Adrenoleukodystrophy (ALD) is a severe inherited disorder that mainly affects males. The disease is associated with progressive damage to the brain and/or the hormone-producing adrenal glands.

There are different types of ALD, with a range of symptoms and differing ages of onset, but the underlying cause of the disease is the same in each type: a mutation, or a change, in the ABCD1 (ATP binding cassette subfamily D member 1) gene. However, additional environmental or genetic factors may also increase the risk of symptoms developing.

ABCD1 and ALD

ABCD1 provides the instructions to make the adrenoleukodystrophy protein (ALDP). A wide range of mutations in ABCD1 have been identified in patients. These mutations cause the production of no ALDP proteins, or smaller and unstable ones that cannot function. Currently, there is no known correlation between the type of mutation and the severity of the disease.

ALDP plays an essential role in the breakdown of a substance called very long chain fatty acids (VLCFAs). VLCFAs are naturally occurring compounds in the body, either taken in with the diet or produced in the body. They form part of the insulating layer around nerve cells, called myelin, and also play other roles. However, high levels of VLCFAs are toxic to cells.

The enzymes to break down VLCFAs are contained inside a microscopic structure called the peroxisome inside cells. Enzymes are proteins that catalyze a specific chemical reaction, in this case degrading VLCFAs. ALDP is located on the membrane of the peroxisome and is essential in allowing the VLCFAs to pass this membrane.

In patients with ALD, little or no functional ALDP results in insufficient transport of VLCFAs into the peroxisome and a reduction in their breakdown. As a result, levels of VLCFAs increase to abnormally high levels inside cells and can accumulate in the central nervous system and the adrenal glands in the kidneys.

Mechanism of VLCFA toxicity

The exact mechanism behind how high levels of VLCFAs cause damage is unknown, but ongoing research has identified potential mechanisms.

It is thought that high levels of VLCFAs in the brain are associated with the increased production of cytokines, immune proteins that trigger inflammation. Inflammation is an immune process that can lead to damage and swelling. This results in the progressive loss of the myelin sheath, or demyelination. The myelin sheath is the insulating layer that protects nerve fibers from damage and ensures that nerve signals are sent from the brain to muscles without being lost.

Furthermore, increased VLCFAs levels may destabilize mitochrondial membranes in brain cells. Mitochondria, sometimes referred to as the powerhouse of the cells, are essential for energy production. The mitochondrial membrane normally tightly regulates what can go in and out of the mitochondria, and by disrupting this, VLCFAs may impair the energy production process and increase the production of other damaging substances inside cells. This can result in the death of brain cells.

Similarly, in the adrenal glands, the accumulation of VLCFAs may cause mitochondrial dysfunction and lead to progressive cell death. It may also be possible that a hormonal imbalance is caused by excess VLCFAs being added to the membrane of the adrenal glands and preventing it from receiving signals from the rest of the body.

ALD as an X-linked disease

ALD is more common in males, who are also more likely to have severe symptoms than women. This is because the ABCD1 gene is located on the X chromosome, one of the two sex chromosomes that play a part in determining gender.

Men only have one X chromosome, which means that if the ABCD1 gene it carries is mutated, then the man will develop ALD.

Women have two X chromosomes, which means that they have two copies of ABCD1. If only one copy is mutated, then the second functioning copy can generally produce enough ALDP to partially compensate. As a result, women will have no or milder symptoms.

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