The GALC gene is a segment of DNA located on chromosome 14 within human cells. It serves as a blueprint, providing instructions for the body to produce a particular protein. Understanding genes like GALC is fundamental for comprehending human health and disease, as this genetic information dictates various biological functions.
The GALC Gene’s Function
The GALC gene codes for the enzyme galactosylceramidase, also known as the GALC enzyme. This enzyme is located within lysosomes, specialized sacs inside cells that break down waste materials. The GALC enzyme performs hydrolysis to break down specific fatty substances known as galactolipids. These galactolipids, including galactosylceramide and psychosine, are found predominantly in the nervous system and kidneys.
Galactosylceramide is a component of myelin, the protective covering that insulates nerve cells and ensures rapid transmission of nerve impulses. The breakdown of galactosylceramide by the GALC enzyme is a normal part of myelin turnover throughout life. Psychosine is a substance that forms during myelin production and is quickly broken down by GALC, as it can be toxic to cells if it accumulates. Proper enzyme function is important for maintaining healthy nerve cells and a properly functioning nervous system.
Genetic Mutations and Their Impact
Mutations in the GALC gene lead to a deficiency or complete absence of the galactosylceramidase enzyme. Over 200 different GALC gene mutations have been identified. A common mutation in individuals of European ancestry involves a large deletion of a segment of the GALC gene. Other mutations include insertions, deletions of smaller DNA segments, or single nucleotide changes.
Enzyme deficiency results in the accumulation of undegraded galactolipids, especially psychosine, within cells. This accumulation is toxic, particularly to oligodendrocytes and Schwann cells, the myelin-producing cells in the central and peripheral nervous systems. Toxicity damages these myelin-forming cells, impairing new myelin formation and destroying existing myelin (demyelination) throughout the nervous system. Without intact myelin, nerves cannot transmit signals properly, leading to neurological dysfunction. GALC gene mutations follow an autosomal recessive inheritance pattern; an individual must inherit two mutated gene copies, one from each parent, to be affected.
Krabbe Disease Manifestations
Krabbe disease, also known as globoid cell leukodystrophy, is a severe neurological disorder caused by GALC gene mutations. This rare inherited condition primarily affects the myelin covering nerve cells, leading to progressive neurological issues. The most common form is infantile-onset Krabbe disease, which typically begins before one year of age.
Early symptoms of infantile Krabbe disease can include irritability, feeding difficulties, muscle weakness or stiffness, and unexplained fevers. As the disease progresses, infants may experience a decline in mental and physical development, vision and hearing loss, increased muscle tone (spasticity), and seizures. The progressive destruction of myelin impacts various bodily functions, leading to significant disability and a shortened lifespan, with affected infants rarely surviving beyond two years of age. Less commonly, late-onset forms of Krabbe disease can begin in childhood, adolescence, or adulthood, with symptoms such as vision problems, walking difficulties, muscle weakness, and a decline in mental ability, which vary considerably among affected individuals.
Diagnosis and Management for Krabbe Disease
Krabbe disease diagnosis often begins with newborn screening, which measures GALC enzyme activity in dried blood spots. Low enzyme activity may indicate a diagnosis, though further testing is required to confirm. Definitive diagnosis is typically achieved through enzyme activity assays (measuring GALC enzyme levels in white blood cells or cultured cells) and genetic testing to identify specific GALC gene mutations. These tests help distinguish between infantile and later-onset forms and identify carrier status.
Current management approaches focus on hematopoietic stem cell transplantation (HSCT), particularly when performed pre-symptomatically or very early in the disease course. HSCT can slow or halt disease progression by providing healthy cells that produce the GALC enzyme, but it cannot reverse existing neurological damage. For individuals with existing symptoms, supportive and symptomatic care is provided to manage symptoms, improve comfort, and enhance quality of life. Ongoing research explores future therapeutic possibilities such as gene therapy, aiming to deliver a functional GALC gene copy to nervous system cells, with early trials showing promise in improving motor function.