Pompe disease is a rare, inherited neuromuscular disorder that progressively weakens muscles throughout the body. It is classified as a lysosomal storage disorder because it involves the accumulation of a substance within the cell’s recycling centers. The disease affects skeletal muscles, which control movement, and smooth muscles, including the diaphragm, leading to difficulties with mobility and respiratory function.
The Genetic Root: Mutation of the GAA Gene
The sole cause of Pompe disease is a mutation in the Acid Alpha-Glucosidase gene (GAA), which is located on the long arm of human chromosome 17. A person develops Pompe disease only when they inherit a pathogenic variant in both copies of the GAA gene. Hundreds of different variants have been identified, including point mutations, small deletions, or insertions. These mutations interfere with the gene’s ability to produce a functional enzyme, and the specific genetic error dictates the severity of the resulting enzyme deficiency.
Metabolic Failure: The Missing Acid Alpha-Glucosidase Enzyme
The primary metabolic failure stems from the defective or absent function of the Acid Alpha-Glucosidase enzyme, also called acid maltase. This enzyme normally works inside lysosomes, which act as the cell’s digestive system for breaking down and recycling complex molecules. Within the lysosome, the enzyme is tasked with breaking down glycogen, a complex sugar molecule used for energy storage. When the enzyme is deficient, the lysosomal glycogen cannot be properly broken down, initiating the accumulation of undigested glycogen within the lysosome.
The Pathological Result: Glycogen Accumulation and Cellular Damage
The direct consequence of the enzyme deficiency is the progressive accumulation of glycogen inside the lysosomes, particularly in muscle cells. As the undigested glycogen builds up, the lysosomes swell dramatically, eventually rupturing and spilling their contents into the rest of the cell. This accumulation and rupture damage muscle tissue, including skeletal, smooth, and cardiac muscle, impairing the fibers’ ability to contract normally. This pathology, combined with a failure of the cell’s autophagy process, leads to the progressive muscle weakness and wasting characteristic of Pompe disease.
Inheritance Patterns and Disease Onset Variation
Pompe disease follows an autosomal recessive inheritance pattern. This means a person must inherit a defective GAA gene from both parents to develop the condition. Individuals who inherit only one mutated copy are carriers; they typically do not show symptoms but can pass the gene variant to their children. When two carriers have a child, there is a 25% chance the child will inherit a mutation from each parent and have Pompe disease.
Disease Onset Variation
The severity of the disease and the age of symptom onset exist along a continuum, tied directly to the level of remaining Acid Alpha-Glucosidase activity. Infantile-Onset Pompe Disease (IOPD) is the most severe form, presenting within the first few months of life. Infants with IOPD have little to no functional enzyme activity, leading to rapid progression, severe muscle weakness, and heart complications. Late-Onset Pompe Disease (LOPD) can manifest anytime from childhood to adulthood and is generally less severe. Individuals with LOPD have mutations that allow for minimal residual enzyme activity, which slows the glycogen buildup and results in a delayed onset and a slower, progressive course of muscle and respiratory weakness.