Pompe disease, also called glycogen storage disease type II, is a genetically inherited
condition caused by insufficient functioning of an enzyme called lysosomal acid alpha-1,4-glucosidase,
or just acid alpha-glucosidase, due to a mutation of the GAA gene. It’s named after the Dutch
pathologist, Dr. J.C. Pompe, who first described it in 1932.
Glucose is used for energy by most cells of the body, and it’s stored inside the cells
as a compact, branch-shaped molecule called glycogen. When a cell needs energy, it uses
enzymes to remove glucose molecules from the branches. One of the organelles within the
cell is the lysosome, which function a bit like a tiny recycling plant. The lysosome
contains enzymes that break down cellular substances so that they can be recycled. Now
for some reason, and it’s not really understood why, but small amounts of glycogen ends up
in the lysosomes, where it’s broken down by an enzyme called acid alpha-glucosidase,
to release glucose from the glycogen chain.
In Pompe disease, a mutation of the GAA gene prevents the production of enough functional
acid alpha-glucosidase, and lysosomes can’t break down glycogen. This leads to a buildup
of glycogen within the cytoplasm and lysosomes, and that leads to cellular damage and destruction.
Normally, glycogen is found in the largest amounts in the cytoplasm of liver cells and
all three types of muscle cell. In individuals with Pompe, glycogen mostly accumulates in
the lysosomes of those cells. Skeletal muscles include various muscles of the body as well
as the diaphragm which is the primary breathing muscle. Cardiac muscle makes up the majority
of a healthy heart, and smooth muscle is found in the walls of blood vessels and many other
organs.
Pompe disease is an autosomal recessive condition - in other words, both parents must be carriers.
The severity of the condition depends on how much functional acid alpha-glucosidase is
produced. If little to no enzyme exists, the infantile-form of the condition typically
occurs. Within the first few months of life, muscular damage to the heart develops, causing
hypertrophic cardiomyopathy - an enlarged heart - and eventual heart failure. Skeletal
muscle weakness causes severely decreased muscle tone of the entire body. Weakness of
the diaphragm and other breathing muscles leads to respiratory failure as well. Other
findings include an enlarged liver which is thought to be largely due to heart failure,
and a large tongue, which is primarily made of muscle.
If there is reduced enzyme, the late-onset Pompe disease, also classified as juvenile
or adult-onset, can present at any age and varies widely in severity. Usually there’s
weakness of the proximal limb muscles, like the shoulders and hips, and progressive diaphragm
weakness, leading to breathing difficulties. Importantly, the heart is not involved.
Diagnosis includes blood tests like creatine kinase to check for general signs of muscular
damage, measuring the acid alpha-glucosidase enzyme activity in either white blood cells
or a dried blood spot, and gene sequencing to assess the GAA gene. While not necessary
for diagnosis, electron microscopy of muscle biopsies often show lots of glycogen in the
cytoplasm and lysosomes.
Treatment includes enzyme replacement therapy with a manufactured form of acid alpha-glucosidase
called alglucosidase alfa - which helps remove the accumulated glycogen from the lysosomes.
There are also supportive therapies such as mechanical ventilation, physical and occupational
therapy, or placement of a feeding tube.
All right, as a quick recap… Pompe disease is an autosomal recessive condition caused
by a mutation of the GAA gene that results in insufficient lysosomal acid alpha-glucosidase.
Lysosomes can’t break down glycogen normally and its buildup damages muscle and other cell
types. The infantile-onset form is characterized by early development of hypertrophic cardiomyopathy
and respiratory failure, while late-onset cases do not involve the heart and can present
at any age. Diagnosis includes a blood test to measure GAA enzyme activity while treatment
includes enzyme replacement and supportive therapy.