Wilson's Disease–Annotated Bibliography

Annotated Bibliography Wilson’s Disease

ATP7B – ATPase, Cu++ transporting, beta polypeptide (2015) Genetics Home Reference. [online] http://ghr.nlm.nih.gov/gene/ATP7B (Accessed April 3, 2015)
  • This NIH reference provided basic background information on how ATP7B functions in a healthy person. This will serve as a comparison to how ATP7B’s function is halted or altered in patients with Wilson’s Disease.
Bai, X., Wang, G., Wu, L., Liu, Y., Cui, L., Shi, H., and Guo, L. (2014) Deep-gray nuclei susceptibility-weighted imaging filtered phase shift in patients with Wilson’s disease. Pediatr Res. 75, 436–442. DOI:10.1038/pr.2013.239
  • This article used SWI to look at copper deposition specifically in the deep grey nuclei in the brains of Wilson’s Disease patients. The authors have found that there is an increased abnormal phase value in the brains of Wilson’s Disease patients and propose that this shift could be used as a biomarker for detecting Wilson’s Disease in patients in the future.

Bearn AG. (1953) Genetic and biochemical aspects of Wilson’s disease. Am J Med.15, 442–449. DOI:10.1016/0002-9343(53)90134-X

  • This landmark study uses genetic ratio analysis calculations to confirm that Wilson’s Disease is inherited in an autosomal recessive pattern.

Braiterman, L. T., Murthy, A., Jayakanthan, S., Nyasae, L., Tzeng, E., Gromadzka, G., Woolf, T. B., Lutsenko, S., and Hubbard, A. L. (2014) Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B. PNAS. 111, E1364–E1373. DOI:10.1073/pnas.1314161111

  •  This study characterizes a novel, stable Wilson’s disease causing mutation that induces local distortions at the transmembrane 1 domain which alters the interactions between transmembrane domains 1 and 2 (TM1 and TM2). The authors state that this mutation prevents the ATP7B protein from exiting the trans-golgi network, unlike previously known Wilson’s Disease mutations that actually disrupt the activity or stability of ATP7B. The characterization of this new type of mutation and the proposed mechanism for how it functions also sheds light on the broader role of TM1 and TM2 in copper regulated trafficking of ATP7B.
Bull, P. C., Thomas, G. R., Rommens, J. M., Forbes, J. R., and Cox, D. W. (1993) The Wilson disease gene is a putative copper transporting P–type ATPase similar to the Menkes gene. Nat Genet. 5, 327–337. DOI:10.1038/ng1293-327
  • In this study published with a suite of Nature Genetics papers in 1993, the authors continued the investigation into the genetic basis of Wilson’s Disease. The authors found that the WD gene codes for part of a copper-transporting ATPase and that it shares some homology with the Menkes Disease copper-transporting ATPase.

Cumings, J.N. (1948) The Copper and Iron Content of Brain and Liver in the Normal and in Hepato-lenticular Degeneration. Brain. 71, 410-415. DOI: http://dx.doi.org/10.1093/brain/71.4.410

  • In this landmark study, Cummings indicates that the issue with Wilson’s disease may be linked to copper metabolism. His study found increased copper content Wilson’s Disease patients’ liver and brain when compared the copper content of brain and liver in patients without Wilson’s Disease.

Cumings, J. N. (1951) The Effects of B.a.l. in Hepatolenticular Degeneration. Brain. 74, 10–22. DOI: http://dx.doi.org/10.1093/brain/74.1.10

  • In this landmark study, metal binding agent 2,3-dimercapterpropanol (BAL) is used for the first time as a therapeutic drug for Wilson’s Disease in a clinical trial and found to be successful at removing copper from impacted tissues.

Dziezyc, K., Tomasz, L., Sobanska, A., and Czlonkowska, A. (2014) Symptomatic copper deficiency in three Wilson’s disease patients treated with zinc sulphate. Neurol Neurochir Pol. 48, 214-218. DOI:10.1016/j.pjnns.2014.05.002

  •  In this case report, the authors describe several cases of copper deficiency after zinc sulfate de-coppering therapy as treatment for Wilson’s disease. This suggests potentially harmful side effects of standard, lifelong Wilson’s Disease therapy and stresses the importance of regularly monitoring copper metabolism in Wilson’s Disease patients. Copper is a necessary cofactor for many enzymes in the body and although excess copper is potentially fatal in the case of Wilson’s Disease, copper deficiency can be harmful as well.

Gourdon, P., Sitsel, O., Karlsen, J. L., Møller, L. B., and Nissen, P. (2012) Structural models of the human copper P-type ATPases ATP7A and ATP7B. Biological Chemistry. 393, 205–216. DOI: 10.1515/hsz-2011-0249

  • This study proposes a homology model for ATP7B and ATP7A based on the crystal structures available for the individual, soluble domains by comparing them to a recently solved protein, LpCopA, from a bacterial model. The authors also determined that the heavy metal binding domains 5 and 6 (HMBD5 and HMBD6) are crucial for function by mapping disease causing missense mutations. Finally, further analysis of the HMBDs allowed the authors to propose a structural model and mechanism where the 6 HMBDs associate in three pairs and communicate via a connecting loop domain between HMBD5 and HMBD6 so that when copper is bound, the autoinhibitory HMBD6 is displaced from the ATPase protein core.

Gupta, S. (2014) Cell therapy to remove excess copper in Wilson’s disease. Ann. N.Y. Acad. Sci. 1315, 70–80. DOI: 10.1111/nyas.12450

  •  This article discusses the potential for cell therapy involving repopulating the liver and bile ducts with healthy hepatocytes as a long term treatment for Wilson’s Disease. It also discusses new noninvasive imaging techniques that allow physicians to monitor the success of this therapy over time.

Hoogenraad, T. U. (2006) Paradigm shift in treatment of Wilson’s disease: zinc therapy now treatment of choice. Brain Dev. 28, 141–146. DOI: 10.1016/j.braindev.2005.08.008

  • This article explains the shift in treatment from using the chelating agent penicillamine as a ‘decoppering agent’ focused at removing accumulated copper form the liver to using zinc. Zinc manages the levels of free copper in the blood stream by inducing metallothionien which binds to free copper and facilitates its excretion in feces. This article will help me to understand the differences between the two forms of treatments and the way that the focus of the treatments has changed over time.

Kalita, J., Kumar, V., Misra, U. K., Ranjan, A., Khan, H., and Konwar, R. (2014) A study of oxidative stress, cytokines and glutamate in Wilson disease and their asymptomatic siblings. J Neuroimmunol. 274, 141-148. DOI:10.1016/j.jneuroim.2014.06.013

  •  In this study the authors determined that patients with Wilson’s Disease had reduced glutathionine levels, reduced total antioxidant capacity, increased cytokine levels, and increased malinodialdehyde levels when compared with their non-Wilson’s Disease carrying siblings. These increases in oxidative stress markers are indicative of an environment with reduced antioxidants which the authors propose is caused by the presence of free copper in Wilson’s Disease patients.

Kandanapitiye, M. S., Wang, F. J., Valley, B., Gunathilake, C., Jaroniec, M., and Huang, S. D. (2015) Selective Ion Exchange Governed by the Irving–Williams Series in K2Zn3[Fe(CN)6]2 Nanoparticles: Toward a Designer Prodrug for Wilson’s Disease. Inorg. Chem. 54, 1212–1214. DOI:10.1021/ic502957d

  •  In this study, the authors design and propose using selective, biocompatible nanoparticles that can be taken up by the cell, target intracellular copper, and selectively detoxify it as a potential new drug therapy for the treatment of Wilson’s Disease.

Katano, Y., Hayashi, K., Hattori, A., Tatsumi, Y., Ueyama, J., Wakusawa, S., Yano, M., Toyoda, H., Kumada, T., Mizutani, N., Hayashi, H., and Goto, H. (2014) Biochemical staging of the chronic hepatic lesions of Wilson disease. Nagoya J Med Sci. 76, 139–148. PMCID:PMC4345718

  • This study proposes using biochemical stages to characterize hepatic copper toxicosis in combination with Wilson’s Disease phenotyping (hepatic, acute, and neurologic) to better understand the biochemical features of Wilson’s Disease hepatic legions. A clearer understanding of these legions paves the way for developing more specific diagnostic testing for Wilson’s Disease in order to move towards earlier diagnosis.

Le, A., Shibata, N. M., French, S. W., Kim, K., Kharbanda, K. K., Islam, M. S., LaSalle, J. M., Halsted, C. H., Keen, C. L., and Medici, V. (2014) Characterization of Timed Changes in Hepatic Copper Concentrations, Methionine Metabolism, Gene Expression, and Global DNA Methylation in the Jackson Toxic Milk Mouse Model of Wilson Disease. Int J Mol Sci. 15, 8004–8023. DOI:10.3390/ijms15058004

  •  This study characterized hepatic copper accumulation, methionine metabolism, global DNA methylation and gene expression in a mouse model for Wilson’s Disease throughout its lifespan from fetus through adulthood. The authors found that there is a close relationship between copper accumulation and the decreased expression and increased methylation of several of the enzymes necessary for methionine metabolism. The authors hypothesize this indicates a correlation between genetic and epigenetic regulation of the onset and later progression of Wilson’s Disease.

Petrukhin, K., Fischer, S. G., Pirastu, M., Tanzi, R. E., Chernov, I., Devoto, M., Brzustowicz, L. M., Cayanis, E., Vitale, E., and Russo, J. J. (1993) Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nat. Genet. 5, 338–343. DOI:10.1038/ng1293-338

  • In this landmark paper, the authors analyzed the haplotypes of 115 Wilson’s disease families and determined that the majority of Wilson’s Disease mutations appear in just 4 haplotypes. They went on to isolate the disease locus within a single marker interval at chromosome 13q14.3, which they identified as the Wilson’s Disease gene.

Rosencrantz, R., and Schilsky, M. (2011) Wilson Disease: Pathogenesis and Clinical Considerations in Diagnosis and Treatment. Seminars in Liver Disease. 31, 245–259. DOI: 10.1055/s-0031-1286056

  • This article provided comparison and analysis of the variety of diagnosis and treatment options for patients with Wilson’s Disease. It also looked at the effectiveness of some newer treatment options such as gene therapy and hepatocyte cell transplantation which have been proposed in animal models.

Scheinberg, I. H., and Gitlin, D. (1952) Deficiency of Ceruloplasmin in Patients with Hepatolenticular Degeneration (Wilson’s Disease). Science. 116, 484–485. PMID:12994898

  • In this landmark study, the authors found that Wilson’s Disease patients had a deficiency in ceruloplasmin. Ceruloplasmin is the protein that is normally found bound to all free copper in serum plasma in non-Wilson’s Disease patients.
Singh, P., Ahluwalia, A., Saggar, K., and Grewal, C. S. (2011) Wilson’s disease: MRI features. J Pediatr Neurosci. 6, 27–28. DOI: 10.4103/1817-1745.84402
  • This article explained the critical features for identifying copper deposition in the brain. It also outlined the characteristic ‘face of the giant panda’ shaped deposition of copper in the brains of Wilson’s Disease patients.

Stromeyer, F. W., and Ishak, K. G. (1980) Histology of the liver in Wilson’s disease: a study of 34 cases. Am. J. Clin. Pathol. 73, 12–24. PMID:7352414

  • This study describes biopsy and autopsy samples of the livers of Wilson’s Disease patients and identified key histological findings helpful in distinguishing Wilson’s Disease from hepatitis. These histological findings can help to diagnose Wilson’s Disease in conjunction with clinical symptoms and other lab findings.

Tanzi, R. E., Petrukhin, K., Chernov, I., Pellequer, J. L., Wasco, W., Ross, B., Romano, D. M., Parano, E., Pavone, L., Brzustowicz, L. M., Devoto, M., Peppercorn, J., Bush, A. I., Sternlieb, I., Pirastu, M., Gusella, J. F., Evgrafov, O., Penchaszadeh, G. K., Honig, B., Edelman, I. S., Soares, M. B., Scheinberg, I. H., and Gilliam, T. C. (1993) The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 5, 344–350. DOI: 10.1038/ng1293-344

  • In this landmark study, published in tandem with the Petrukhin et al.1993 paper, the authors confirm the pWD gene as the Wilson’s Disease based on their studies which map the gene to the genetically defined disease gene region and identified 4 independent, specific, disease causing mutations in that region. They also identified highly conserved sequences that they believe to be essential to ATPase function. Finally, the authors derived an amino acid sequence from the pWD gene which predicts a protein with copper-transporting ATPase activity and is also homologous to the Mc1 gene for Menkes disease, another disease caused by improper transport of copper in the cell.

Turnlund, J. (1998) Human Whole-Body Copper Metabolism. J. Clin. Nutr. 67, 960S-964S. PMID: 9587136

  • This study explains the basics of dietary copper absorption and metabolism in a healthy human. This study provided some baseline information for a healthy individual that I can then use to compare to an individual with Wilson’s Disease.

Utzman, L, and Denny-Brown, D. (1948) Amino-Aciduria in Hepato-Lenticular Degeneration (Wilson’s Disease). Am. J. Med215, 599-611. PMID:18875448

  • This landmark case study provided information on the link between amino-aciduria and Wilson’s Disease in patients.

Walshe, J. M. (1956) Penicillamine, a new oral therapy for Wilson’s disease. Am. J. Med. 21, 487–495. DOI:10.1016/0002-9343(56)90066-3

  • In this landmark study Penicillamine, a degradation product of penicillin that is able to mobilize large amounts of copper for excretion in urine, was determined to be an effective treatment for Wilson’s Disease.
Wilson (Wilson’s) Disease Association. [online] http://www.wilsonsdisease.org (Accessed April 10, 2015)
  • The Wilson’s Disease Association provided the information for current diagnostic tools, symptoms, and patient resources for Wilson’s Disease.

Wilson, S. a. K. (1912) Progressive Lenticular Degeneration: A Familial Nervous Disease Associated with Cirrhosis of the Liver. Brain. 34, 295–507. DOI:http://dx.doi.org/10.1093/brain/34.4.295

  • In this landmark publication Wilson characterizes the symptoms and signs of 10 patients with the disease now known as Wilson’s Disease, which he called “progressive lenticular degeneration”. In this 214 page publication he outlines clinical symptoms including the trademark Kayser-Fleisher rings, historical background, and disease pathology displaying lesions in liver and brain tissue. Wilson also postulated that the disease causes were not genetically related, which was subsequently disproved.

Xiang-Xue Zhou, Hao-Lin Qin, Xun-Hua Li, Hai-Wei Huang, Ying-Ying Liang, Xiu-Ling Liang, and Xiao-Yong Pu (2014) Characterizing brain mineral deposition in patients with Wilson disease using susceptibility-weighted imaging. Neurology India. 62, 362–366. DOI: 10.4103/0028-3886.141221

  • This study looks at the feasibility of characterizing mineral deposits in the brain using susceptibility weighted imaging (SWI) and determined that it is likely more sensitive than MRI. SWI also detected the presence of potentially abnormal iron metabolism in addition to abnormal copper metabolism in Wilson’s Disease patients.