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Year : 2018  |  Volume : 11  |  Issue : 2  |  Page : 92-93  

Wilson's disease: An update

1 Department of Psychiatry, Dr. D Y Patil Medical College, Hospital and Research Center, Dr D Y Patil Vidyapeeth, Pune, Maharashtra, India
2 Departments of Psychiatry, Dr. D Y Patil Medical College, Hospital and Research Center, Dr D Y Patil Vidyapeeth, Pune, Maharashtra, India

Date of Web Publication18-May-2018

Correspondence Address:
Suprakash Chaudhury
Departments of Psychiatry, Dr. D Y Patil Medical College, Hospital and Research Center, Dr D Y Patil Vidyapeeth, Pune, Maharashtra
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Source of Support: None, Conflict of Interest: None


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How to cite this article:
Chaudhury S, Patkar P. Wilson's disease: An update. Med J DY Patil Vidyapeeth 2018;11:92-3

How to cite this URL:
Chaudhury S, Patkar P. Wilson's disease: An update. Med J DY Patil Vidyapeeth [serial online] 2018 [cited 2020 Jul 2];11:92-3. Available from: http://www.mjdrdypv.org/text.asp?2018/11/2/92/232639

Samuel Alexander Kinnier Wilson first described the condition, which bears his name, in his seminal publication “Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver.” He identified some key features of the disease including its hereditary nature and the co-occurrence of liver cirrhosis with neurological deficits, predominantly involving the extrapyramidal system.[1]

  Pathophysiology Top

Copper is an essential element for cellular function, yet free copper is extremely toxic and can produce irreversible cellular damage. Transport of necessary copper to intended sites and safe elimination of excess copper through the biliary system is vital. The hepatic protein ATP7B encodes a copper-transporting P-type ATPase [2] and resides in hepatocytes in the trans-Golgi network, transporting copper into the secretory pathway for incorporation into apoceruloplasmin, forming ceruloplasmin. Excess is excreted eventually into the bile. Reduced or absent function of the ATP7B protein results in decreased biliary copper excretion. This gradually not only compromises hepatic function but also unbound copper spills out of the liver into the blood stream and then deposits itself into various organs. The functional consequences of pathogenic ATP7B mutation are increased intracellular copper levels. This produces oxidative stress and free radical formation as well as mitochondrial dysfunction, which results in cell death in the liver, brain, kidneys, heart, eyes, and joints. As this disease damages multiple systems at one time, it poses a diagnostic challenge. In Wilson's disease (WD), accumulation of copper in the liver starts in early infancy and continues through adult life. Initially, hepatocytes show steatosis and distinctive mitochondrial changes, which may progress to chronic hepatitis and ultimately cirrhosis. In the brain, the highest copper levels are in the lenticular nuclei, which undergo degeneration with increasing copper accumulation.[3],[4]

  Genetics Top

WD is an autosomal recessive monogenic inherited condition. Heterozygotes with mutation of a single allele do not manifest the disease. Only homozygotes who inherit disease-producing mutations of both alleles of the WD gene will manifest the disease. ATP7B, the causative gene of WD, is located on chromosome 13. More than 500 ATP7B mutations have been identified, most commonly missense mutations, small deletions/insertions in the coding region, or splice junction mutations. Rare genetic mutations include exon deletions, promoter region mutations, concurrent presence of three pathogenic alterations, and monogenic disomy.[3],[5] The clinical variability of WD, the variable penetrance, and the lack of genotype–phenotype correlations suggest the presence of modifier genes such as an E4 allele of apolipoprotein E or polymorphisms in the methylenetetrahydrofolate reductase gene which may determine the level of copper tolerance or copper storage capacity of an individual.[6]

  Prevalence Top

Although the prevalence figure of 1:30,000 for WD is widely cited, recent mass screening studies suggest a considerably higher prevalence of 1:1500–1:3000 for WD.[7],[8]

  Clinical Manifestations Top

Onset lies usually in early teens. However, early onset in infancy (youngest at 9 months) and late onset in adults >70 years are well recognized.[9],[10] One quarter of patients have involvement of more than one organ system at the time of presentation.[11] The most common mode of presentation is with hepatic dysfunction or neurological symptoms in 40% each whereas 20% present with psychiatric symptoms.[12]

The neurological manifestations in WD are extrapyramidal disturbance characterized by rigidity, tremor, dystonia, and athetoid writhing movements of the limbs. These features may initially be transient and affected by emotional disturbances and may erroneously be diagnosed as conversion disorder. Another classical feature seen in WD is a flapping tremor. Spastic dysarthria and dysphagia have been reported. A quarter of the patients with neurological WD exhibit cerebellar dysfunction.[13] Although neurological WD may present as a dystonic, an ataxic and a Parkinsonian syndrome, the majority of patients exhibit mixed features.[14],[15] Ocular examination may reveal Kayser–Fleischer rings and sunflower cataracts.[4] Endocrinal symptoms include amenorrhea, delayed puberty, hypothyroidism, and hyperparathyroidism. Recurrent abortions may occur in untreated women with WD. Osteoarthritis and Fanconi's syndrome have been reported.[16]

The frequency of psychiatric symptoms in WD is still undecided, but many reports reveal their existence in 65% of cases. Over two-thirds of the patients need the psychiatric management even before WD is established.[17] Wilson believed that psychiatric symptoms form a fundamental part of the clinical picture. He also observed psychotic and hysterical symptoms, mood change, and disordered behavior. Psychiatric symptoms have a higher prevalence among patients with WD, especially in individuals with established neurological signs, compared to the general population.[18] Personality changes and mood symptoms are the most frequently seen behavioral changes.[12] Depression is more commonly seen. Psychosis has been described at various points in the course of WD but is rare. Disinhibited, bizarre or reckless behavior, poor school or work performance, and suicidal attempts have been reported. Impairment of some aspects of memory, executive functions, and visuospatial processing has been observed. Due to the varied manifestations, WD should be ruled out in young men presenting with unexplained psychiatric symptoms along with neurological signs. Children with persistent abdominal symptoms and poor scholastic achievement should also be evaluated for WD.[3],[4]

  Management Top

Chelating agents have vastly improved the prognosis of WD. Early diagnosis and regular treatment with chelating agents and oral zinc to reduce copper absorption may reverse or attenuate symptoms and prevent disease progression. Even with chronic active hepatitis or cirrhosis, the prognosis is excellent if patients adhere fully to treatment. Liver transplantation is indicated and lifesaving in patients with acute liver failure or irreversible end-stage liver disease.[4]

  References Top

Wilson SA. Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain 1912;34:295-507.  Back to cited text no. 1
Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, Ross B, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 1993;5:344-50.  Back to cited text no. 2
Bandmann O, Weiss KH, Kaler SG. Wilson's disease and other neurological copper disorders. Lancet Neurol 2015;14:103-13.  Back to cited text no. 3
Tavill AS. Wilsons Disease. Cleveland Clinic Center for Continuing Education. Available from: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/wilson-disease/. [Last accessed on 2017 Jul 07].  Back to cited text no. 4
Coffey AJ, Durkie M, Hague S, McLay K, Emmerson J, Lo C, et al. A genetic study of Wilson's disease in the United Kingdom. Brain 2013;136(Pt 5):1476-87.  Back to cited text no. 5
Gromadzka G, Rudnicka M, Chabik G, Przybylkowski A, Czlonkowska A. Genetic variability in the methylene tetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson's disease. J Hepatol 2011;55:913-9.  Back to cited text no. 6
Hahn SH, Lee SY, Jang YJ, Kim SN, Shin HC, Park SY, et al. Pilot study of mass screening for Wilson's disease in Korea. Mol Genet Metab 2002;76:133-6.  Back to cited text no. 7
Ohura T, Abukawa D, Shiraishi H, Yamaguchi A, Arashima S, Hiyamuta S, et al. Pilot study of screening for Wilson disease using dried blood spots obtained from children seen at outpatient clinics. J Inherit Metab Dis 1999;22:74-80.  Back to cited text no. 8
Kim JW, Kim JH, Seo JK, Ko JS, Chang JY, Yang HR, et al. Genetically confirmed Wilson disease in a 9-month old boy with elevations of aminotransferases. World J Hepatol 2013;5:156-9.  Back to cited text no. 9
Ala A, Borjigin J, Rochwarger A, Schilsky M. Wilson disease in septuagenarian siblings: Raising the bar for diagnosis. Hepatology 2005;41:668-70.  Back to cited text no. 10
El-Youssef M. Wilson disease. Mayo Clin Proc 2003;78:1126-36.  Back to cited text no. 11
Brewer GJ. Behavioral abnormalities in Wilson's disease. Adv Neurol 2005;96:262-74.  Back to cited text no. 12
Walshe JM, Yealland M. Wilson's disease: The problem of delayed diagnosis. J Neurol Neurosurg Psychiatry 1992;55:692-6.  Back to cited text no. 13
Machado A, Chien HF, Deguti MM, Cancado E, Azevedo RS, Scaff M, et al. Neurological manifestations in Wilson's disease: Report of 119 cases. Mov Disord 2006;21:2192-6.  Back to cited text no. 14
Taly AB, Meenakshi-Sundaram S, Sinha S, Swamy HS, Arunodaya GR. Wilson disease: Description of 282 patients evaluated over 3 decades. Medicine (Baltimore) 2007;86:112-21.  Back to cited text no. 15
Leggio L, Addolorato L. Abenavoli L, Gasbarrini G. Wilson's disease: Clinical, genetic and pharmacological findings. International Journal of Immunopathology and Pharmacology. 2005;18:7-14.  Back to cited text no. 16
Akil M, Schwartz JA, Dutchak D, Yuzbasiyan-Gurkan V, Brewer GJ. The psychiatric presentations of Wilson's disease. J Neuropsychiatry Clin Neurosci 1991;3:377-82.  Back to cited text no. 17
Zimbrean PC, Schilsky ML. Psychiatric aspects of Wilson disease: A review. Gen Hosp Psychiatry 2014;36:53-62.  Back to cited text no. 18


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