The proper APA Style reference for this manuscript is:
WIMBERLY, C. A. (2000). Adrenoleukodystrophy. National Undergraduate Research Clearinghouse, 3. Available online at http://www.webclearinghouse.net/volume/. Retrieved December 9, 2023
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Adrenoleukodystrophy
CASEY A. WIMBERLY
MWSC DEPARTMENT OF BIOLOGY
Sponsored by: TODD ECKDAHL (eckdahl@missouriwestern.edu)
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| Adrenoleukodystrophy as well as the rest of the leukodystrophies are very rare, but deadly disorders. I have described how this rare disorder effects those who have the disorder. I have listed and described symptoms, mutations of the gene, treatments being used right now to lessen the effects of this disorder. I have illustrated two of the mutations occurring on the ALD gene, at the amino acid level and described some others Unfortunately as of now there is not a cure for ALD, but researchers keep looking for therapies as well as a cure. The scary thing is that everyone is carrier of about six serious genetic disorders just like ALD, but the chances of someone carrying the disorder mating with another who is also a carrier are so great, there is really nothing to be concerned about. |
NATURE OF ADRENOLEUKODYSTROPHY Adrenoleukodystrophy (ALD) is an X-linked genetic disorder. Females are carriers, so only male offspring who are homozygous recessive for the gene are supposed to show the phenotype. In a mild form of the disorder female carriers are affected. Symptoms of this mild form of ALD include paraparesis of the lower body, excessive muscle tone, very mild peripheral neuropathy, and urinary problems. The neonatal form can affect male and female newborns. In this form mental retardation may occur, along with some abnormalities of the face, seizures and hypotonia. This form of ALD ends up being very progressive. As I have begun listing there can be many different types of ALD. The form most noted by its childhood-onset occurs usually between four and ten years of age, this only affects boys. This form may cause a variety of learning disabilities, seizures, deafness, and problems with eyesight, fatigue and poorly articulated speech. All of these problems can add up to poor performance in school. There is also a form that waits until adulthood, between the ages of twenty-one and thirty-five. This form progresses slowly, but as with all forms of the disorder one to ten years of life is expected after prognosis. Adrenoleukodystrophy is an extremely rare genetic disorder. It is part of a whole group of disorders called the "leukodystrophies". Let`s break down the word leukodystrophy. "Leuko" is greek meaning white, the matter consisted of fatty myelin sheath. "Dystrophy" which means abnormal growth. What happens is the myelin sheath around nerves in the brain or the spinal cord deteriorates or breaks down. This occurs because the body is unable to break down "very-long-chain-fatty acids". This fatty acid build up causes the myelin sheath to deteriorate. Once this has occurred the nerve can not function anymore. As I said before ALD occurs in different forms at different ranges of age. The three main ways ALD presents itself are in the brain, the spinal cord, or around the adrenal gland. About fifty percent of time the disorder occurs in the brain. Brain tissue is broken down, normal function can not occur so the child dies. This is the case that I said the ages ranged from four to ten. The second way ALD is presented has been or can be mistaken for Multiple Sclerosis, because it affects the spinal cord. This is the form occurring in adults. The third way ALD presents itself is around the adrenal gland. Very-long-chain-fatty acids build up around the adrenal gland causing it to lose function.
GENETIC BASIS Adrenoluekodystrophy is and X- linked genetic disease. Which means it is on the X chromosome at position Xq28. The gene is positioned between the DXS15 gene and the LICAM gene, about 650 kilobase pairs from the color pigment gene. It consists of 2750 base pairs and is made up of 10 exons. Of those 2750 base pairs 451 are A`s (Adenine), 455 are T`s (Thymine), 919 are C`s (Cytosine) and 885 are G`s (Guanine), in a normal gene. The most frequent mutation of this gene is missense, which means a mutation in the amino acid sequence. Resulting in a wrong protein being made that causes the mutation. From 20 samples, 11 were missense and 2 were nonsense, 5 were deletions and 1 was insertion. In another study out of 110 samples of the gene 50 percent were missense. In isolating the gene Polymerase Chain Reaction was done as well as positional cloning. PCR was done on the number 1 and number 5 exon, which resulted in mutation 50 percent of the time. So the majority of the time the mutations occur on the first and fifth exon, but mutations have been recorded on the third, fourth and ninth exons, but these are much less common. In the figure on the following page, I have illustrated some example of the location were two of these mutations occur and the amino acids involved. On the third exon the replacement of a C with a G at the 1551 nucleotide changes the amino acid arginine to glycine, also on the third exon a G is replaced with an A creating arginine instead of glutamine. At the fourth exon a conversion of arginine to tryptophan at the 1638 nucleotide also was found in people affected with adrenoleukodystrophy.
MUTATION DIAGRAM1 829 906 1258 1451 2750 Exons 1 -5 GAA, GAG CCU glutamic acid proline to toAAA, AAG CGU lysine argenine
TREATMENT Unfortunately cures for adrenoleukodysrophy are non-existent so far. However there are some treatments that can help slow down this disorder. Such as a diet low in fatty foods and cholesterol. Some cholesterol lowering drugs are also used for this purpose. Psychological counseling for the patients and family are part of treatment as well. As far as a medication or drug to cure this disorder there are none. Once this disorder has begun to do its neurological damage the effects are irreversible. Once it has taken its course the effected are only expected to last between 1-10 years, that is from the time symptoms are detected. An oil was tested that was supposed to build back the fatty acid, but only affected the fatty acid around the liver, not the brain where it is needed in the case of ALD (Moser 1993). There was motion picture called "Lorenzo`s Oil", which had to do with a young boy diagnosed with ALD. It was a fictional movie and explained scientific things falsely, such as the oil actually working. It also made the United Leukodystrophy Foundation out to be unhelpful and uncaring.
REFERENCES(Boehm et al., 1999; Braiterman et al., 1999; Melhem et al., 1999; Moser et al., 1999a; Moser & Moser, 1999; Moser, 1993; Moser, 1999; Moser, Kemp & Smith, 1999b)Boehm, C. D., Cutting, G. R., Lachtermacher, M. B., Moser, H. W. & Chong, S. S. (1999). Accurate DNA-based diagnostic and carrier testing for X-linked adrenoleukodystrophy. Mol Genet Metab 66, 128-36.Braiterman, L. T., Watkins, P. A., Moser, A. B. & Smith, K. D. (1999). Peroxisomal very long chain fatty acid beta-oxidation activity is determined by the level of adrenodeukodystrophy protein (ALDP) expression. Mol Genet Metab 66, 91-9.Melhem, E. R., Barker, P. B., Raymond, G. V. & Moser, H. W. (1999). X-linked adrenoleukodystrophy in children: review of genetic, clinical, and MR imaging characteristics. AJR Am J Roentgenol 173, 1575-81.Moser, A. B., Kreiter, N., Bezman, L., Lu, S., Raymond, G. V., Naidu, S. & Moser, H. W. (1999a). Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 45, 100-10.Moser, A. B. & Moser, H. W. (1999). The prenatal diagnosis of X-linked adrenoleukodystrophy. Prenat Diagn 19, 46-8.Moser, H. W. (1993). Lorenzo oil therapy for adrenoleukodystrophy: a prematurely amplified hope. Ann Nuerol Aug, 121-2.Moser, H. W. (1999). Treatment of X-linked adrenoleukodystrophy with Lorenzo`s oil [editorial]. J Neurol Neurosurg Psychiatry 67, 279-80.Moser, H. W., Kemp, S. & Smith, K. D. (1999b). Mutational analysis and the pathogenesis of variant X-linked adrenoleukodystrophy phenotypes [editorial; comment]. Arch Neurol 56, 273-5. |
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