A look into the complex world of genetic disorders, their histories, and how we treat them.
By Ian MacArthur
Insulation plays a crucial role in our daily lives. It keeps our homes warm in winter, prevents our coffee from rapidly cooling, and protects our bodies from the cold. Yet another sort of insulation plays an indispensable part in our well-being from moment to moment. This is the insulation of our nervous system, a role carried out by the layer of proteins and a fatty acids known as myelin. The myelin layer facilitates the efficient transmission of nervous signals throughout the body. Without it, transmissions would slow and communication between nerves would cease to occur.
Myelin degradation is a key characteristic in the pathology of adrenoleukodystrophy, a rare sex-linked genetic disorder. Adrenoleukodystrophy, or ALD, is a member of a family of diseases known as peroxisomal disorders. These disorders are characterized by the inhibited function of the peroxisome, the organelle responsible for much of the cell’s fatty acid metabolism. In ALD, failure to breakdown very long chain fatty acids (VLCFA) results in the destruction of the essential myelin layer.
|The black portions in the middle of this ADL brain are
where demyelination has occurred. White matter normally
appears white in MRIs, like in the bottom half of this brain.
(Image via Wikimedia Commons)
ALD is a consequence of a mutation in the ABCD1 gene located on the X chromosome, the maternally inherited sex chromosome. The gene codes for a transport protein responsible for conveying VLCFAs to peroxisomes where they are broken down and disposed of by the cell. The mutated protein is unable to transport VLCFAs, leading to fatty acid build up in nervous tissue. When this occurs, VLCFAs interact with the myelin and cause this crucial insulator to degrade, thereby slowing nervous signals and crippling the adrenal gland.
The most severe form of ALD appears in children as early as four years of age. The first symptoms to appear are those characteristic of adrenal insufficiency, including aggression, poor vision, and seizures. As myelin degradation progresses, sensory, motor, and neurological function decline, eventually leaving the patient in a vegetative state. Death occurs within five years of the onset of symptoms. Although childhood ALD is the most common form of the disease, related illnesses have been observed in middle-aged adults.
Adrenoleukodystrophy is a recessive X-linked disorder. The X and Y sex chromosomes are so called for their role in determining the sex of a child. Because they receive only one X and one Y chromosome, ALD is much more prevalent in males than in females, who receive two copies of the X chromosome. This is because females must inherit two mutated X chromosomes in order to develop symptoms while males must only inherit one.
Although no cure for the disease has been developed, treatments are available that may delay the onset or mitigate the severity of symptoms. A mixture of oleic and erucic acid known as Lorenzo’s Oil has been shown to postpone the onset of ALD in pre-symptomatic children by lowering VLCFA levels in blood. Bone marrow transplants have also provided effective treatment for childhood ALD, and current experimental techniques that couple bone marrow transplantation with gene therapy have shown to be promising. Despite these developments, adrenoleukodystrophy remains daunting to cure in patients already exhibiting symptoms. Nevertheless, progress will ceaselessly be made in the lengthy effort against this tenacious killer.