Treatment

As mentioned in previous posts, Menke's Disease (MD) is a disease that is caused by the disregulation of copper because of a faulty ATP7A gene. There is currently no cure, but the injection of copper-histidine has been identified as a replacement treatment to prevent death, reduce neurological damage and improve symptoms associated with MD (National Institutes of Health, 2016). Those who are diagnosed swiftly and those who have retained some ATP7A function, have the best outcome. While those who have had a delay in diagnosis and those who have a complete loss-of-function of ATP7A may not respond at all to copper-histidine treatment (Kaler et al., 2008).

Since this project is for a Health Care Genetics course, I'd like to discuss some treatments that may be possible in the future. Current MD advances have not established a cure, but treating the genetic cause may offer a cure.

Nonsense mutations make up about 18% of the ATP7A mutations involved in MD (Moller et al., 2009). There are 3 stop codons: UAG, UAA and UGA. A nonsense codon is a stop codon that is prematurely in a position of the RNA that halts the complete translation of a protein. The product is a truncated form of the functional version (Nussbaum, et al., 2016). There are drugs being developed that allows the translational apparatus to misread the stop codon and skip it so that translation does not stop. The product is a protein that is full in length (Nussbaum, et al., 2016).

Gene therapy has been at the for-front of genetic medicine, and those who have been affected by MD are anxiously awaiting gene therapy as a cure. Because this is a recessive gene that causes loss-function of the ATP7A receptor, gene replacement could be an option. If someone could figure out how to introduce the ATP7A gene into a newborn who has MD, then MD could be cured.

Because the ATP7a gene is only 4,500 bp long, using an adeno-associated virus(AAV) could be used as a vector to introduce the fully functional ATP7A gene in to a person with MD. AAVs do not elicit a strong immune response and therefore do not get destroyed easily by the human immune system. An AAV is able to infect dividing and non-dividing cells, and is therefore a good choice for MD because it is important that the ATP7A gene is expressed inside of all neurons. DNA transfer into cells using viral vectors are associated with risks such as an adverse immune response, mutations causing malignancy, and inactivation of another gene. Because MD is a fatal disease, many would agree that gene therapy would offer a favorable risk to benefit ratio.

Here is a video that illustrates how an AAV introduces a gene into a cell:

(Uniqure, 2017)

References

Kaler, S., Holmes, C.S., Goldstein, D.S., Tang, J., Godwin, S.C., Donsante, A... Patronas, N. (2008, February 7). Neonatal diagnosis and treatment of Menkes disease. The New England Journal of Medicine, 358(6), 605-614. Retrieved from 
http://dx.doi.org.sunypoly.idm.oclc.org/10.1056/NEJMoa070613

Moller, L.B., Mogensen, M., & Horn, N. (2009, October). Molecular diagnosis of Menkes disease: Genotype-phenotype correlation. Biochimie, 91(10), 1273-1277. Retrieved from 
https://doi.org/10.1016/j.biochi.2009.05.011

Nussbaum, R. L., McInnes, R. R., & Willard, H. F. (2016). Genetics in medicine. Philadelphia, PA: Elsevier.

Uniqure. (2017, July 7). How AAV gene transfer works - General audience [Video File]. Retrieved from https://www.youtube.com/watch?v=SUOskEqLpyY