Louise Comberland

Histology
October 14, 2014
Pompe Disease: A Literature Review
Pompe disease also known as glycogen storage disease type II is a very rare
disorder that affects the muscles of the heart as well as skeletal muscles. A deficiency in the acid
alpha glycosidase (GAA) is a major contributor to the lysosomal storage disorder. The lysosome
of the cell can be characterized as the waste disposal system of the cell, ridding the cytoplasm of
unwanted material. The lack of GAA causes an expansion of lysosomes which are filled with
glycogen in multiple tissues, skeletal and cardiac being the most severely affected (Figure 1a, b).
GAA is synthesized in the endoplasmic reticulum and is responsible for the cleavage of the
alpha-1, 4 and the alpa-1, 6 bonds of glycogen to glucose. A lack of this essential enzyme leads
to the buildup of glycogen in the lysosomes. Complete deficiencies cause infantile Pompe
disease which can be characterized by hypotonia, cardiomegaly, hepatomegaly, and death due to
cardiorespiratory failure all within the first year. Other symptoms are feeding problems, poor
weight gain, enlarged tongues and hearts. Partial deficiency leads to milder effects and the
creation of subdivisions starting from infantile and ending in adult Pompe disease
(Jegadeeswari). Patients with the non-classic infantile Pompe disease show slower progression
and less harsh cardiomyopathy. Another symptom is respiratory weakness which eventually
leads to death after a course lasting many years. Autophagy, or self-eating, is an intracellular
degradation system that delivers cytoplasmic elements to the lysosome (N. Raben). It affects the
trafficking of the replacement of GAA and interrupts its delivery to the lysosome (Lim).
Treatment and therapy for Pompe include Enzyme Replacement Therapy, second generation
drugs such as Albuterol, as well as gene therapy.

Pompe Disease was the first lysosomal storage to disease to be discovered. The
disease is named after J.C. Pompe, who first discovered it in a seven month old girl who
exhibited severe muscle weakness and died of what was thought to be pneumonia (Lim). After
death, an autopsy was performed and hypertonic cardiomyopathy was the cause of death and an
unusual finding laid in the fact that glycogen was found throughout her body. In years to follow
W. Putschar, G. Bishhoff and H.G. Hers included the doctors and biochemists that observed and
described the disease. H.G. Hers found the metabolic defect in the disorder and with that, the
concept of lysosomal storage disorders was established (Lieberman). He discovered that the
enzyme maltase carried out the hydrolysis of glycogen to glucose at an acidic pH. Dr. Hers
realized that his newly discovered enzyme resides in the lysosomes. Based on his research, the
concept of lysosomal storage disorders was established, and the search for other missing
lysosomal enzymes began. The cause of Pompe disease became known 30 years after its initial
description, and it took even longer to develop the first therapy. In the very first adult case, Engel
described irregular autophagy in great detail. Electron microscopy of muscle biopsies from adult
patients revealed the presence of glycogen in the cytoplasm, in lysosomes, and in autophagic
vacuoles (Figure 1a, b). Engel reported that autophagic vacuoles in skeletal muscle were
associated mainly with childhood and adult cases, and were much less frequent in the infantile
form.
The mechanism of autophagy is one of catabolism and involves cell degradation
of unnecessary or dysfunctional cellular components through the lysosome. There are three
autophagic pathways responsible for integrating cargo into the lysosomes. Microautophagy is the
engulfment of cytoplasmic components directly into the lysosomal lumen (Lim). CMA, or
chaperone mediated autophagy requires molecular chaperones and translocation through a

receptor on the lysosomal membrane. The third form is what Pompe disease is classified under
and it is macroautophagy. Macroautophagy works to supply amino acids and energy under
starvation and also operates to rid cells of misfolded proteins as well as worn-out organelles
(Lim). The process begins with the formation of a double membrane called an autophagosome.
The autophagosome fuses with the lysosome and can also fuse with early and late endosomes
before fusion with the lysosome. The term autophagic flux refers to the process where the
formation of autophagosomes is followed by their fusion with lysosomes and degradation of the
cargo occurs successfully (Figure 2) (Lieberman). The failure of a downstream step of
autophagy, fusion between autophagosomes and lysosomes, would result in incomplete flux, and
increase in the number of autophagosomes (Lim). In Pompe patients, muscle fibers could
indicate defects in autophagosome-lysosome fusion.
On a cellular level, the occurrence of Pompe stems from the malfunction of few
or many intricate processes but a major impact can be seen in the physical and pathological
effect of Pompe on the human body. Infantile Pompe Disease is viewed as the deadlier of the two
forms. The symptoms begin at the first few months of life. The usual symptoms begin with
feeding problems, poor weight gain, muscle weakness, and head lag. There is a floppy baby
appearance (Figure 3) with features such as an enlarged tongue or macroglossia, nasal flaring
due to respiratory distress, and poor facial muscle tone. Most infants suffering with Pompe
usually live to see 8.7 months and this is usually due to cardiorespiratory failure. Late onset or
juvenile/adult Pompe can be as early as the first 10 years of childhood to as late as the 60th year
of life. The difference in the two forms of Pompe is that the late onset lacks cardiac involvement.
Skeletal involvement is more prominent with a weakness in the lower limbs. The death of
someone with adult Pompe usually occurs with the progression of respiratory weakness and

failure. Late onset features include impaired cough, recurrent chest infections, hypotonia,
difficulty chewing and swallowing and reduced vital capacity. Delayed motor milestones as well
as progressive muscle weakness include features that may affect the person suffering on a daily
basis and that can alter ones lifestyle. The later the age of onset, the slower the rate of
progression. Naturally occurring animal models of Pompe disease include cattle, dogs, cats,
sheep, and Japanese quails (Lim).
The cardiomyopathy associated with Pompe is a product of the accumulation of
glycogen in the cardiac tissue (Figure 4). Spontaneous glycogenolysis was shown to occur in the
myocardium and the accumulation of glycogen in the myocardial fibers progressed to a point
where their contraction is impaired and effective cardiac action is no longer possible (Di
Sant'Agnese). The myocardium is usually in disarray and the myofibers lose the usual parallel
disposition and makes whirls around areas of fibrosis (thickening/hardening of tissue) which
leads to the impairment of the heart (figure 5a, b). A major factor in the occurrence of
cardiomyopathy and the mortality associated with it is an increase in aortic stiffness. Glycogen
accumulation in smooth muscle fibers and in the endothelial layer of arteries has been shown in
aortic stiffness, morphological studies, and autopsy reports of patients with Pompe disease
(Figure 6) (Kuperus). It is possible that glycogen accumulation in the endothelium damages the
vascular wall, making it more vulnerable to atherosclerosis; in the presence of other
cardiovascular risk factors, this process might increase arterial stiffness (Kuperus). During the
course of the disease, patients with Pompe disease may develop striated muscle atrophy with
some increase in connective tissue (Kuperus). If the same process occurs in the vascular smooth
muscle, it could help explain the increase in aortic stiffness.

In an effort to aid in helping those with Pompe, Enzyme Replacement Therapy

and pharmaceuticals were introduced. Enzyme replacement therapy has been seen as essential to
decrease heart size, maintain normal heart function, improve muscle function, tone, and strength,
and reduce glycogen accumulation (Kanters). In 2006, the drug Myozyme received broad-label
marketing approval in Europe, and later in the U.S. This is the first therapy for Glycogen storage
disease type II (GSDII), and the first attempt to direct recombinant enzyme to skeletal muscle.
This therapy is based on a straightforward hypothesis to explain the disease pathogenesis,
namely that the progressive enlargement of glycogen-filled lysosomes, lysosomal rupture, and
release of glycogen and toxic substances into the cytosol would ultimately result in organ
dysfunctions (Lim). The stages and progression of skeletal muscle damage have been described
for the classical infantile form: small glycogen-filled lysosomes in between intact myofibrils are
typical for stage 1; an increase in cytoplasmic glycogen and the size and number of lysosomes
combined with fragmentation of myofibrils constitute stage 2; after that, glycogen-filled
lysosomes are tightly packed, some show membrane rupture, and only few myofibril fragments
remain in stage 3; finally, in stages 4 and 5, most glycogen is cytoplasmic, the contractile
elements of muscle cells are completely lost, and the cells bloat due to the influx of water.
Enzyme replacement therapy has proven to have substantial effects on survival and reduction of
glycogen in muscle in infantile Pompe disease (Figure 7) (Kanters). The current enzyme
replacement therapy (ERT) clears lysosomal glycogen effectively from the heart but less so from
skeletal muscle. (S. Raben) Lumizyme is an injection that contains GAA and is used for
treatment in people from 8 years old to adults suffering with late onset Pompe Disease.
It can be concluded that Pompe disease indeed is a rare autosomal recessive
lysosomal storage disease that affects the human body on both a cellular and histological level.

Autophagy and the lysosome are major components of the cellular failure that lead to this
horrendous pathological disorder. Pompe disease can be characterized by a deficiency of an
important lysosomal acid and by intralysosomal storage of glycogen in many different organs.
Target organs for the storage of glycogen include cells of the nervous system, heart, liver and,
skeletal muscles. The two forms (early onset, late onset) of Pompe disease present symptoms at
different points in the life of the affected person and has prognoses at two different sides of the
spectrum ranging from death at an early age to respiratory issues that can be mediated with the
help of medication and healthy living. The rarity but severity of the disease calls for constant
experimentation and research to support the constant treat of new disorders that branch from the
unwanted buildup of glycogen in cells. The National Institute of Neurological Disorders and
Stroke (NINDS) supports Pompe research through grants to major research institutions across the
country. Most of Pompe-related research focuses on finding better ways to prevent, treat, and
ultimately cure this disease. The development of enzyme replacement therapy is unquestionably
a major scientific and commercial achievement in the history of Pompe. Enzyme replacement
therapy has proven to be very efficient in rescuing the cardiac abnormalities associated with
Pompe, and thus significantly extends the life span of those being treated. The autophagic
pathway is a critical player in the pathogenesis of Pompe disease and other lysosomal storage
diseases, recommending it as a potential site for therapy. The development of Enzyme
replacement therapy to be used in treating Pompe disease is a novel approach that may be useful
in the future treatment of other diseases with disturbed autophagy, saving lives and spreading
knowledge along the way.

REFERENCES

(Figure 1 a, b: muscle biopsy showing large vacuoles in a case of Pompe disease)

(Figure 2: Autophagy. Degradation of glycogen

in the lysosomes by acid -glycosidase)

(Figure 3: hypotonia. Floppy baby caused by Pompe

disease)

(Figure 4: cardiac tissue associated with

glycogen lakes and glycogen)

(Figure 5a Microscopic view of the

myocardium with the typical disarray of hypertrophic cardiomyopathy in an infant who died in
congestive heart failure.)

(Figure 5b typical lacework appearance of

the myocardium in a patient with type II Pompes disease.)

(Figure 6: Glycogen accumulation in vascular smooth muscle fibers. (Black arrowheads))

(Figure 7: reduction of glycogen storage in

muscle after ERT. (A) Untreated (B) treated)

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