MLD is one of several related genetic disorders known as leukodystrophies. These disorders are genetic and characterized by the progressive loss of nerve function. In MLD, this loss of function is caused by a buildup in cells of lipids, known as sulfatides (also referred to as galactocerebroside [ga-lack-toe-ser-ree-bro-side] sulfate or galactosylceramide [ga-lack-toe-sil-ser-a-mide] sulfate). This accumulation occurs primarily in the cells of the nervous system and kidneys, but also to a lesser extent in several other tissues.
Sulfatides are essential to the function of the nervous system. Most sulfatides in the nervous system are present in oligodendrocytes (all-li-go-den-dro-sites) and Schwann cells. These cells produce the covering that wraps around nerves of the central and peripheral nervous systems to insulate and protect them, similar to the function of electrical tape around copper wiring. This covering is called the myelin sheath. (See diagram below.) Like shorted electrical wires, when the myelin is deficient, the nerves cannot properly transmit signals. Sulfatides make up about 4% to 6% of all myelin lipids and cover almost two-thirds of the myelin surface.
Sulfatides, at modest levels, do have a purpose. They provide structure in myelin and also act as signaling molecules that help cells communicate with one another. Sulfatides have been shown to play a role in controlling the generation and spreading of both oligodendrocytes and Schwann cells. However, too much sulfatide accumulation can have negative consequences.
In patients with MLD, sulfatides accumulate in the cells of various tissues and organs because an enzyme that helps break them down, arylsulfatase A (air-rul-sul-fuh-tase A) or ASA (sometimes referred to as ARSA), is missing or is not working efficiently. Various cell types in the kidneys, gallbladder, liver, and pancreas can accumulate sulfatides; however, the central and peripheral nervous systems, including the brain, are the most affected by sulfatide accumulation. Because ASA is an enzyme that is located within lysosomes (disposal system of cells), MLD can also be classified as a lysosomal storage disorder.
The buildup of sulfatides in both the central and peripheral nervous systems results in a progressive loss of myelin (demyelination) and a delay in new myelin formation. Without the myelin sheath, the nerves cannot transmit signals to and from the brain, and the body loses its ability to function normally.
The symptoms of this impairment of the nervous system vary depending on the type of MLD present.
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