Pompe disease – causes, symptoms, diagnosis, treatment, pathology

Pompe disease – causes, symptoms, diagnosis, treatment, pathology


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.

6 thoughts on “Pompe disease – causes, symptoms, diagnosis, treatment, pathology

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