Metachromatic leukodystrophy (MLD) is caused by a genetic defect that leads to a deficiency in a specific enzyme called arylsulfatase A (ASA). This enzyme normally helps break down certain fats called sulfatides, which are important components of the protective covering (myelin) around nerve cells in the brain and nervous system. When arylsulfatase A is missing or not working properly, sulfatides build up inside the cells, especially in the nervous system, causing damage to the myelin sheath. This damage disrupts the normal transmission of nerve signals, leading to the progressive neurological problems seen in MLD.
The root cause of this enzyme deficiency is mutations in the ARSA gene, which provides instructions for making arylsulfatase A. MLD is inherited in an autosomal recessive pattern, meaning a person must inherit two defective copies of the ARSA gene—one from each parent—to develop the disease. If a person inherits only one defective gene, they are a carrier and typically do not show symptoms but can pass the mutation to their children.
In some rare cases, mutations in another gene called PSAP, which encodes a protein called prosaposin, can also cause a form of MLD. Prosaposin is important because it produces saposin B, a helper protein that activates arylsulfatase A. Without saposin B, even if arylsulfatase A is present, it cannot function properly, leading to sulfatide accumulation similar to ARSA mutations.
The accumulation of sulfatides primarily affects the white matter of the brain and peripheral nerves. White matter consists largely of myelinated nerve fibers, and the buildup of sulfatides causes progressive demyelination, which means the myelin sheath deteriorates. This demyelination impairs nerve conduction, resulting in symptoms such as muscle weakness, loss of coordination, cognitive decline, and eventually severe neurological disability.
The timing and severity of symptoms depend on the specific mutations and how much enzyme activity remains. MLD can present in different forms:
– **Late-infantile form:** Symptoms appear before age 2 and progress rapidly.
– **Juvenile form:** Symptoms start between ages 2 and 16 with a slower progression.
– **Adult form:** Symptoms begin in adulthood and progress more slowly.
At the cellular level, the excess sulfatides interfere with normal cell function and cause inflammation and cell death in the nervous system. This leads to widespread damage beyond just the myelin, affecting neurons and other supporting cells.
In summary, metachromatic leukodystrophy is caused by inherited mutations that lead to a deficiency or malfunction of arylsulfatase A or its activator saposin B. This results in the harmful buildup of sulfatides in nerve cells, causing progressive destruction of the myelin sheath and severe neurological impairment. The genetic nature of the disease means it is passed down through families, and the specific mutations determine the age of onset and disease severity.
