Gaucher disease (GD) is a rare, inherited metabolic disorder classified as a lysosomal storage disorder. A genetic flaw prevents a specific enzyme from properly breaking down certain fatty substances. The resulting buildup of these materials within cells leads to progressive damage in various organs and tissues throughout the body.
Identifying the Chromosome and Gene
The genetic defect responsible for Gaucher disease is found on human Chromosome 1. Specifically, the gene is designated GBA (Glucosylceramidase Beta Acid) and is located on the long arm of this chromosome, at position 1q21. The GBA gene contains the precise instructions for manufacturing the enzyme known as glucocerebrosidase, also called beta-glucosidase.
This enzyme is a protein responsible for a step in metabolism, and its proper function is necessary for health. Mutations, of which over 300 have been described in the GBA gene, change the structure of the enzyme, preventing it from working normally or reducing the amount produced. The location of the GBA gene on an autosome—a non-sex chromosome—determines the way the disease is passed down through families.
The Enzyme Deficiency and Metabolic Effect
The glucocerebrosidase enzyme normally resides in the lysosomes, which are the recycling centers within cells. Its function is to break down a specific fatty molecule, known as glucocerebroside (or glucosylceramide), into simpler components: glucose and ceramide. This breakdown is a continuous process, as glucocerebroside is a constituent of the cell membranes of red and white blood cells that are constantly being recycled.
When a person has Gaucher disease, the mutated GBA gene causes a severe deficiency in the active enzyme. The failure to break down glucocerebroside means this fatty substance accumulates within the lysosomes of certain immune cells called macrophages. These engorged macrophages, now referred to as “Gaucher cells,” cluster in various organs, initiating the pathology of the disease.
The accumulation of these Gaucher cells leads to the enlargement of organs like the spleen and liver, a condition known as hepatosplenomegaly. This cellular buildup also affects the bone marrow, causing bone lesions, pain, and contributing to blood disorders such as anemia and a low platelet count.
How Gaucher Disease is Inherited
Gaucher disease is inherited in an autosomal recessive pattern. This means that for an individual to develop the disease, they must inherit two copies of the defective GBA gene—one copy from their mother and one from their father. If a person inherits only one copy of the mutated gene, they are considered a carrier.
Carriers typically do not show any symptoms of the disease because the single functional copy of the GBA gene is usually sufficient to produce enough active enzyme. If two people who are both carriers have a child, there is a 25% chance with each pregnancy that the child will inherit a defective gene from both parents and therefore have Gaucher disease. There is also a 50% chance the child will be an asymptomatic carrier, and a 25% chance they will inherit two normal copies of the gene.
The disease affects both males and females equally because the GBA gene is located on an autosome rather than a sex chromosome.