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What is Adrenoleukodystrophy?

Adrenoleukodystrophy (ALD), sometimes referred to as X-ALD, is an inherited genetic disorder affecting the adrenal glands and the central (brain & spinal cord) and peripheral nervous system (controling our limbs, etc). There are two forms of ALD – a childhood form and an adult form. The childhood form of the disease is quite devastating as the primary damage is of the form of a progressive neurodegeneration with symptoms that expand from mild to severe with a very poor prognosis for survival. 

Currently, there is no cure for ALD, but research has made some remarkable inroads – "Lorenzo's Oil" is not a cure but if taken early in the course of the disease it may slow its progression. There are also ongoing studies looking at the benefits of gene therapy and bone marrow transplant. 

  • ALD occurs in 1:20,000 newborns and symptoms can appear from childhood to adulthood.
  • Childhood cerebral ALD is the most severe form, with an age of onset in early childhood, primarily in boys (~age 4–10 yrs). The adrenal disorder can be treated, but there is no treatment for the neurological damage, which means the long-term prognosis is poor. 
  • Adrenomyeloneuropathy (AMN) is the adult form of ALD. Symptoms manifest in young to mid adulthood (ages 20–40 years) and are less severe than the childhood form of ALD. Female carriers of ALD may develop AMN. 
  • Neonatal adrenoleukodystrophy is not the same as childhood cerebral ALD (X-ALD). Neonatal ALD is not inherited via the X-chromosome (it has an autosomal inheritance pattern) and thus affects infant girls and boys to the same degree. The long-term prognosis for infants affected by neonatal ALD is poor.

ALD primarily affects males because the gene responsible for ALD is located on the X-chromosome. Females are genetically XX, while males are XY. If a male inherits an X-chromosome with a defective ALD gene (containing deletions and/or mutations), he will develop ALD. A female with two X-chromosomes could potentially be a ‘carrier’ of ALD if one of her X-chromosomes has a defective ALD gene. She might be free of ALD symptoms herself, but still carries the risk of passing on the faulty gene to her children, particularly her sons. 

The gene that causes ALD is the ABCD1 gene. Normally, the ABCD1 gene would encode a protein called the 'ALD protein' (ALDP), which is responsible for breaking down very long chain fatty acids. People with ALD accumulate high levels of saturated, very long chain fatty acids (VLCFA) in their brain and adrenal cortex because the gene defect either diminishes or stops completely the production of ALD protein that would normally break down these fatty acids. The ALD protein is localised to a cellular structure called a peroxisome and ALD is sometimes called a ‘peroxisomal disorder’.

While the adrenal disorder that arises with ALD can be treated with medication, the primary damage caused by ALD is the progressive loss of myelin from nerve cells. Myelin is an insulating membrane that surrounds axons of nerve cells. Axons are long extensions of nerve cells and these specialised structures send out nerve signals to neighbouring nerves and muscles. Myelin surrounds the axon in a manner that resembles 'beads on a string'. By surrounding the axon in this way, myelin helps the nerve send its signal out more quickly and effectively -–the signal is transmitted by jumping between the gaps of the beads to reach the nerve terminal more quickly. Without this insulating membrane, the signal has to travel the length of the axon; the signal may diminish before it reaches its destination, if at all. The ability of the nerve cell to function without myelin becomes severely limited. 

The connection between VLCFA and myelin breakdown is unknown, but researchers think the accumulation of VLCFA triggers an inflammatory response that damages myelin, in a process similar to other demyelinating disorders such as multiple sclerosis. Scientists are currently trying to understand more about this mechanism.