November 2020 Case Competition: Winning Abstract #2

Zellweger syndrome is a lethal disease that tends to result in death within the first year of the infant’s life (Heymans et. al., 1983). Common signs and symptoms of Zellweger syndrome include abnormal facial features such as a bulging forehead, upslanted eyes and a broad nose bridge. Zellweger syndrome is an autosomal recessive disorder that occurs due to mutations in peroxins, a protein that helps make up the peroxisome organelle. This disorder can occur due to a mutation in any of the 12 genes that encode peroxins. However, over 70% of individuals diagnosed with Zellweger tend to have a mutation in the PEX1 gene. When these mutations occur, peroxisomes are unable to assemble and cannot maintain their normal function of breaking down organic molecules, such as fatty acids. This leads to the accumulation of both long fatty acid chains and branched fatty acids, which are hallmarks of Zellweger syndrome (Shimozawa et al., 1992).

Currently, the treatment options for Zellweger syndrome are limited to the reduction of symptoms and managing the symptoms of the condition (“Zellweger Syndrome Information Page”, n.d.). Difficulties in treatment mainly arise as the abnormalities and symptoms of Zellweger syndrome begin during fetal development. Treatment is limited to correct these abnormalities after birth (Schutgens et al., 1987). A recent study by the Hospital for Sick Kids, is now testing the potential of the FDA-tested drug Hydroxychloroquine or Chloroquine to treat Zellweger’s. The drug works to inhibit peroxisome degradation and improve peroxisome function. This will alleviate symptoms, improve life expectancy, and create a better quality of life (“Malaria drug may help kids with rare genetic disorder, SickKids study finds”, 2017).

The risk of inheriting Zellweger syndrome varies depending on one’s geographical location. The risk in the United States is currently 1 in 50,000 newborns while the risk in Quebec is 1 in 12 newborns (“Zellweger Syndrome Information Page”, n.d.). The prevalence of Zellweger is especially high in Quebec due to a founder effect of 5 unrelated cases of a mutation in the PEX6 gene between 1990 and 2010 (Levesque et al., 2012). The PEX6 gene is a founder gene of Zellweger syndrome which is involved with 10-16% of Zellweger cases (Levesque et al., 2012). Currently, there is not a lot of specific data about the prevalence of Zellweger in different countries or in Canada as a whole, however, this will soon be available as more countries are implementing X-ALD scans in newborns (Klouwer et al., 2015).

Currently, Zellweger syndrome is most commonly diagnosed by either a blood or urine test, which can detect elevated levels of certain substances. For example, a blood test is able to detect elevated fatty acid chains, which can be used in the diagnosis of Zellweger syndrome (Zellweger Spectrum Disorders, 2008). Alongside this, an ultrasound can also be used to check for cysts on the kidneys or an enlarged liver. Lastly, a genetic test can be used to search for a mutation in one of the genes associated with Zellweger syndrome to confirm the diagnosis (Steinberg et al., 2012).

Abbira Nadarajah, Gurleen Chahal, Ishman Fervaha, Jill Shah

---

References

Heymans, H. S., Schutgens, R. B., Tan, R., van den Bosch, H., & Borst, P. (1983). Severe plasmalogen deficiency in tissues of infants without peroxisomes (Zellweger syndrome). Nature, 306(5938), 69-70.

Klouwer, F. C., Berendse, K., Ferdinandusse, S., Wanders, R. J., & Engelen, M. (2015). Zellweger spectrum disorders: clinical overview and management approach. Orphanet journal of rare diseases, 10(1), 151.

Levesque, S., Morin, C., Guay, S. P., Villeneuve, J., Marquis, P., Yik, W. Y., ... & Dewar, K. (2012). A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population. BMC medical genetics, 13(1), 72.

Malaria drug may help kids with rare genetic disorder, SickKids study finds. (2017, March 27). Retrieved November 13, 2020, from http://www.sickkids.ca/AboutSickKids/Newsroom/Past-News/2017/malaria-drug-kids-rare-genetic-disorder.html

Schutgens, RBH et al. (1987). Zellweger Syndrome: Biochemical Procedures in Diagnosis, Prevention and Treatment. J. Inher. Metab. Dis, 10 (1), 33-45.

Shimozawa, N., Tsukamoto, T., Suzuki, Y., Orii, T., Shirayoshi, Y., Mori, T., & Fujiki, Y. (1992). A human gene responsible for Zellweger syndrome that affects peroxisome assembly. Science, 255(5048), 1132-1134.

Steinberg, S, J., Raymond, G.V., Braverman N.E., & Moser A.B. (2012). Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum. GeneReviews, 15(2), 83.

Zellweger Spectrum Disorders. (2018). NORD.

Zellweger Syndrome Information Page. (n.d.). Retrieved November 13, 2020, from https://www.ninds.nih.gov/Disorders/All-Disorders/Zellweger-Syndrome-Information-Page

Cite This Article:

Nadarajah A., Chahal G., Fervaha I., Shah J., Pham E. November 2020 Case Competition: Winning Abstract #2. Illustrated by Z. Hasan. Rare Disease Review. January 2021. DOI: 10.13140/RG.2.2.16500.99204