Krabbe Disease

Krabbe Disease is a rare and ultimately fatal type of leukodystrophy, or a condition in which the white matter of the brain degenerates. Consequentially, Krabbe Disease is also known as globoid leukodystrophy (one characteristic of the condition is the presence of globoid cells). Krabbe disease is also classified as a lysosomal storage disorder because the disease is caused by deficiency of an enzyme called galactocerebrosidase that is found in the lysosomes of cells (Wenger et al., 1974).

Globoid cells are macrophages with a high content of galactolipids-- the presence of globoid cells is characteristic of Krabbe Disease  Source: http://frontalcortex.com/?page=oll&topic=24&qid=1394
Globoid cells are macrophages with a high content of galactolipids– the presence of globoid cells is characteristic of Krabbe Disease
Source: http://frontalcortex.com/?page=oll&topic=24&qid=1394

About 1 in 100,000 individuals are diagnosed with Krabbe Disease (Duffner et al., 2012). There are four classifications of Krabbe disease based on the age at which symptoms first develop.

Early infantile form arises between three and six months of age—the predominant symptoms are blindness, missed developmental milestones, failure to thrive (stunted growth and poor appetite), a rigid posture due to neurological damage in which the baby remains on his or her back with the limbs rotated inwardly (called decerebrate rigidity), and frequent muscle spasms leading to muscular rigidity (Lyon et al. 1991). Early infantile Krabbe Disease is the most common disease phenotype (more than 90% of patients experience early infantile onset) and most severe form of the condition—death usually occurs between ages one and three (Duffner et al. 2012).

Late infantile form is classified by onset of symptoms between seven months and one year of age, and juvenile form is classified by onset of symptoms in one through ten year old children. Symptoms of both of these forms of Krabbe disease include decreased cognitive function, overall muscle weakness, loss of muscle control, optic nerve and muscle disintegration, and vision loss (Lyon et al. 1991).

Adolescent/adult onset (individuals experience symptoms after 11 years old) is extremely rare and progresses the most slowly—it is characterized by muscle stiffness and weakness, loss of bladder control, and occasionally paralysis. Late symptom onset is correlated with slower disease progression and increased survival rates (Duffner et al. 2012).

Krabbe Disease is an autosomal recessive diseaseIt is caused by one of several mutations in a gene called GALC, which codes for the protein galactocerebrocidase. This enzyme normally breaks down lipids called galactocerebroside, psychosine (also called galactosyl ceramide) and monogalactosyl diglyceride (MGD) into smaller, non-toxic compounds (Wenger et al., 1974). Mutations to GALC result in very low levels of functioning galactocerebrocidase in cells—this means that galactocerebroside, psychosine, and MGD are not properly or fully broken down inside the lysosomes. As a result, psychosine accumulates in the cell. Psychosine is extremely toxic to cells in the nervous system that produce myelin (Igisu and Suzuki, 1984). It causes these cells to die (Giri et al., 2006). When these cells die, they can no longer produce myelin to protect newly produced neurons—this causes neurons to undergo cell death as well. Psychosine also directly impairs existing neurons ability to transmit signals in a way that injures and ultimately kills these neurons (Castelvetri et al. 2013). The overwhelming death of neurons presents through the neurodegeneration-based symptoms previously described and ultimately leads to death (Lyon et al. 1991).

Part A of this figure depicts galactocerebroside which is normally broken down in the lysosome. Parts B and C are different molecular representations of the enzyme implicated in Krabbe Disease called galactocerebrosidase. Image Source: Hill et al. 2013
Part A of this figure depicts galactocerebroside which is normally broken down in the lysosome. Parts B,C, D,E, and F  are different molecular representations of the enzyme implicated in Krabbe Disease called galactocerebrosidase and its interactions with galactocerebroside. Image Source: Hill et al. 2013
This is the structure of psychosine, the toxic compound that causes the pathology of Krabbe Disease. Image Source
This is the structure of psychosine, the toxic compound that causes the pathology of Krabbe Disease. Image Source

Currently, there is no cure for Krabbe Disease (Duffner et al., 2009). The most successful (and predominant) therapy used is called hematopoietic stem cell transplantation—in this treatment, stem cells that develop into blood cells with normal GALC genes are injected into the patient’s body (Copelan, 2006). Research on Krabbe Disease, however, is ongoing, and several potential avenues of treatment such as the use of neural stem cells to deliver the functional GALC to the patient’s brain are being explored (Uchida et al. 2012).

Click on the following links to learn more about Krabbe Disease!

History and Metabolic Context of Krabbe Disease

Molecular Basis of Krabbe Disease

Treatments for Krabbe Disease

Proposals for Future Research

23 Replies to “Krabbe Disease”

  1. Wow, this is an interesting article on Krabbe Disease. This disease also reminds me of Parkinson’s Disease and Huntington’s Disease, could you describe a little more about the characteristics that distinguish Krabbe? I also noticed that globoid cells are characteristic to Krabbe, do these cells play a particular role in the neuron degradation?

    1. Thank you so much for your comments and for taking the time to read this page, Steph!

      I think the biggest distinguishing clinical feature that sets Krabbe apart from these other neurodegenerative diseases is the age at which Krabbe Disease usually occurs. More than 90% of all cases of Krabbe disease begin very shortly after the child is born, whereas Huntington’s Disease and Parkinson’s Disease generally occur much later in life by comparison. Otherwise, the clinical symptoms of Parkinson’s Disease and Krabbe Disease are actually fairly similar (not necessarily the biochemistry behind them though)– Krabbe Disease patients, however, do not generally suffer the same psychiatric effects at Huntington’s Disease patients.

      The globoid cells are currently thought to be a sign of the disease(the cells look the way they do because of the accumulation of psychosine and remaining galactocerebroside) rather than playing an active role in neuronal degeneration, but since these are immune cells in the brain, I would not be surprised if they perhaps render the brain more susceptible to infection. There are a few current studies trying to learn more about globoid cells, so we shall have to see what happens!

  2. Great review of Krabbe Disease! I thought the title page was very clear and understandable. You mentioned the use of stem cell transplantation to treat the disease, have any researchers tried to just destroy psychosine by producing an enzyme to degrade it or anything of this sort? Also, does psychosine play any biologically needed roles in the cell?

    1. Thank you for taking the time to read this page, Ramzy!

      Galactocerebroside is one of the major components of myelin– oligodendrocytes and Schwann cells (the cells that produce myelin in the central and peripheral nervous systems, respectively) use this compound as a building block in myelin biosynthesis. The lysosomes of these cells also break down old myelin– galactocerebrosidase is the enzyme in this metabolic pathway that has the role of breaking down galactocerebroside (check out http://www.sciencedirect.com/science/article/pii/S0092867400800938)

      As far as I have read, no one seems to have tried to produce an alternative enzyme to destroy psychosine. I think this is probably in part because you would run across the same issues as you do when attempting any kind of enzyme replacement therapy in the nervous system– efficient delivery, crossing the blood brain barrier, and the concern of causing an immune system response in the break. I also think that these obstacles (particularly efficient delivery) are magnified in Krabbe Disease because the psychosine accumulation affects so many cells in such great quantities.

  3. Nice title page! Pretty understandable. Do you know what role does galactocerebroside plays in the cell? Is it part of the cell membrane or does it do something else? Also, is psychosine specifically toxic to nervous system cells that produce myelin, or cells in general? If it does specifically target those cells, is there an explanation as to why this is the case?

    1. Thank you for taking the time to read this page, Hudson!

      Galactocerebroside is one of the major components of myelin– oligodendrocytes and Schwann cells (the cells that produce myelin in the central and peripheral nervous systems, respectively) use this compound as a building block in myelin biosynthesis. The lysosomes of these cells also break down old myelin– galactocerebrosidase is the enzyme in this metabolic pathway that has the role of breaking down galactocerebroside (check out http://www.sciencedirect.com/science/article/pii/S0092867400800938)

      Psychosine is toxic to all cells, but galactocerebroside is found almost exclusively in oligodendrocytes and Schwann cells, or the myelin producing cells of the body (the microglia in the brain being one of the exceptions), so the enzyme deficiency and subsequent psychosine accumulation occurs primarily in nervous system cells (Igisu and Suzuki 1994).

  4. You provided a great outline of the disease and it was full of detail! Despite the amount of detail, it was still very understandable to a general audience regardless of their scientific background. However, a few questions came to my mind. Like Hudson, I am also curious about the role of galactocerebroside in the cell. In addition, what is the cause of the differences in the age of onset for the different forms of Krabbe Disease?

    1. Thank you for taking the time to read this page, Radhika! Galactocerebroside is one of the major components of myelin– oligodendrocytes and Schwann cells (the cells that produce myelin in the central and peripheral nervous systems, respectively) use this compound as a building block in myelin biosynthesis. The lysosomes of these cells also break down old myelin– galactocerebrosidase is the enzyme in this metabolic pathway that has the role of breaking down galactocerebroside (check out http://www.sciencedirect.com/science/article/pii/S0092867400800938)

      The reason for different ages of onset is not fully understood. There are many different types of mutations in the GALC gene– some of the mutations seem to be almost exclusively associated with particular ages of onset, but the correlations are not perfect (check out doi: 10.1093/hmg/ddt190).

  5. Very clear! The order in which you put the information is highly effective and informative to the reader and easy to follow. As a matter or formatting, I would maybe split up the types (early infantile, adolescent, etc.) into multiple paragraphs just because that one paragraph is really long. But overall, solid job!

    1. Thank you so much for taking the time to read this page, Mary! I took your advice and split the forms of the disease into multiple paragraphs. I really appreciate your feedback!

  6. Very good article and clear. I now have a better understanding of the disease. Are there areas in the world where the disease is more prevalent? Are there any tests or ways to understand if you have a higher probability of having a child with the disease?

    1. Thank you for taking the time to read this page, Byron!

      The Druze population in Northern Israel and the Muslim Arab populations surrounding Israel historically have higher rates of Krabbe disease than do other populations (up to 1 in 130 individuals). In case you want to read more about these populations, here is the article where I found this information! http://europepmc.org/abstract/MED/2010272

      Krabbe Disease is a genetically inherited disease, so parents could meet with a genetic counselor to assess the likelihood of their future child getting the disease based on any family history of the disease and based on blood tests to see if either or both parents carry one mutant copy of the GALC gene and to see if either of the parents have low levels of the galactocerebrocidase due to a mild genetic mutation.
      This genetic analysis is slightly complicated because there are lots of different ways the GALC gene I discussed above can be mutated and it isn’t easy to test all of the mutations. Another complicating factor is that even if a child is born with two copies of the mutation, the disease still might not ever manifest itself.

      For more information on on testing for Krabbe disease before conceiving a child, check out this MedLine Plus entry (http://www.nlm.nih.gov/medlineplus/ency/article/001198.htm) or this article (http://www.nature.com/gim/journal/v12/n9/full/gim201089a.html)!

      I hope this response answers your questions! Thank you again for reading the page!

  7. I feel as this title page is extremely well written and very accessible to a non-science person. I noticed you spelled Psychosine as psychsoine once in the third paragraph. I feel like there is a lot of detail in the second section and it would be helpful to split it up as previously suggested. I would also try to make the second image a little bigger because it is very difficult to see. I had no idea what Krabbe disease was prior so I found this title page very interesting. I personally think it would be helpful to identify the biochemistry of the disease first then lead into the 4 types of diseases because at the end of the biochemistry based paragraph you demonstrate that it causes neurodegeneration and that would be a good transition to the different types of the disease related to age. That would result in a clear transfer from the biochemistry to the phenotypes. That is just a suggestion, definitely sounds great as it is. Also, what is the conection between the globloid cells and the biochemistry. That connection could be interesting. Great title page. Very Very clear and interesting to read.

    1. Thank you for taking the time to read this page and provide feedback, Ian! I fixed the psychosine typo. The globoid cells actually are a result of the galactocerebrosidase deficiency rather than a primary cause of disease pathology. Globoid cells are microglia (macrophages in the brain) that assume the very irregular shape of globoid cells because of the large amount galactocerebroside and psychosine accumulating in them (check out http://jcb.rupress.org/content/153/2/429.full). This unique cell phenotype only occurs in patients with Krabbe . disease and is used as part of the diagnostic process. My thought process (although to my knowledge, this idea has not yet been tested) is that the presence of these now dysfunctional macrophages could render the brain more vulnerable to infection.

  8. This page is extremely well done and super easy to follow! I particularly liked how you started off explaining what types of ways the disease affects a person and then what causes the problems themselves. It made it much easier for me to visualize the connection between the cause of the disease and the symptoms by picturing the problems you talked about. Great job!

    1. Thank you so much, Morgan! I appreciate you taking the time to read my page!

  9. Nice! Great overview of the disease. It’s easy to understand for those in the sciences and is made accessible to those who are unfamiliar with these topics. Maybe it would be helpful to break up the paragraphs with headings to help guide your reader?

    1. Thank you, Erin! I think splitting up the sections on the forms of Krabbe disease is a good idea!

  10. Really interesting and informative page! As a high school student who has only had experience in Biology, I was able to understand almost everything on this page and, if I didn’t understand something, it tended to have a hyperlink to another page that would help me figure it out. Well done!

    1. Thank you so much for your comments, Zach! I really appreciate you taking the time to read my title page!

  11. Excellent! I really enjoyed the article, I think it was well written and informative, while at the same time very easy to understand. The lay out is logical and I liked how you divided it up into sections to discuss the various forms of the disease. The figures are very cool (and handy for understanding the biology of the disease) and the hyperlinks to papers and websites is brilliant! Thank you for the opportunity to comment on your page!

    1. Thank you so much for taking the time to read this page and for commenting, Bri!

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