2.1 Krabbe Disease

More than 200 GALC gene mutations that cause Krabbe disease have been identified. Krabbe disease is a brain disorder that usually begins in infancy (infantile Krabbe disease) and causes movement and eating problems, impaired development, and seizures. The most common mutation in affected individuals of European ancestry (often called 30-kb del) deletes a large segment of the GALC gene. Other mutations insert additional DNA building blocks (nucleotides) into the GALC gene, delete a small number of nucleotides from the gene, or replace single nucleotides with incorrect nucleotides.

These GALC gene mutations severely reduce or eliminate the activity of the galactosylceramidase enzyme. As a result, galactosylceramide and psychosine cannot be broken down. The accumulation of these galactolipids causes damage to myelin-forming cells, which impairs the formation of myelin and leads to the loss of myelin (demyelination) in the nervous system. Without myelin, nerves in the brain and other parts of the body cannot transmit signals properly, leading to the signs and symptoms of Krabbe disease.

Some individuals develop symptoms of Krabbe disease in childhood, adolescence, or adulthood (late-onset Krabbe disease). It is thought that these individuals have a mutation that allows some activity of the galactosylceramidase enzyme, which delays onset of the condition. The severity of the condition may also be affected by the presence of additional common variations (polymorphisms) in the GALC gene that affect the activity of the galactosylceramidase enzyme.