Adrenoleukodystrophy Ald Gene
|The proper APA Style reference for this manuscript is:|
JACOBS, A. A. (2000). Adrenoleukodystrophy Ald Gene. National Undergraduate Research Clearinghouse, 3. Available online at http://www.webclearinghouse.net/volume/. Retrieved April 9, 2020
ALICIA A. JACOBS
-NONE- DEPARTMENT OF
Sponsored by: TODD ECKDAHL (firstname.lastname@example.org)
|Adrenoleukodystrophy is an X-linked disorder involving the accumulation of very long chain fatty acids (VLCFA) and demyelination of the brain and spinal cord, and primarily affects males. It is carried by females and is only passed through the generations from mother to son. The primary method of prevention is genetic counseling. Diagnosis may include an MRI, or a test for high levels of VLCFA. Treatments include special diets, bone marrow transplants and the possibility of gene therapy in the future. There are no known cures, but it is possible, if the disease is detected soon enough, to treat the disease to a point that the affected individual is able to lead an active life. A great amount is still unknown about adrenoleukodystrophy, but studies are continuing with the hope of someday discovering a cure. |
NATURE OF THE DISEASE Adrenoleukodystrophy (ALD) is a relatively rare, hereditary, X-linked disorder of peroxisomal fatty acid oxidation (7) affecting only males. This disease impairs very long chain fatty acids (VLCFA) metabolism (1) caused by lignoceroyl-CoA ligase deficiency, and occurs in about one out of every 20,000 live births (4). To date, according to the Southern Medical Journal, there are seven subtypes of adrenoleukodystrophy (7). The most common of these, childhood cerebral ALD (CCALD), affects about 37 percent of individuals with adrenoleukodystrophy (7). This form of ALD usually occurs in "previously normal" boys between the age of 5-10 years. Some signs include behavioral, gait, auditory and urinary disturbances, slow progressive stiffness, weakness in the lower limbs, disorders relating to attention deficit, and hyperactivity (7). Though adrenoleukodystrophy may not appear until adolescence or young adulthood, it is much more common in childhood, and generally the progressive deterioration results in the affected individual reaching a complete vegetative state in about 5 years, and eventually death (7). There are several methods for determining the presence of adrenoleukodystrophy. A test may be performed to determine the level of very long chain fatty acids in the affected individual. Abnormally high levels are an excellent indication of ALD (7). Computed tomography (CT scan) and magnetic resonance imaging (MRI) are also used to examine the brain for any asymmetric intensity or lesions, though the MRI is more helpful since it gives a clearer picture of the brain (7). At this point there is no known cure for adrenoleukodystrophy, but there are various treatments available for the affected individual. One treatment is in the form of a bone marrow transplant. It has been labeled the "treatment of choice" for individuals in the early stages of ALD since it can postpone the rate of neurological deterioration (7). There is a new method in the making but has not been proven yet. A study conducted in 1999 found that retroviral-mediated adrenoleukodystrophy-related protein corrects very long chain fatty acid accumulation in fibroblasts (1). However, if this method is approved, it will be a while before it is tried on humans. Another somewhat controversial method of treatment is with a combination of vegetable oils named Lorenzo`s oil after the son of the parents who developed it (4). It does not cure ALD, but it appears to slow, or even completely stop the continued degeneration (20). The oil decreases very long chain amino acids levels by delaying their synthesis (4). Scientists agree that the oil decreases the level of toxic compounds in the blood that contribute to the disease, but it is still controversial since it does not reverse any damage already caused by the disease (20).
GENETIC BASIS Adrenoleukodystrophy is inherited in an X-linked recessive manner. About 93% of all cases inherited the ALD gene from one parent (6). Though all daughters of a male with the adrenoleukodystrophy disease are carriers, they are usually not seriously affected. They do, however, have a 50% chance of passing the mutation on to their offspring with each pregnancy (13). Unlike the daughters though, the sons are seriously affected by the mutation. If any male offspring inherit the mutation, they will have the disease, though the sons of an affected male do not inherit the diseased gene (6). The affected gene was identified for research purposes in Drosophila by isolating DNA adjacent to the P-element insertion by plasmid rescue (5). A cDNA clone was obtained before the analysis. The mutant located the P-element insertion between the 5` untranslated region and the start codon of an open reading frame (5) and is the only gene like it in Drosophila. There are over 200 different known mutations, but most are unique to a "particular kindred" (13). Of all the mutations for this gene, the most common recurring mutation is an AG deletion at nucleotide 1801-1802 (6). This one mutation occurs in about 12% of families, and does not appear to favor any particular ethnic group over another (13). Several other mutations also occur. The latest studies indicate 68% of the identified mutations are non-recurrent, and of the disease causing mutations, about 7% are large deletions, around 24% are frameshifts, approximately 3% are splice defects, about 9% are nonsense mutations, around 5% are in-frame deletions-insertions, and about 53% are missense mutations (13). The ALD gene was discovered in 1993, with the chromosome locus at Xq28 (21) and the corresponding protein was discovered to be a member of the ATP binding cassette (ABC) protein transporter family (22). When the gene for adrenoleukodystrophy was first being studied, it was thought that the corresponding protein was an enzyme (22). This thought arose from the fact that individuals with ALD accumulate high levels of saturated, very long chain fatty acids in their brain, as well as their cerebral cortex. This is a result of the enzymes failing to break down the fatty acids as in normal function (22). There are continuous studies occurring as scientists search to understand how the transporter effects the function of the fatty acid enzyme, and possible methods for effective treatment. (22). One study conducted included 29 unrelated patients with ALD. It involved mutational analysis by genomic Southern Blot analysis and direct nucleotide sequence analysis of reverse transcriptase-polymerase chain reaction derived from total RNA that was originally extracted from cultured skin fibroblasts, lymphoblastoid cells or peripheral blood leukocytes (2). All phenotypes of the disease were associated with mutations resulting in protein truncation or subtle amino acid changes, but there was no difference in the phenotypic expressions between missence mutations involving conserved amino acids and nonconserved amino acids (2). All mutations were confirmed by sequencing DNA in carriers (10). With the exception of two mutations (delAG1801 and P560L), nearly every ALD family has a different mutation (11). This makes it nearly impossible to associate genotypes with phenotypes. In the future it may become possible to find a pattern to the mutations with the disease, and eventually map out each one. If so, then it will become possible to associate genotypes with phenotypes. Unfortunately though, in the meantime it remains virtually impossible.
GENE EXPRESSION Adrenoleukodystrophy protein (ALDP) is a member of the ATP binding cassette (ABC) protein transporter family which has the characteristic feature of functioning as dimers of two related halves (6). ALDP is one of these halves and is referred to as a half transporter (6). The peroxisomal membrane contains three ABC transporters which include PMP70, PMP69 (P70R), and the ALD related protein (ALDR) (13). ALDR (mapped to 12q11) is of particular interest as it has a 66 percent identity to ALDP and can substitute for the function of ALDP in restoring the capacity of ALD fibroblasts to metabolize VLCFA (6). The gene product is not present in about 70 percent of individuals with ADL (6). A defect in ALDP causes the accumulation of VLCFA though it is not know exactly why (13). There are no obvious correlations between the phenotypes and genotypes of patients with ALD, indicating that other genetic or environmental factors modify the phenotypic expressions of ALD (2). Another study supported this idea by indicating that one or more unknown genes contribute to the difference of phenotypic expression of ALD (3).The gene for adrenoleukodystrophy encodes a 745 amino acid protein (10). A deficiency in the peroxisomal enzyme that catalyzes the formation of Co-A derivatives of VLCFA (lignoceroyl-CoA ligase) results in the accumulation of saturated unbranched VLCFA in the rough endoplasmic reticulum of tissues throughout the body (23). The VLCFA with particular emphasis are hexacosanoic (C26:0), pentacosanoic (C25:0) and tetracosanoic (C24:0) (23). Mutations affecting a single amino acid were concentrated in the region between the third and fourth putative transmembrane domains and in the ATP-binding domain (12). Based on the results of one of several studies conducted, some think that only one gene is responsible for ALD (12). More studies have indicated that the mutations are what cause the disease. One study tested 30 healthy individuals and was unable to find any mutations in the ALD gene of any of them (10).Though adrenoleukodystrophy affects nearly every part of the body, some organs and portions are more affected than others. The adrenal cortex and the central nervous system white matter are particularly affected. In an individual with ALD, the accumulation of VLCFA in the adrenal cortex results in a limited capacity to convert cholesterol, leading to active steroids, and an increased viscosity of the plasma membrane causing receptor dysfunction (23). The CNS white matter of an ALD patient develops acute and symmetric demyelinating lesions, and perivascular infiltration of lymphocytes (23).
DETECTION / TREATMENT / CURES There are several different methods for diagnosing adrenoleukodystrophy. Though it is easiest to detect by the phenotype in males, it is much harder to diagnose the disease in females, since they rarely display the symptoms. About 85-95 percent of females are asymptomatic and only 10-15 percent have adrenoleukodystrophy, though it is less severe and has a late onset (23). The symptoms are one of the first things examined when adrenoleukodystrophy is suspected. There are also tests to check the level of very long chain fatty acids (VLCFA), adrenal dysfunction, and MRI in the affected individual. When examining for the symptoms, there are many characteristics to look for. Some of the symptoms include Attention Deficit Disorder, epilepsy, brain tumors, multiple sclerosis, visual disturbances, clumsiness, progressive stiffness and weakness of legs, abnormalities of sphincter control, sexual dysfunction, autonomic disturbance unexplained vomiting and weakness or coma, hemiparesis, aphasia, dementia, and impotence without neurologic or endocrine disturbance (6). Though an individual with ALD may have only one of these symptoms, it is more common for them to have several. The tests for diagnosing adrenoleukodystrophy in males include VLCFA levels, MRI abnormalities and testing adrenal function. The VCLFA test is the most important of the three. It measures very long chain fatty acids (VLCFA) in plasma, and confirms abnormal results in 99.9 percent of males with adrenoleukodystrophy (13). The brain MRI is always abnormal in neurologically symptomatic males and shows a characteristic pattern (symmetrical enhanced T-2 signal in the parieto-occipital region) (13). It is frequently the first diagnostic lead. The most sensitive test for adrenal dysfunction is an elevated ACTH level and an impaired rise of plasma cortisol due to the administration of ACTH (6). Females can also be tested with an MRI and for VLCFA, but since the percentages of detection by these tests are much lower in females, they are not considered as useful (23). Testing females for carrier status is completed in two steps. The VLCFA test is performed first (abnormal results indicate the female is indeed a carrier) and if the results are normal, DNA-based mutation analysis is conducted (after the disease-causing mutation has been identified in the family) (6). Prenatal testing is also available. Again, high levels of VLCFA in cultured amniocytes or chronic villus cells are an excellent indication the fetus will have adrenoleukodystrophy (23). Though as of yet there are no known cures for adrenoleukodystrophy, there are several treatments to impair the disease. Lorenzo`s oil is one such treatment. This is a mixture of oils (glycerol trioleate-trierucate) developed by the parents of a boy suffering from adrenoleukodystrophy (18). This oil lowers the levels of VLCFA, reducing the amount of demyelination (8). However, though this special blend of oils nearly prevents the disease from doing further damage, it does not improve the condition of affected individuals(17). Lorenzo`s oil, along with a VLCFA-restricted diet, has been proven to normalize C26:0 levels in as little time as four weeks (23). Bone marrow transplants are also available, though they are still experimental. It has a high rate of mortality (about 20 percent) and is not recommended for patients with a performance IQ less than 80 (X-Link). The results are poor in severe cases and in less severe cases, the results have been mild (23). At best, a bone marrow transplant only postpones the demyelination for an undetermined, short, period of time (23). One new breakthrough still being researched is the possibility of gene therapy. Studies are now in progress on mice. Up to this point, retroviral-mediated adrenoleukodystrophy-related gene transfer corrects VLCFA accumulation in ALD fibroblasts regardless of whether the adrenoleukodystrophy protein was present or not (1). Since prenatal testing is now available and fairly accurate overall, this disease is a good candidate for gene therapy. Hopefully in the future, the severity of adrenoleukodystrophy will be lessened or eliminated completely. Only time will tell.
Submitted 5/5/00 10:52:25 AM
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