Infantile Tay-Sachs Disease

This image displays the fundamental difference in the nerve cell between a healthy individual and one affected with Tay-Sachs disease. The healthy individual is able to degrade and remove the ganglioside while the affected individual is unable to remove the ganglioside, allowing for the accumulation of it and the eventual death of the nerve cell.
This image displays the fundamental difference in the nerve cell between a healthy individual and one affected with Tay-Sachs disease. The healthy individual is able to degrade and remove the ganglioside while the affected individual is unable to remove the ganglioside, allowing for the accumulation of it  in the lysosome and the eventual death of the nerve cell.

Tay Sachs Disease (TSD) is a rare recessive genetic disorder that results in the neurodegeneration of the central nervous system. TSD is categorized as a type of GM2 gangliosidosis, which indicates that the pathology of the disease is due to the accumulation of the GM2 ganglioside inside neuronal lysosomes because of either the lack of the functional enzyme responsible for their degradation or presence of a non-functional enzyme in the lysosome. There are varying degrees of severity of TSD: late-onset is the least severe and can manifest anytime between late-childhood into adulthood, juvenile or subacute developing between 2 and 10 years of age and resulting in death around 12 to 15 years of age, and lastly infantile being the most severe, always resulting in death within 4 years of age (Gravel et al. 2001). Recent statistics indicate that there is a 1 in 27 carrier rate in Ashkenzai Jewish, the French-Canadian, and Cajun population in Louisiana while the carrier rate is about 1 in 250 in the the population as a whole (National Tay-Sachs and Allied Diseases). Currently there are no effective cures for TSD; however three techniques are being developed as a way to combat the disease: enzyme replacement therapy (which is focused on re-introducing the functional enzyme), gene therapy (which is focused on re-introducing the functional gene), and substrate reduction therapy  (which is focused on reducing the accumulating substance responsible for the disease) (Cox 2012).

Infantile TSD
is characterized by reversal or loss of motor movement within the first
year of development, an abnormal startle response, and low muscle tone (Bley
et al. 2011
). Affected infants appear normal at birth with the earliest symptoms manifesting around 3 to 5 months of age. According to Gravel et al., there is
progressive weakness that is associated with poor head control, loss of
developmental motor skills or failure to achieve developmental milestones
such as crawling or sitting unsupported, seizures, and a lack of awareness of
the child’s surroundings. Within the second year, the child will have
difficulty swallowing, increased seizure activity and eventually a complete
lack of awareness of his/her surroundings. Death is typically within the first
two to four years of life and is caused by aspiration pneumonia, a type of pneumonia that is commonly caused by the colonization of bacteria in the lungs after food has fallen into the lungs, which typically arises because of the weakening of the muscles (Marik, 2001).

This figure shows the accumulation of the GM2 ganglioside of concern in the nerve cells of the spinal cord. The ganglioside was detected using an anti-GM2 monoclonal antibody. Source: Huang JQ, Trasler JM, Igdoura S, Michaud J, Hanai N, Gravel R. “Apoptotic Cell Death in Mouse Models of GM2 Gangliosidosis and Observations on Human Tay-Sachs and Sandhoff Diseases.” Hum Mol Genet. 1997(6): 1879 – 1885.
This figure shows the accumulation of the GM2 ganglioside of concern in the nerve cells of the spinal cord. The ganglioside was detected using an anti-GM2 monoclonal antibody, a molecule that is able to identify and tag other specific molecules. Source: Huang JQ, Trasler JM, Igdoura S, Michaud J, Hanai N, Gravel R. “Apoptotic Cell Death in Mouse Models of GM2 Gangliosidosis and Observations on Human Tay-Sachs and Sandhoff Diseases.” Hum Mol Genet. 1997(6): 1879 – 1885.

The genetic mutation responsible for the manifestation of the disease is in the HexA
gene, which encodes for the α-subunit of the β-hexosaminidase A enzyme, also known HexA. There are two major isozymes of β-hexosaminidase, HexA and HexB, with HexA being responsible for the breakdown of the GM2 ganglioside and no known physiological function for HexB (Okada and O’Brien 1969); therefore a mutation that renders the HexA enzyme less effective or ineffective results in the accumulation of the GM2 ganglioside in the lysosome, which results in neurodegeneration of the nerve cells of the central nervous system through the stimulation of the inflammation response which leads to a form of regulated cell death known as apoptosis. Studies of the mutations correlated to the infantile form of TSD find that the mutation typically results in a non-functional HexA enzyme, allowing for the immediate accumulation of the ganglioside and the rapidly progressing nature of the disease.  Due to the genetic nature of the disease, it has been demonstrated that this disease is much more common in the Ashkenazi Jewish population. However, recent research shows that the disease is becoming more common in certain populations including French Canadians and Cajuns; therefore, means of screening for the disease must break the conventional method of screening and expand to looking for genetic mutations outside of those that are specific to the Ashkenazi Jew population (Hoffman et al. 2013).

The strategies being developed to combat the disease are, as previously mentioned, enzyme replacement therapy/gene therapy and substrate reduction therapy. There have been limitations to both approaches, specifically the delivery of the enzyme or the inhibitory molecule to the central nervous system (CNS) and the brain. Delivery of the therapy to the brain is especially difficult because of the blood-brain-barrier. There has been new research in development that may be more successful at delivering the molecule to its intended target via the use of viruses (Guidotti et al. 1999; Martino et al. 2005) or possibly utilizing chaperones to regulate the folding and transport of the enzyme to the lysosome (Boyd et al. 2013). Therefore, methods of screening and treating the disease are important because of the broad spectra of population it affects.

For more information, check out the following links:

History and Metabolic Context of Tay – Sachs Disease

The Molecular Bases of Tay – Sachs Disease

Disease Management and Treatment for Tay – Sachs Disease

Conclusions and Proposals

11 Replies to “Infantile Tay-Sachs Disease”

  1. I think the links you provide are very effective because they allow your readers to get more information without you having to make your entry too long. However, it might be beneficial for you to add a few more, especially for the last section where you write about strategies to combat the disease. It wasn’t quite clear to me how each of the therapies works.
    I also really appreciate the image that you provide. It does a good job of illustrating what you are describing.

    1. Thank you for your comment! I have added in new links to the definitions. If you feel that there are more to be made, feel free to let me know!

  2. This is a very informative review! I think adding primer definitions to words such as mutation, enzyme, isozyme, chaperone, and blood-brain-barrier might help make especially the last two paragraphs a little more accessible. Though you provide primer links to enzyme replacement therapy and substrate reduction therapy, it may be helpful to have a sentence explaining the general concept of attempting to treat the disease by either providing functional enzyme to the patient or by blocking accumulation of the toxic metabolite.

    I am really intrigued by the idea of substrate reduction therapy. Does this mean inhibiting an enzyme in the biosynthesis pathway that produces GM2 in the first place? What is GM2’s function in the cell? I can appreciate the necessity of avoiding overproduction of GM2, but it just seems to me that if we are producing GM2 frequently, it likely serves a physiological purpose– is there any concern in the literature about the ramifications of inhibiting its production altogether? Also, is there any worry about the broader implications of knocking down another enzyme in an already enzyme-deficient cell?

    1. Thanks for the feed back. I posted a comment kinda explaining everything before I realized that there was a reply button. Plus by the time that I got around to replying, there had been similar questions being asked so I thought that I would just get it out of the way in one go.

      However, if you still have questions that need to be addressed in the front page, let me know. I know that I’m going to cover a lot of these questions in the following pages of the website.

  3. Great, very clear review. I agree with adding a couple more links to the primer page. Additionally, perhaps some more information about what a lysosome is, and why it is so crucial that GM2 does not accumulate in it could be very helpful. I was wondering what role does the other isozyme of HexA play? Is it possible that this isozyme could have a potential therapeutic role if its activity can be modified in such a way that it also degrades GM2? Thanks!

    1. Thanks for the feedback! I didn’t realize that there was a reply button before I posted a comment answering your questions, so there is a large comment at the bottom of the page by me that addresses all of the questions I received in one go (I hope it did).

      However, if you have more questions, definitely feel free to ask.

  4. This is a great review. Rebecca covered most of my concerns in her first paragraph. Definitely explain in as few words as possible how the two different therapies work. Definitely create a primer for isozyme and if it’s already created, just link it to the primer page, but also write a quick blurb about what and isozyme is. Also, I don’t think you ever explicitly say the the B-hexosaminidase A is located in the lysosome. That would help explain how GM2 builds up. And a couple of words of about what a lysosome does would be helpful too. Even something like “it’s basically a cellular trash can”.

    You also quickly mention that the death of infants happens within a couple of years and is caused by pneumonia. Why pneumonia? How is it related to TSD?

    Also maybe explain a little bit about how the build up of GM2 causes neurodengeneration. Link the blood-brain-barrier to the primer page and explain a little bit why it presents a problem for treatments.

    1. Thanks for the feedback Dom. I posted a comment answering everyone’s questions and attempting to get to concerns in one go just below. If you have anymore questions, feel free to let me know.

  5. As someone who knows next to nothing about cell biology or their functions, I could follow this summary. Some terms required a quick search but overall the explanation flows logically. The basic processes and affects on children are well explained and the complexity of treating such a disease is represented.
    Overall, a solid page; however, some of the language can come off a bit dense for the uninitiated towards the end.

    1. Thanks for the feedback. I will definitely add in more definitions toward the end!

  6. I am going to attempt to answer everyone’s comment and questions in this one comment. Therefore, if I don’t explicitly answer your question, feel free to point that out and I will definitely answer it.

    Concerning ganglioside function and the ganglioside connection to neurgodegeneration:
    The function of gangliosides, as a whole, is cell-to-cell communication. They are typical compounds with the plasma membranes and the highest ganglioside content is found in the gray matter of the brain and the neuronal plasma membrane. Since they are part of the plasma membrane, it would make sense that they are involved in cell-to-cell communication and have been demonstrated to be involved in cell differentiation. I think this may start to answer your question Dom about why GM2 ganglioside accumulation results in neurodegeneration. With the accumulation as the disease progresses, it has been found that the lysosomes balloon up, which eventually leads to abnormal wiring of the neuronal circuits. There is also an increased number of apoptotic cells with the increased numbers of swollen lysosomes, most likely because the cell triggers its own death due to the loss of function of the lysosomes with the ballooning; however, the latter half of the sentence is just speculation on my part for now. There is most likely literature out there that may have the answer, but I would need to find it and read up on it.

    Concerning substrate reduction therapy:
    The idea behind substrate reduction therapy is to inhibit the biosynthesis of the ganglioside in order to prevent the eventual accumulation of the GM2 ganglioside. There have been concerns about preventing the accumulation to begin with considering that it plays a role in cell-to-cell communication. However, the use of substrate reduction therapy has been successful in alleviating the symptoms on Gaucher’s disease, which is also a lysosomal storage disorder very much like TSD. Initial studies, as I will discuss within the context of the website, show that this hasn’t been very successful for TSD because of the fact that the problems associated with TSD stem from the brain. Gaucher’s disease stems from the spleen. Drug administration to the brain is much more difficult compared to delivery to the spleen. So, since there have been positive experiences with the use of substrate reduction as a method of treating a lysosoma storage disorder, the results can’t be exactly predicted when the diseases lie in very different parts of the body. I will look into how successful substrate reduction has been in Gaucher’s and use that information to form conjectures about how it might function within TSD.

    Concerning the isozymes of B-hexosamindase:
    I need to rephrase the way I explain HexA and isozymes. HexA and HexB are isozymes of beta-hexosaminidase. I will explain more about the difference in structure, but basically it is that HexA is composed of a alpha-subunit and beta-subunit while the HexB enzyme is a homodimer of the beta-subunit. The hexosamindases are capable of hydrolyzing a broad spectrum of substrates, but the biggest difference between the two is that HexA is able to hydrolyze negatively charged substrates, such as the GM2 ganglioside, and neutral substrates while HexB is only capable of neutral substrate degradation. HexA is also able to bind to the GM2 Activator Protein, which delivers the ganglioside to the enzyme. Also, due to the composition of the individual enzymes, there is a different in pH tolerance, which HexB being retaining a higher stability in a wider range of pHs and temperature. Therefore, there have been studies in which scientist desired to generate a recombinant HexB, which can retain its stability and is able to bind to the GM2 Activator Protein-GM2 ganglioside complex. However, there hasn’t been any success in determining which residues are important to the activator protein-ganglioside complex at the moment and is something that needs to be explored.

    Concerning TSD and pneumonia:
    From my findings, patients with Tay-Sachs often develop problems with their lungs and airways because of the progressive muscle weakness that is associated with the disease. With this decreased muscle weakness, food and liquid can fall into the lungs, resulting in an infection called aspiration pneumonia. However, at the moment, I have not read much on this topic and will provide further information as I find it.

    Concerning definitions:
    Thanks! I will definitely add some more definitions and add the links.

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