Adrenoleukodystrophy

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Disease

Adrenoleukodystrophy (ALD) is a metabolic disorder that causes cerebral damage and eventually death. The mutation causes problems with a transporter protein, coded by the ABCD1 gene, that aids in the breakdown of very long-chain fatty acids (VLCFA). The ALD protein (ALDP) is located in the wall of the peroxisomes of cells. A buildup of these VLCFAs deteriorates the myelin sheaths that surrounds the axons of neurons in the nervous system. It was originally thought that the decreased activity of the peroxisomal enzyme very long-chain acyl-CoA synthetase caused the increase in VLCFAs. The enzyme converts VLCFA to their CoA thioesters. However, recent studies may have disproven this theory saying that the accumulation of VLCFA is independent of the enzyme activity itself. Unfortunately, ALD affects about 1 in 20,000 people worldwide.

There are a couple forms of this disease: childhood cerebral, adrenomyeloneuropathy (AMN), and Addison's disease.

Childhood cerebral form starts to show in children as young as 2 years old. In this stage of development, ALD can be the most fatal. It can take only 2 years to reach the vegetative state after being diagnosed.

AMN usually occurs in middle-aged men. The symptoms do not develop as quickly nor as severely as they do for the younger patients.

With Addison's disease, the adrenal gland has difficulty producing the steroid hormones needed. Most patients with Addison's disease only have this problem but can develop the other symptoms of AMN.


Chromosome location


The mutation that causes adrenoleukodystrophy is located on the long arm of the X chromosome at the ABCD1 location. ABCD1 stands for ATP-binding cassette, subfamily D, member 1. This is at location 28 between the base pairs of 152,990,322 to 153,010,215, which is a difference of 19,893 base pairs.


ABCD1.jpg

Source: Genetics Home Reference

Characteristics of the Disease


Symptoms depend on the stage of development.

Joey Johnson.jpg


For the childhood form:

seizures, loss of hearing, visual impairment, difficulty in school, aphasia (losing the ability to verbally communicate), muscle spasms, muscle tone deterioration

If symptoms are very severe, can cause a coma or paralysis.


For AMN:

loss of urination control, development of muscle weakness, impairment of thought process and visual memory


For Addison's disease:

coma, increased pigmentation, weight loss due to decreased appetite and losing muscle mass, vomiting, development of muscle weakness

Treatment or Management of the Condition


Adrenoleukodystrophy is more than likely fatal. The only known treatment that works is steroids to work with the improperly functioning adrenal glands. Another major treatment is bone marrow transplant. This is not a guaranteed method, as it is only good to use if a patient has this surgery at the very early stages of development of ALD. The bone marrow provides many corrective factors that may help to degrade the VLCFAs and a beneficial substance that may prevent some forms of the disease. Lorenzo's oil is a third type of treatment. This supplement is named after Lorenzo Odone, a young boy who had ALD and whose parents initiated the research for this liquid. It is comprised of two "oils", glyceryl trioleate (GTO) and glyceryl trierucate (GTE). The oil acts as a competitive inhibitor to the enzyme that builds the VLCFA complexes. It has been tested on several hundreds of patients but has not had good results overall.

Molecular Genetics

There is a mutation database for ALD that now has at least 412 different types of mutations recorded that caused ALD. 109 of them were caused by a frameshift mutation; 50 caused by nonsense mutations; 221 caused by missense mutations; 24 caused by deletions and insertions of amino acids; and 15 caused by a deletion of one or more exons.

The type of mutation that causes ALD does not indicate in any manner as to how severe the symptoms will be.


Genetic Testing

For pregnant women, chorionic villus sampling or amniocentesis testing can be done to evaluate the cells, as these tests are also used to determine other chromosomal disorders as well. Female carriers can be tested with a VLCFA test or a DNA probe test. Specialists can look at concentrations of VLCFA in the plasma cells, however, only a select few laboratories test for this. It is found that the VLCFA concentration test is accurate enough to detect correctly about 85% of the time. Sometimes the results can come out as a false negative for ALD, so further blood testing is recommended. A secondary screening to help verify results is an MRI scan. If ALD is present, there will be two symmetrical white areas in the brain that are very apparent and abnormal.

Below, C26 is hexacosanoic acid levels.

Plasma VLCFA.jpg MRI.jpg


Other relevant information


Mustard seed oil, as used in the kitchen, can be used as a substitute for Lorenzo's oil. It has a high concentration of erucic acid.

There was a movie made in 1993 called "Lorenzo's Oil" that tells the story of Lorenzo Odone. He only recently died in 2008 after being diagnosed with ALD at age 5 in 1984. Lorenzo's Oil (1992).jpg

References


http://ghr.nlm.nih.gov/condition/x-linked-adrenoleukodystrophy

http://www.ulf.org/types/XALD.html

http://www.nlm.nih.gov/medlineplus/ency/article/001182.htm

http://ghr.nlm.nih.gov/gene/ABCD1

Info and Plasma VLCFA plot: http://www.x-ald.nl/clinical-diagnosis/diagnosis-of-x-ald/

MRI photo source: http://imaging.consult.com/image/topic/dx/Pediatrics?title=Adrenoleukodystrophy%20(Pediatric%20Brain)&image=fig7&locator=gr7&pii=S1933-0332(07)70724-3

Photo of Joey Johnson: http://www.joejohnson.net/leukodystrophy_connections.htm

Berger, J., and J. Gartner. "X-linked Adrenoleukodystrophy: Clinical, Biochemical and Pathogenetic Aspects." Biochimica Et Biophysica Acta (BBA) - Molecular Cell Research 1763.12 (2006): 1721- 732. Science Direct. Web. 21 Apr. 2011. <http://www.sciencedirect.com/science?_ob=ArticleListURL&_method=list&_ArticleListID=1733068904&_sort=r&_st=13&view=c&_acct=C000062356&_version=1&_urlVersion=0&_userid=4143599&md5=595c436faa033379f2a505b86ecf0110&searchtype=a>.

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