Genetic Disorders: Wilson’s Disease

Medicine and Health

Introduction

Wilson’s disease (WD) is an uncommon autosomal recessive inherited disorder that is characterized by a copper imbalance in the body. Although copper is essential for the survival of living organisms, an excessive cellular copper load can lead to functional failure or death of the cell. WD impedes the normal biliary excretion of copper leading to itsaccumulation in various organs (Merle et al. 2007). Copper-transporting P-type ATPase (ATP7B) in hepatocytes transport copper from intracellular chaperone proteins to their designated secretory pathway. ATP7B is encoded by the WD gene, MIM 277900, hence its mutation results in a WD diagnosis (Ferenci, 2005). The accumulation of copper in organs such as the liver and brain results in the development of hepatic diseases such as liver cirrhosis and neuropsychological degeneration. The estimated frequency of WD is about 17 per million which translates to a carrier frequency of 1 in 122 (Lorincz, 2010).  

Disease Inheritance 

A study was conducted in the United Kingdom (2013) in an attempt to identify the rate of mutations in the WD gene ATP7B. 181 individuals with a confirmed WD diagnosis underwent genetic testing to determine the potential of non-ATP7B gene mutation causing the disease. According to the study, 116 different ATP7B mutations were identified and the overall chance of a mutation in a gene other than ATP7B causing a WD phenotype is very low due to the detection frequency of the specific mutation being 98% (Coffey et al, 2013). The study supplied strong confirmation for monogenic inheritance of WD, where traits for the disease are determined by single gene or allele expression and highlighted the need to consider rare genetic occurrences in clinical practice such as the presence of three mutations of the ATP7B gene or uniparental disomy.

Clinical Manifestations: 

Patients with WD most commonly present with hepatic and neuropsychiatric symptoms. Considering clinical manifestations peak at around seventeen years of age, children often present asymptomatically. This means that accurate diagnosis is more difficult in children than in adults. Signs and symptoms of WD can be categorized into four categories: hepatic, neurologic, psychiatric and other. Hepatic symptoms include, but are not limited to, liver cirrhosis, active hepatitis with fibrosis andabnormal results on a liver function test. Neurologic and psychiatric symptoms include, but are not limited to, tremor, ataxia, dystonia, dysarthria epilepsy, cognitive impairment, dysphagia, mood and/or personality disorders, choreoathetosis, hallucinations and delusions (Loudianos et al, 2014). The most common symptoms relating to the eyes include Kayser-Fleischer ring and Sunflower cataracts, relating to fertility include infertility and amenorrhea, relating to the kidneys include tubular dysfunction, relating to the heart include cardiomyopathy and arrhythmias and relating to other organs include gallstones and endocrine disturbances (Loudianos et al, 2014). 

​Kayser-Fleischer rings are considered the hallmark of WD and are present in 95% of patients that present with neurological manifestations (Rodriguez-Castro et al, 2015). Dysarthria is present in relatively 85-97% of individuals with Wilson’s disease and is characterized as weakness, paralysis or damage to/in the muscles used for speech (Lorincz, 2010). WD tremors are also common and may be difficult to differentiate from essential tremors which can involve the arms, legs and head. Considering essential tremors often involve voice and symmetry, differentiating them from WD tremors can be easier when looking for asymmetric tremors in the extremities and voice tremors (Lorincz, 2010). Face of the panda is commonly found in midbrain MRI images of patients with WD which is due to a loss of intensity in the center of the midbrain. Liver disease is not as easily linked to WD as neurological manifestations. Manifestations of WD in the liver range from isolated biochemical abnormalities with no accompanying symptoms to cirrhosis of the liver. According to the European Association for the Study of the Liver (2012), Hepatic manifestations have an earlier onset than other types of symptoms and can precede neurological symptoms by as much as 10 years.

Diagnosis:

There are many ways in which a WD diagnosis can be made. Providers look for common manifestations—such as the ones presented above—and may perform diagnostic tests. Common diagnostic tests include serum ceruloplasmin, serum-free copper, 24-hour urinary copper, hepatic copper and slit lamp examination of Kayser-Fleischer rings (Bandmann et al, 2015).Ceruloplasmin carries copper in the blood and its levels are below the normal range in patients with active or neurological WD. The combination of liver disease and a decrease in ceruloplasmin levels in the blood may cause serum-free copper levels to rise. For this reason, the concentration of serum-free copper may be used as a diagnostic tool for WD (Bandmann et al, 2015). Urinalysis is perhaps the easiest of all tests to perform and it analyzes the quantity of copper excreted in a 24-hour period. Elevated levels, especially in patients without cholestatic liver disease, is an indication of WD. 

Unfortunately, due to the potential for false positives, the diagnostic tests used for a WD diagnosis are not reliable in isolation. For example, low ceruloplasmin levels may indicate a WD diagnosis but may also present as a consequence of an alternate condition such as malabsorption (Lorincz, 2010). For these reasons, one test alone is unable to provide sufficient evidence to confidently diagnose WD. As a result, most providers use an amalgam of tests, signs and symptoms in the diagnostic workup process and consider the possibility of false positives. A less common, yet more accurate, type of diagnostic test is genetic testing. In the past, direct genetic testing for ATP7B was restricted due to the low detection of mutation and extended processing time (Bandmann et al, 2015). The advancement of technology has allowed for the reduction of both the turnaround time and the cost of genetic investigations making it highly likely for this type of testing to play a more critical role in the confirmation of a WD diagnosis in the future.

Disease Treatment and Management:

​Early treatment (prior to symptom manifestations) can prevent liver and neurological deterioration as well as increase the life expectancy of an individual suffering from WD (Rodriguez-Castro et al, 2015). If treatment compliance is adequate, the prognosis of a WD diagnosis is highly favorable compared to the natural course of the disease which is characterized by an implacable deterioration of both neurological organs and the liver. Therefore, the main goals of treatment are to prevent the onset of symptoms and clinical deterioration. In severe cases, such as with acute-chronic liver failure or end-stage liver disease, treatment can be lifesaving and often involves a liver transplant. 

Asymptomatic patients are treated with zinc salts and chelators at a lower dosage than symptomatic patients. Chelators such as penicillamine, trientine or tetrathiomolybdate remove excess copper in the body and zinc salts prevent the absorption of copper in the intestines (Rodriguez-Castro et al, 2015). Due to the rare nature of WD, current pharmacological studies and clinical trials have not been performed on drugs used to treat the disease. As a result, most of the current drugs available to treat WD have not been adequately tested for their effectiveness and potential adverse effects, and they lack registered clinical trials, research projects or networks. 

A multitude of drugs are available and used to treat WD. As mentioned, D-penicillamine, trientine, tetrathiomolybdate and dimercaprol are common chelators used to rid the body of excess copper, and zinc salts block intestinal absorption of copper. D-penicillamine and trientine both promote the excretion of copper through urine and their absorption is maximized when administered one to three hours prior to meals (Ferenci, 2005). Tetrathiomolybdate is a decoppering agent that prevents the absorption of copper in the GI tract (similar to zinc) and makes copper in circulation unavailable for uptake. Zinc increases metallothionein action in the gastrointestinal tract. Metallothionein is more sensitive to copper than it is to zinc; as a result, zinc increases the binding of copper to metallothionein and prevents its entrance into circulation (Ferenci, 2005). 

The most important factor in determining the prognosis of a WD diagnosis is the time frame for onset of symptom manifestation. Patients with hepatic symptoms have earlier onset of symptoms and a faster diagnosis compared to patients that present with neuropsychiatric symptoms (Merle et al, 2007). In diagnosing asymptomatic or younger patients, family screening has shown evidence of being highly effective in early diagnosis—roughly 4 years sooner and a good long-term outcome. In addition to the onset of symptom manifestation, positive prognosis is dependent on patient access and compliance to treatment (Merle et al, 2007).

References

Bandmann, O., Weiss, K. H. & Kaler, S. G. (2015). Wilson’s disease and other neurological 

copper disorders. The Lancet Neurology, vol. 14(1): 103-113. https://doi.org/10.1016/S1474-4422(14)70190-5

Coffey, A. J., Durkie, M., Hague, S., McLay, K., Emmerson, J., Lo, C., Klaffke, S., Joyce, C. J., 

Dhawan, A., Hadzic, N., Mieli-Vergani, G., Kirk, R., Allen, E., Nicholl, D., Wong, S., 

Griffiths, W., Smithson, A., Griffin, N., Taha, A., Connolly, S., Gillett, G. T., Tanner, S., 

Bonham, J., Sharrack, B., Palotie, A., Rattray, M., Dalton, A. & Bandmann, O. (2013). A genetic study of

Wilson’s disease in the United Kingdom. Brain, vol. 136(5): 1476-1478. https://doi.org/10.1093/brain/awt035

European Association for the Study of the Liver. (2012). EASL clinical practice guidelines: 

Wilson’s disease. Journal of Hepatology, vol. 56(3): 671-685. https://doi.org/10.1016/j.jhep.2011.11.007

Ferenci, P. (2005). Wilson’s disease. Clinical Gastroenterology and Hepatology, vol. 3 (8): 726-

733. https://doi.org/10.1016/S1542-3565(05)00484-2

Lorincz, M. T. (2010). Neurologic Wilson’s disease. New York Academy of Sciences, vol.1184(1): 

173-187. https://doi.org/10.1111/j.1749-6632.2009.05109.x

Loudianos, G., Lepori, M. B., Mameli, E., Dessi, V. & Zappu, A. (2014). Wilson’s Disease. Prilozi 

(Makedonska akademija na naukite i umetnostite. Oddelenie za medicinski 

nauki), vol.35(1), 93–98.

Merle, U., Schaefer, M., Ferenci, P. & Stremmel, W. (2007). Clinical presentation, diagnosis and 

long-term outcome of Wilson’s disease: A cohort study. Gut, vol. 56(1): 115-120. 

https://doi.org/10.1136/gut.2005.087262

Rodriguez-Castro, K. I., Hevia-Urrutia, F. J. & Sturniolo, G. C. (2015). Wilson’s disease: A review 

of what we have learned. World Journal of Hepatology, vol. 7(29): 2859-2870

https://doi.org/10.4254/wjh.v7.i29.2859

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