Krabbe disease is caused by mutations in a specific gene responsible for producing an important enzyme called galactocerebrosidase, often abbreviated as GALC. This enzyme plays a crucial role in breaking down certain fats (lipids) that are found in the protective covering of nerve cells known as myelin. When GALC is missing or not working properly due to genetic mutations, these fats accumulate abnormally inside cells, leading to damage and destruction of the myelin sheath. This loss of myelin disrupts normal nerve function and causes the severe neurological symptoms seen in Krabbe disease.
The root cause lies at the genetic level: individuals with Krabbe disease inherit defective copies of the GALC gene from both parents, making it an autosomal recessive disorder. This means that both copies of this gene must be mutated for the disease to develop. If only one copy is faulty, a person typically becomes a carrier without showing symptoms but can pass on the mutation to their children.
GALC’s role is primarily within lysosomes—special compartments inside cells that digest and recycle various molecules. In Krabbe disease, because GALC activity is deficient or absent, toxic substances such as psychosine build up inside lysosomes particularly within certain brain cells like oligodendrocytes and microglia. Psychosine accumulation is especially harmful because it kills these cells responsible for maintaining healthy myelin.
Without functioning oligodendrocytes to produce and maintain myelin around nerve fibers in the central nervous system (brain and spinal cord), nerves become damaged over time leading to progressive neurological decline including muscle weakness, developmental delays, seizures, vision loss, and eventually severe disability or death if untreated.
The exact mutations causing Krabbe disease vary widely among patients; some involve small changes like point mutations altering single amino acids in GALC protein structure while others may be larger deletions removing parts of the gene entirely. The severity and age at which symptoms appear can depend on how much residual enzyme activity remains—less activity generally leads to earlier onset and more rapid progression.
In summary:
– **Genetic mutation**: Changes occur specifically in the *GALC* gene.
– **Enzyme deficiency**: Mutations reduce or eliminate galactocerebrosidase production.
– **Lipid buildup**: Failure to break down lipids leads to toxic accumulation.
– **Myelin destruction**: Damage occurs mainly through death of myelin-producing brain cells.
– **Autosomal recessive inheritance**: Both parents must pass on mutated genes for offspring to be affected.
This cascade from faulty genes through biochemical disruption ultimately causes all clinical features associated with Krabbe disease—a devastating neurodegenerative condition rooted deeply in molecular genetics affecting lipid metabolism within nerve-supporting cells.
