Pompe disease — also known as acid alpha-glucosidase (GAA) deficiency, acid maltase deficiency, or glycogen storage disease type 2 — is a rare disease that particularly affects the heart and skeletal muscles.

The disease is caused by genetic mutations in the GAA gene, which encodes for the acid alpha-glucosidase enzyme. This enzyme is responsible for breaking down the complex sugar molecule glycogen into glucose, which the cells then use to produce energy.

How mutations in the GAA gene cause Pompe disease

About 500 different mutations in the GAA gene have been identified in people with Pompe disease. Some of these mutations lead to the complete absence of the acid alpha-glucosidase enzyme while others may cause only a reduction in the activity of the enzyme.

In either case, glycogen builds up to toxic levels inside cellular compartments called lysosomes over time, leading to damage in organs, tissues and particularly in muscles.

Glycogen that is accumulated inside lysosomes displaces or distorts the contractile elements of skeletal muscle called myofibrils that are tiny fibers found inside muscles, which interrupts the cell’s contractile capacity.

The accumulation of glycogen also leads to lysosomal enlargement and eventually rupture, which releases lysosomal enzymes that further damage muscle cells.

How the mutation is inherited

Pompe disease is inherited in an autosomal recessive pattern. This means that to manifest the disease, a person must inherit two mutated copies of the GAA gene, one from each parent. So, each parent must either have the disease or be carriers of the disease.

If both parents are carriers, there is 25 percent risk that their child will develop the disease and 50 percent risk that they also will be a carrier. There is a 25 percent chance that the child of two carrier parents will not inherit any mutated copies of the gene.

If only one of the parents is a carrier, there is 50 percent chance that the child will be a carrier and a 50 percent chance he or she will not inherit the mutated gene.

Symptoms variations and enzyme activity

The symptoms of Pompe disease may emerge at any age from birth to late adulthood and this is associated with the severity of the mutation in the GAA gene. These mutations may lead to a partial loss of functional acid alpha-glucosidase enzyme or, in more severe cases, to a total loss of functional enzyme.

In individuals with the late-onset form of this disease, enzyme activity is only partially lost and usually is less than 40 percent. In babies with the early-onset form, enzyme activity usually is completely or almost completely absent.

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