enzymes. In 1963 Hers described the occurrence of the lysosomal enzyme acid maltase (acid a-glucosidase) in normal human tissues as well as the absence of this enzyme in the liver, the heart, and the skeletal muscles of patients with Pompe’s disease. So some other synonyms for Pompe’s disease were introduced namely acid maltase deficiency (AMD) and acid alpha-glucosidase deficiency. In 1964 Baudhuin et al. demonstrated glycogen storage in the liver of Pompe patients to be present mainly within the lysosomes.

Courtecuisse et al (1965), Zellweger et al. (1965) and Engel and Dale (1968) described that the disease may also occur after infancy and these so-called late-onset forms are somewhat arbitrary subdivided according to the age at onset in childhood, juvenile and adult types. In contrast to the infantile type, patients with these types lack cardiac signs and after death glycogen storage is found in skeletal muscles but not in the heart.

The patients present with gradually progressive weakness of the muscles of the trunk, the limb-girdles, and /or respiration. In the childhood and juvenile types the patients mostly become wheelchair-bound and/or dependent on artificial respiration within the first or second decade of life. In patients with the adult form, the occurrence of symptoms may be delayed until late adulthood and respiratory problems may vary considerably. Ultimately patients with the late-onset forms mostly die from respiratory failure, often many years after the beginning of the disease.

In view of evaluating the outcome of enzyme replacement it is extremely important to obtain a clear insight in the variability and the natural course of the disease.

Facts

1. There are two main clinical variants of Pompe’s disease: The infantile form and the variant with late on-set, which is subdivided in childhood, juvenile, and adult onset forms.
2. The activities of the enzymes involved in extralysosomal degradation of glycogen are normal.

Missing links

1. The infantile and late-onset patients show such a different clinical picture that it is hard to believe that they suffer from the same disease.
2. The pathogenesis is poorly understood.
3. Why do we see such a variation in biochemical and pathological expression in different organs?
4. What is the reason that glycogen degradation occurs in two different pathways: lysosomal and extralysosomal? Does the lysosomal pathway have a specific meaning?