Syeda Areeba Fatimasf1073@wildcats.unh.edu

Abstract


Wilson’s Disease (WD) is an autosomal recessive disease that is caused by a mutation in the ATP7B gene. This results in the accumulation of copper in the liver, brain, and eyes.

Research question(s)
1. Are there better diagnostic techniques for Wilson's Disease?
2. Is there a permanent cure for Wilson's Disease?

Basic method of investigation: The literature research regarding Wilson’s disease was made with the help of National Center of Biotechnology Information (NCBI). Various bioinformatic tools were used to study more about the gene and protein related to Wilson’s disease such as: BLAST, MEGA, and STRING.

Implication/future work:

  1. Main findings are that WD is normally diagnosed using routine mutation analysis, however MLPA analysis is thought to be much better.
  2. WD is usually treated with copper chelator drugs, which is not a permanent cure. There are some studies that have suggested that WD can be permanently cured with cell therapy.


Background


Wilson's disease (WD) is an autosomal recessive genetic disease caused by mutations in the ATP7B gene that makes a transporting protein ATPase (Todorov, 2016 & Cater 2004). The mutation in ATP7B usually includes insertions, deletions, and frame shifts of base pairs that make a faulty protein which is not able to transport copper properly (Chen, 2015). In a normal functioning hepatocyte (liver cell) that does not contain the ATP7B mutation, excess copper is filtered by the liver and released into bile, a fluid made by the liver to excrete metabolic waste. The ATP7B mutations in the hepatocytes lead to copper accumulation in the tissues and organs such as brain, liver, and eyes. This accumulation of copper can become toxic, leading to neurological disorders such as fine motor skills disorder, hallucination, schizophrenia, dystonia, tremor, and cognitive and mood disorders (Günther, 2009). WD can also cause anemia, skeletal muscle disorder, and liver cirrhosis which may lead to edema and fatigue.

wilson.jpg
Image obtained from Dr. Tind's article on Wilson's Disease. This image is used with his permission. URL
http://www.drthindhomeopathy.com/disease/wilsons-disease/

Symptoms

The symptoms of WD vary depending on the organ most affected by the disease. As we know, WD mostly affects the liver, and brain.

Liver related symptoms

Accumulation of copper in the liver can cause nausea, fatigue, loss of appetite, weight loss, swelling caused by edema usually around the ankles, and spider like blood vessels. These symptoms are very common and it is hard to distinguish them as WD symptoms. Therefore, WD often goes unnoticed and can cause liver cirrhosis or liver failure as the disease progresses.

Brain related symptoms

The brain related symptoms occur after the liver has already accumulated a lot of copper, which include tremors, muscular stiffness, and problems with speech. Some symptoms might also include neurological problems such as personality changes, psychosis, schizophrenia, and depression.

Other Symptoms

Due to WD copper accumulation in the eyes, Kayser-Fleischer rings can result. This is a very unique WD symptom.
Kayser-Fleischer_Ring_WDA.jpg
Image obtained from National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.
Retrieved from: https://www.niddk.nih.gov/health-information/liver-disease/wilson-disease



Diagnosis


The symptoms of WD are very common and often shared with other diseases, which poses difficulty in diagnosing WD. Some of the common methods of diagnosis are blood tests, urine tests, and physical exams. In the blood and urine test, the increase in concentration of copper can help determine WD. In some WD patients, copper accumulation in the brain leads to the development of a “rusty” ring around the iris, which is called a Kayser-Fleischer ring. This could be observed during a physical exam. The results of these tests are only conclusive after a substantial amount of damage has already occurred to the liver due to copper accumulation.


DNA sequencing has been shown as a more reliable diagnostic tool than the methods mentioned previously. DNA is sequenced using routine sequencing such as shotgun sequencing, and sanger sequencing as better methods for diagnosis. However, the mutations of the disease can be difficult to identify. WD related mutations are usually not detectable by routine sequencing. There is also a wide range of mutations among people of different origins, making it hard to have one standard procedure to identify the mutation and diagnose WD (Todorov, 2016 & Chen, 2015). However, recent breakthroughs have improved the detection of WD related mutations.


Treatment


There is no permanent cure for WD. The patients are prescribed lifelong medications of copper chelators that bind with excess copper and excrete it through urine. The patients are asked to watch their diet, and are advised not to eat foods that are rich in copper content such as: shellfish, liver, and nuts. These treatments help in stabilizing the copper content in the body, but they do not provide a permanent cure. Cell therapy provides hope for the development for a permanent cure for WD.

Research Questions:

1. Are there better diagnostic techniques for Wilson's Disease?
2. Is there a permanent cure for Wilson's Disease?

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