The GALC gene provides the instructions for creating an enzyme necessary for maintaining a healthy nervous system. Mutations in this gene lead directly to a severe, progressive neurological disorder. These genetic changes compromise the body’s ability to process certain fatty substances, resulting in their toxic accumulation. This failure sets off cellular destruction that underlies the pathology of Krabbe disease.
The Role of Galactocerebrosidase
The GALC gene directs the production of galactocerebrosidase (GALC), an enzyme that functions inside lysosomes, the cell’s recycling centers. GALC is responsible for the breakdown (hydrolysis) of specific lipids known as galactolipids in the nervous system and kidneys. The enzyme’s main substrates are galactosylceramide and a highly toxic lipid called psychosine.
Galactosylceramide is a structural component of myelin, the fatty sheath that insulates nerve fibers. Normal GALC activity breaks down old lipids as part of the regular myelin turnover process. Psychosine is a byproduct of myelin production that is toxic to cells, but GALC quickly breaks it down under healthy conditions. When the GALC gene is mutated, the enzyme deficiency causes both substrates to remain undegraded within the lysosome.
The Connection to Krabbe Disease
A deficient or non-functional GALC enzyme is the direct cause of Krabbe disease. This deficiency halts the metabolic clearance of galactolipids, leading to the accumulation of psychosine to high levels in the central and peripheral nervous systems. The buildup of this toxic lipid is the primary mechanism of neurological damage in the disorder.
Psychosine destabilizes cell membranes and triggers pathways that induce oxidative stress in myelin-producing cells. This toxicity causes the death of oligodendrocytes in the brain and Schwann cells in the peripheral nerves, leading to widespread demyelination. The destruction of myelin prevents nerves from transmitting signals properly, causing progressive neurological impairment. Macrophages attempting to clear the accumulated lipids transform into multinucleated “globoid cells,” a distinctive pathological feature of the disease.
Understanding Krabbe Disease Inheritance and Symptoms
Krabbe disease follows an autosomal recessive inheritance pattern, meaning a child must inherit a mutated GALC gene from both parents to develop the condition. Carriers, who have one normal and one mutated copy, are typically healthy but have a 25% chance of passing the disease to their child during each pregnancy. Over 200 different GALC gene mutations have been identified, and the specific combination of these variants influences the severity and age of onset.
Infantile-Onset Krabbe Disease
The most common and severe form is infantile-onset Krabbe disease, with symptoms beginning around four to six months of age after normal development. Early signs include extreme irritability, fevers, feeding difficulties, and increased sensitivity to noise. As the disease progresses, infants experience rapid developmental regression, spasticity, muscle weakness, vision and hearing loss, and seizures.
Later-Onset Forms
Later-onset forms appear in childhood, adolescence, or adulthood and progress more slowly. Initial symptoms may include difficulty walking, vision changes, or sensory neuropathy. These milder presentations are often due to residual activity from the defective GALC enzyme.
Diagnosis and Current Treatment Approaches
Diagnosis begins by measuring GALC enzyme activity, often performed through newborn screening (NBS). A finding of low activity requires immediate follow-up with a second-tier test, such as measuring the level of toxic psychosine in the blood. The definitive diagnosis is confirmed by genetic testing to identify two pathogenic mutations in the GALC gene.
Early detection via newborn screening is important because the only treatment that significantly alters the disease course must be administered before symptoms begin. This treatment is Hematopoietic Stem Cell Transplantation (HSCT), typically using umbilical cord blood stem cells from a healthy donor. HSCT replaces the patient’s faulty cells with donor cells that produce functional GALC enzyme, which migrates into the central nervous system to clear toxic psychosine. While HSCT is not a cure and is less effective once symptoms have started, it can slow or halt neurological damage in pre-symptomatic infants. Research continues into advanced therapies like gene therapy, which aims to deliver a healthy copy of the GALC gene directly into the nervous system.