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Andrew Marcoux BIOL 10004 Research Report: Adrenoleukodystrophy Submitted: July 4th, 2012

2 Adrenoleukodystrophy, or ALD, is a disease which affects the systems white matter, and the adrenal glands. ALD slows down the metabolism of very long chain fatty acids (VLCFAs) within the brain. This is due to a mutation on a part of the X chromosome which is responsible for providing instructions for making transport proteins (which are responsible for the transportation of fats, sugars and amino acids). The gene affected in ALD is known as the ABCD1 gene, which means ATP-binding cassette, sub family D, member #1. This gene, when affected by ALD, contains the mutation responsible for the symptoms and conditions of adrenoleukodystrophy. Adrenoleukodystrophy primarily affects males due to the fact that it is an X chromosome linked disorder. Since males have only one X chromosome, the prevalence of this disease is much higher than women, who have two X chromosomes. Since females have the two X chromosomes, and typically only one is affected, females are generally not phenotypically affected by this disease. Many females with an ABCD1 mutation on the X chromosome can go on to live normal lives, with little to no symptoms of adrenoleukodystrophy.

The three main phenotypes of adrenoleukodystrophy in affected males are: Childhood cerebral form Adrenomyeloneuropathy (AMN) Addison disease

3 The childhood cerebral form shows itself most often between the ages of 4-8 years in affected males. The symptoms resemble those of attention deficit disorder and hyperactivity. After these symptoms arise, continuous impairment of basic motor, visual and auditory functions occur, and can ultimately lead to total disability within two years. This phenotype is the most severe of the adrenoleukodystrophys, and has a higher mortality rate compared to any other phenotype of ALD.

Adrenomyeloneuropathy is a much slower developing phenotype of adrenoleukodystrophy. It manifests later on in a persons life, usually showing symptoms inbetween ages 20-30. The common symptoms of this phenotype include sphincter disturbances, sexual dysfunction, paraparesis and impaired adrenocortical function (Moser, n.d.). This is a much milder form of adrenoleukodystrophy which, when diagnosed, can be treated with adrenal hormone replacement therapy.

Addison's disease shows symptoms of adrenocortical deficiency in-between ages 2-8. This phenotype involves the insufficiency of steroid hormones produced by the adrenal glands, which affects the ability to break down glucose, and the retention of sodium in diet. This phenotype of adrenoleukodystrophy is very rare, and can restrict the proper growth of

4 important endocrine organs, such as the hypothalamus and pituitary gland. Treatment often involves hormone replacement therapy.

Although males are primarily affected by adrenoleukodystrophy, females can have some complications from having the disease. These symptoms often involve some abnormalities with sphincter control, some sensory disturbances, and progressive paraparesis. Many females with adrenoleukodystrophy wont show many signs of the disease throughout their life, and can go on with normal lives unaware of the disease being present. Females are also known to have completely normal adrenal functions throughout their life with the disease.

Adrenoleukodystrophy is a disease which is contracted through a genetic inheritance. Since this disease is passed on genetically, this means that that a parent of the child has this abnormality within their genes, and is passed onto the child through reproduction. Females are not majorly affected by this disease, since it affects one X chromosome, and therefore, the female becomes a carrier of the disease. Nearly 93% of all cases of adrenoleukodystrophy are passed on genetically from one of the parents. Although this is seen as a genetically inherited disease, nearly 7% of all cases of adrenoleukodystrophy are brought on by a de novo mutation. A de novo mutation is the mutation of a haploid sex cell, which can result in

5 the development of certain diseases, like adrenoleukodystrophy and autism, for the first time in a familys gene pool. Although females are known as carriers of the disease, males can also pass it on genetically. Men are able to pass this disease onto all their daughters, but none of their sons (Moser, n.d.), and females have a 50% chance of transmitting the affected gene in each pregnancy.

6 Adrenoleukodystrophy primarily affects two major organs, which is the brain and adrenal glands. Since this disease is known for the inability to metabolize very long chain fatty acids properly, it over-accumulates, leading to brain damage and nervous system issues. VLCFAs are known to act as insulation within the nervous system, and are also a part of the brain membranes. When too many VLCFAs accumulate, they slow down nerve impulses, and progressively start problems. Some common signs of ALD affecting the brain would be seizures, hearing loss and degeneration of visual and auditory function (Partridge, 2009).

The adrenal glands are endocrine organs, which are responsible for releasing stress hormones into the body, and are also responsible for secreting aldosterone. Adrenoleukodystrophy affects the adrenal glands by progressively impairing them from performing their normal duties. The early diagnosis of adrenoleukodystrophy can prevent most damage to the adrenal glands. At this point, hormone therapy is started, and the conditions are monitored.

There are currently very few treatment options available for adrenoleukodystrophy. Since the disease is not extremely common, there has not been too much research towards the treatment and cure of it. With hormone replacement therapy, corticosteroid therapy, physical therapy and general supportive care, many sufferers of ALD can go on to lead very normal lives. Recently, two researchers discovered the mixture of two types of acids extracted from olives and rapeseed called Lorenzos oil. This oil is a 4:1 mix of erucic acid and oleic acid, and is used to

7 treat adrenoleukodystrophy, and the symptoms that come with the disease. This mixture helps the body slow down the production of VLCFAs, which help greatly with the impedance of the disease.

The current life expectance solely depends on how early the disease is diagnosed, which phenotype is present, and how quickly treatment is started. There is no set life expectancy of adrenoleukodystrophy; however, if the disease is left untreated, total paralysis, blindness, coma or death could occur in just a few years. Most sufferers of ALD live normal lives, with the exception of diet. People with ALD are advised to eat a diet lower in fats, and higher in proteins, and are, if required, to attend therapy sessions to deal with any extreme circumstances of the disease (Partridge, 2009).

There is currently no major research being conducted for adrenoleukodystrophy. The current methods of treatment are seen as useful in treating the disease, and are only being enhanced upon. The current best method of treatment include an early MRI and adrenal function test for families with a history of ALD, along with the immediate start of treatment when any signs of ALD are present.

8 References

American Medical Association complete medical encyclopedia. (2003). New York: Random House Reference.

Management of mental disorders (Australian ed., 4th ed.). (2004). Darlinghurst, NSW: World Health Organization Collaborating Centre for Evidence in Mental Health Policy.

Partridge, K. (2009). The brain. New York: H.W. Wilson Co.

Steinberg, S., Moser, A., & Raymond, G. (n.d.). X-Linked Adrenoleukodystrophy - GeneReviews - NCBI Bookshelf. National Center for Biotechnology Information. Retrieved June 28, 2012, from http://www.ncbi.nlm.nih.gov/books/NBK1315/