Adrenoleukodystrophy (ALD) is a rare, fatal genetic disorder that affects the brain, adrenal cortex, and testes of male patients. It is an X-linked disease, meaning that the gene that causes ALD is carried on the X chromosome (Migeon et al., 1981). Since males only have one X chromosome, they bear the full force of the disease. The most severe form of this disease, the childhood cerebral form, only affects young boys. After developing normally for 3-10, about 35% of boys with this disease will present with impaired motor function, and their health rapidly degrades until their death (Cartier et al., 2009). The biochemical reasons behind this are only partially understood.
In cells, there are vesicles (sac-like structures) called peroxisomes that degrade unwanted cellular materials. Peroxisomes degrade very long chain fatty acids (VLCFA) in a process called β-oxidation that produces energy for the cell. In ALD, however, this process is impaired (Weber et al., 2014). In order for VLCFA to enter the peroxisome, they must be taken in by a transport protein called ABCD1 (also called ALDP). Since the ABCD1 gene codes for the ABCD1 protein, mutations in the ABCD1 gene will lead to a non-functional protein. Since ABCD1 is not functional in ALD, VLCFA are not brought into the peroxisome to be broken down, and they accumulate in the cell (Mosser et al., 1993). This can be seen in Figure 1. VLCFA accumulation causes an inflammatory response that destroys neurons. Neurons have a myelin sheath, which is crucial for neurons to function. The inflammatory response triggered by VLCFA accumulation degrades this myelin, causing neural death (Schlüter et al., 2012).
There are several treatments that have been proposed and have shown promise. The first one ever demonstrated was called Lorenzo’s Oil. This, however, was only shown to be effective in ALD patients who have not shown any symptoms. It also does not cure the disease, but only postpones the progression of the disease (Moser HW et al., 2005). The only cure that has been demonstrated is bone marrow transplantation. Bone marrow cells give rise to microglia, which cause the inflammatory response in the brains of ALD patients. By replacing these cells, the myelin of neurons will remain intact and affected persons will not suffer the symptoms of this disease (Cartier et al., 2009).
Bone marrow transplants are done by killing all of a person’s normal bone marrow cells and giving them someone else’s bone marrow stem cells. These stem cells will give rise to all of the normal blood cells, including microglia. The difficulty with this is that every person expresses certain markers on the surface of their cells. Transplant patients have to find someone whose bone marrow cells express markers similar enough to their own so that their body does not think that it is foreign material that needs to be destroyed, leading to transplant rejection. Because of this, many people do not find the match that they need (Cartier et al., 2009). More recently, a therapy has been developed that puts a twist on transplantation. A group of scientists have taken a person’s own bone marrow stem cells and corrected them with gene therapy (Figure 2). They did this by using viral vectors, which means that they made a virus that contained the gene for ABCD1. They then made this virus infect the bone marrow stem cells that they took from the ALD patient. The corrected stem cells were then transplanted back into the patient now that they and the cells they give rise to will express ABCD1 (Cartier et al., 2009). This cures ALD and circumvents the issue of transplant rejection.
I think that this is an excellent cover page! I like the overall flow of the cover page from the genetic aspect to the biochemical aspects to the treatments available today. I feel that the materials were presented in a manner that was accessible to both a peer scientist (myself) and to someone without as much background knowledge. That being said, I do feel that vesicles could be linked to the biochemistry primer (it might not be as intuitive to a non-science major) and I feel that making a link to β-oxidation could present the opportunity to expand on what β-oxidation actually is for a non-science major. I like the way that viral vectors is explained in this cover page, and it might be possible to quickly explain β-oxidation in the same manner. I felt that the cover page went into enough detail about the disease and its causes as well as providing enough biochemical information to not bore a student peer. I was concerned at first about the first figure itself; I thought that the axis could have been labeled better and that at first I was confused as to what it was showing because of it) but I agree that this is an important figure to show. This figure does strongly suggest the increase in VLCFA in ALD patients is the major contributing factor to this disease. I am interested to see more about the Cartier et al. (2009) study in which the patients own bone marrow stem cells were coaxed using gene therapy. Although I feel that this is ample information for the cover page, it might be interesting to investigate other papers that talk about the negative effects of this treatment. In an article by Hussein et al. (2011) titled, “Copy number variations and selection during reprogramming to pluripotency” the authors talk about the dangers of turning cells to stem cells and back to another cell. Although this therapy skips the middleman and might eliminate this problem of copy number variation because the cells start out as stem cells, I still think it would be interesting to look into different negative side effects of this treatment as well (if any). I also know that viral vectors can sometimes insert randomly as well, so (although this isn’t cover page material) I am interested to see how any negatives of this treatment are brought to light.
Aside from a few comments made above I again think that this is a good cover page. I wouldn’t go into too much detail in this section about any of the biochemisty of ALD, and I would maybe consider linking a the few terms mentioned above to provide a non-scientist reader more opportunities to understand β-oxidation.
Thanks for the primer tips, and good catch on the figure (must have been all that Cell Bio!). As for the Cartier et al. paper, it’s super interesting, and I would suggest reading it for your own edification because it’s about as wild as you can get as a scientist.
Fun fact, this is the first successful clinical test of gene therapy of hematopoietic stem cells. It is kind of sad to say, but a big reason had to be that the risks that you reference pale in comparison to not trying anything. Both patients had older brothers who died from X-ALD so I kind of inferred that the parents of these two children were willing to try anything. So that’s why they were able to take these risks. The authors freely admit at a few points that they did not know what they were doing.
What they were able to do, however, was track the integration sites of the genes (using a certain kind of PCR) so I think that had they inserted into tumor suppressor genes, they would have found it. They make this a point to discuss so it seems like they are aware of the dangers and are trying to work around it. The genes inserted into coding dense regions of DNA, as is typical of lentiviruses, but it did not seem like this was a matter of concern for the authors. There are definitely negatives to this that you highlight and from bone marrow transplants in general. The severity of this disease and the limited number of options warrant the risks, though.
I think this page is very well written and seems to flow very well! I was just wondering if there is any mention in the literature about the heterozygous phenotype in women and if this disease follows a classical-Mendelian inheritance pattern where expression of the the dominant allele can completely overpower the recessive allele. I was just curious because the page mentioned that it is an x-linked disease and since it’s fatal, I’m assuming males do not reach reproductive maturity to pass on the gene and I was wondering what the female phenotype since they would need to be a carrier of the disease.
The other question I had (and I’m not sure if it’s mentioned at all in the literature) is why the symptoms develop after 6-8 years of normal development. Does it have to do with the progression of puberty in boys and how the expression of genes changes?
Overall I think this is a great title page, there were just some things I was wondering while reading and it’s 100% possible those things would be included later on because they may be a little too technical for a page like this.
The inheritance pattern can best be described as confusing. There is no correlation between genotype and phenotype. People within a family (i.e. have the SAME EXACT mutation) have wildly different phenotypes.
There’s a ton of literature about AMN (the form that females typically get) and I ran across a lot because the underlying biochemical defect is the same in the childhood cerebral form (CALD) and AMN. AMN is known as the “default” form of X-ALD because basically all males and most females who have the mutated ABCD1 gene will get this. The CALD form happens in males if there is a “trigger” that sets off the inflammatory response. What that trigger might be takes up a bunch of my molecular basis page, and it is not really well known. So, the reason that it takes 6-8 years to develop has a lot to do with these factors. My guess, which is somewhat referenced in the literature, is that it takes a little bit of time for the VLCFA to accumulate and breakdown myelin for the inflammatory response to be triggered. Once this is triggered though, it is a very quick process that leads to this disease being fatal.
Very interesting disease and write-up. As a non-scientific reader there were a few of areas which caused me to pause and re-read a couple of times but by the end I had the general idea and understanding why the corrected stem cells were a cure. Adding a definition for “vesicles” and “peroxisomes” would be helpful. The second paragraph reference to the “transport protein called ABCD1” and the next sentence reference to the “ABCD1 gene” was confusing for me. Are these one and the same or two different items with the same name or is there a connection between the protein and the gene? It would help the reader if the second to last sentence in last paragraph wording was a bit more clear “The corrected stem cells…” .
Thank you for telling me what I need to clarify. In reference to your gene/protein question: a gene codes for a protein. So the ABCD1 gene is the DNA “blueprint” that gets translated into the ABCD1 protein. The protein is what actually functions in the cell. Those definitions are defined on the primer page so I will be sure to link them. Thanks again.
Nice synopsis, and an interesting disease. I’m curious how the presence of extra VLCFA inside the cell degrades the myelin sheath (which if I understand correctly is on the outside of the neurons), and how microglia prevents this.
This will not be the most satisfying answer because these are two of the major “unknowns” about the disease.
The major theory about how VLCFA leads to myelin breakdown is that VLCFA from inside the cell gets incorporated into the myelin membrane. This is a normal process because they are normally a component of the membrane. The problem arises because they are usually not present in as high of concentration as is seen in X-ALD. So, the structure of VLCFA (which is really big as the name implies) destabilizes the membrane and it breaks apart. This then elicits an inflammatory response.
How? Again, no one is too sure, but it seems like the release of the myelin components are taken up by microglia. This is because microglia function as macrophages (link to primer). This means that they take in the VLCFA that got released when the membrane breaks apart. Since they can’t get rid of them, the microglia send out signals for other immune system cells to come and help it. This leads to the severe myelin degradation seen in X-ALD.
Hey, buddy. This title page is great! It was easy and simple to read. You do a great job of quickly explaining certain terms that non-scientists may not know.
I do have a couple of general questions about the disease. You mention that young boys will start showing symptoms and their health will rapidly degrade. Is there an average amount of time that the boys have to live? Basically how rapidly does this occur?
Also, how is it that people don’t show symptoms? I understand that the build up of VLCFA needs to take place and considerable damage has to occur before symptoms may be noticeable. The first treatment that worked for patients only worked for ALD patients that didn’t show symptoms. How is this possible? Especially if this is a genetic disease. Is it due to different polymorphism that are found in this disease?
Also, maybe go a little more into how the inflammatory response destroys neurons and myelin.
Great question! The onset of the childhood cerebral form (CALD) is 3-10 years old. Once this happens it could be anywhere from a few months to a few years that the child will be in a vegetative state or pass away.
For your second question, the big thing you should know about X-ALD is that it doesn’t follow any rules. The same mutation can lead to the mild form of X-ALD (AMN) or CALD. The basic process is that myelin will have this kind of mild, spontaneous breakdown because VLCFA destabilize the membrane (or so they think. It’s still not really clear). In the CALD form, this mild myelin breakdown triggers an inflammatory response that actively demyelinates the brain.
So, if you normalize VLCFA before they trigger this response, the myelin breakdown should stop and the response won’t get triggered. That seems to be the most likely explanation, but as I said, this a little bit of evidence and a lot of speculation.
Interesting disease. I especially found it intriguing that this is an x-linked disease, but yet seems according to the information here to be prevalent in males. It would seem you would have a better chance of acquiring the disease as a female because of the two X chromosomes. However, it has been a long time since I worked with Punnett squares.
Thank you for your comment. I will be sure to clear this up in my revision. The disease is caused by a mutation in the gene for ABCD1. If you are a female, you will have 2 X chromosomes so if that gene is mutated in one, the other one will be OK. This means that females are protected by the 2nd X chromosome. Males, on the other hand, only have one X chromosome so if the gene is mutated on that, they do not have another chance of getting a normal copy.
The gene therapy on the patient’s own bone marrow followed by transplant is WILD. I’ve never heard of another condition with such a therapy. Very cool.