hepatolenticular degeneration


Summary: A rare autosomal recessive disease characterized by the deposition of copper in the BRAIN; LIVER; CORNEA; and other organs. It is caused by defects in the ATP7B gene encoding copper-transporting ATPase 2 (EC, also known as the Wilson disease protein. The overload of copper inevitably leads to progressive liver and neurological dysfunction such as LIVER CIRRHOSIS; TREMOR; ATAXIA and intellectual deterioration. Hepatic dysfunction may precede neurologic dysfunction by several years.

Top Publications

  1. He K, Chen Z, Ma Y, Pan Y. Identification of high-copper-responsive target pathways in Atp7b knockout mouse liver by GSEA on microarray data sets. Mamm Genome. 2011;22:703-13 pubmed publisher
    ..The results of our study may help us better understand the molecular mechanisms of high-copper effects in mice liver in genome-wide. ..
  2. Merle U, Tuma S, Herrmann T, Muntean V, Volkmann M, Gehrke S, et al. Evidence for a critical role of ceruloplasmin oxidase activity in iron metabolism of Wilson disease gene knockout mice. J Gastroenterol Hepatol. 2010;25:1144-50 pubmed publisher
    ..01). Atp7b(-/-) mice demonstrated decreased serum iron parameters and hemoglobin levels most likely related to a low serum ceruloplasmin oxidase activity and not due to total body iron deficiency. ..
  3. van den Berghe P, Stapelbroek J, Krieger E, de Bie P, van de Graaf S, de Groot R, et al. Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin. Hepatology. 2009;50:1783-95 pubmed publisher
    ..These findings might enable novel treatment strategies in WD by directly enhancing the protein expression of mutant ATP7B with residual copper export activity. 1795.). ..
  4. Fryer M. Potential of vitamin E as an antioxidant adjunct in Wilson's disease. Med Hypotheses. 2009;73:1029-30 pubmed publisher
  5. Terwel D, Löschmann Y, Schmidt H, Scholer H, Cantz T, Heneka M. Neuroinflammatory and behavioural changes in the Atp7B mutant mouse model of Wilson's disease. J Neurochem. 2011;118:105-12 pubmed publisher
    ..These mice can be used to evaluate therapeutic strategies to alleviate behavioural disturbances and cerebral pathology observed in WD. ..
  6. Dmitriev O, Bhattacharjee A, Nokhrin S, Uhlemann E, Lutsenko S. Difference in stability of the N-domain underlies distinct intracellular properties of the E1064A and H1069Q mutants of copper-transporting ATPase ATP7B. J Biol Chem. 2011;286:16355-62 pubmed publisher
    ..We conclude that the structural stability of the N-domain rather than the loss of ATP binding plays a defining role in the ability of ATP7B to reach the trans-Golgi network, thus contributing to phenotypic variability in WD. ..
  7. Prashanth L, Sinha S, Taly A, Vasudev M. Do MRI features distinguish Wilson's disease from other early onset extrapyramidal disorders? An analysis of 100 cases. Mov Disord. 2010;25:672-8 pubmed publisher
    ..Parkinson's disease--7, mitochondrial disorders--2, Hallervorden-Spatz disease--8, non-Wilsonian hepatolenticular degeneration--2, toxic/metabolic disorder--1, and others--20...
  8. Schilsky M. Wilson disease: current status and the future. Biochimie. 2009;91:1278-81 pubmed publisher
    ..Future therapies may include hepatocyte transplantation and gene therapy, both of which have been tested and shown to work in animal models of Wilson disease. Future human studies await advances in these areas. ..
  9. Coffey A, 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;136:1476-87 pubmed publisher

More Information


  1. Ovchinsky N, Moreira R, Lefkowitch J, Lavine J. Liver biopsy in modern clinical practice: a pediatric point-of-view. Adv Anat Pathol. 2012;19:250-62 pubmed publisher
    ..This review presents specific indications, considerations, methods, complications, contraindications, and alternatives for pediatric liver biopsy. ..
  2. Braiterman L, Nyasae L, Leves F, Hubbard A. Critical roles for the COOH terminus of the Cu-ATPase ATP7B in protein stability, trans-Golgi network retention, copper sensing, and retrograde trafficking. Am J Physiol Gastrointest Liver Physiol. 2011;301:G69-81 pubmed publisher
  3. Weiss K, Gotthardt D, Klemm D, Merle U, Ferenci Foerster D, Schaefer M, et al. Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease. Gastroenterology. 2011;140:1189-1198.e1 pubmed publisher
    ..It is important to identify patients who do not respond to zinc therapy and have increased activities of liver enzymes, indicating that a chelating agent should be added to the therapeutic regimen. ..
  4. Huster D. Wilson disease. Best Pract Res Clin Gastroenterol. 2010;24:531-9 pubmed publisher
  5. Lowette K, Desmet K, Witters P, Laleman W, Verslype C, Nevens F, et al. Wilson's disease: long-term follow-up of a cohort of 24 patients treated with D-penicillamine. Eur J Gastroenterol Hepatol. 2010;22:564-71 pubmed publisher
  6. Wiggelinkhuizen M, Tilanus M, Bollen C, Houwen R. Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease. Aliment Pharmacol Ther. 2009;29:947-58 pubmed publisher
    ..There is lack of high-quality evidence to estimate the relative treatment effects of the available drugs in Wilson disease. Therefore, multicentre prospective randomized controlled comparative trials are necessary. ..
  7. Litwin T, Gromadzka G, Członkowska A, Gołębiowski M, Poniatowska R. The effect of gender on brain MRI pathology in Wilson's disease. Metab Brain Dis. 2013;28:69-75 pubmed publisher
    ..We speculate that these differences are potentially related to an oestrogen protective effect and are due to differences in gender-related clinical forms. ..
  8. Shimizu N, Fujiwara J, Ohnishi S, Sato M, Kodama H, Kohsaka T, et al. Effects of long-term zinc treatment in Japanese patients with Wilson disease: efficacy, stability, and copper metabolism. Transl Res. 2010;156:350-7 pubmed publisher
    ..We recommend maintaining a spot urinary copper excretion less than 0.075-?g/mg creatinine. The authors conclude that zinc acetate is an effective and safe treatment for Japanese patients with Wilson disease. ..
  9. Masełbas W, Chabik G, Członkowska A. Persistence with treatment in patients with Wilson disease. Neurol Neurochir Pol. 2010;44:260-3 pubmed
    ..0001). Lack of persistence with use of prescribed medication is rather frequent among patients with Wilson disease. Lack of compliance decreases chances for improvement and might be the cause of clinical deterioration. ..
  10. da Costa M, Spitz M, Bacheschi L, Leite C, Lucato L, Barbosa E. Wilson's disease: two treatment modalities. Correlations to pretreatment and posttreatment brain MRI. Neuroradiology. 2009;51:627-33 pubmed publisher
    ..Neuroimaging pattern of evolution was more favorable for the group that received exclusively D-P. ..
  11. Barada K, El Atrache M, El Hajj I, Rida K, El Hajjar J, Mahfoud Z, et al. Homozygous mutations in the conserved ATP hinge region of the Wilson disease gene: association with liver disease. J Clin Gastroenterol. 2010;44:432-9 pubmed publisher
    ..We hereby report the association of liver disease with homozygous mutations in the conserved ATP hinge region of exon 18 of the ATP7B gene. ..
  12. Arnon R, Annunziato R, Schilsky M, Miloh T, Willis A, Sturdevant M, et al. Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults. Clin Transplant. 2011;25:E52-60 pubmed publisher
    ..LT is an excellent treatment option for patients with WD. Patients transplanted for CLD had higher patient survival rates than patients with FHF. ..
  13. Weiss K, Stremmel W. Evolving perspectives in Wilson disease: diagnosis, treatment and monitoring. Curr Gastroenterol Rep. 2012;14:1-7 pubmed publisher
    ..In this article, we review current diagnostic and therapeutic approaches in WD. ..
  14. Ala A, Schilsky M. Genetic modifiers of liver injury in hereditary liver disease. Semin Liver Dis. 2011;31:208-14 pubmed publisher
    ..Homozygosity for the A1-ATZ mutation is generally required for the development of liver disease in A1-AT although there is increasing evidence for modifier effects from a heterozygous genotype in other liver diseases. ..
  15. Schilsky M, Ala A. Genetic testing for Wilson disease: availability and utility. Curr Gastroenterol Rep. 2010;12:57-61 pubmed publisher
    ..This test eventually will be incorporated into the diagnostic armamentarium, allowing timely diagnosis and perhaps reversal or even prevention of further copper-induced injury. ..
  16. Lorincz M. Neurologic Wilson's disease. Ann N Y Acad Sci. 2010;1184:173-87 pubmed publisher
    ..This review focuses on the neurologic features of Wilson's disease, its diagnosis, and treatment options. ..
  17. Rosencrantz R, Schilsky M. Wilson disease: pathogenesis and clinical considerations in diagnosis and treatment. Semin Liver Dis. 2011;31:245-59 pubmed publisher
    ..Despite all the advances we still have to consider the diagnosis of Wilson disease to test patients for this disorder and properly establish the diagnosis before committing to life-long treatment. ..
  18. Linn F, Houwen R, van Hattum J, van der Kleij S, van Erpecum K. Long-term exclusive zinc monotherapy in symptomatic Wilson disease: experience in 17 patients. Hepatology. 2009;50:1442-52 pubmed publisher
    ..The outcome of exclusive zinc therapy is generally good in cases of neurologic disease. A less satisfactory outcome in hepatic disease may relate to less efficient decoppering. ..
  19. Gromadzka G, Rudnicka M, Chabik G, Przybyłkowski A, Członkowska A. Genetic variability in the methylenetetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson's disease. J Hepatol. 2011;55:913-9 pubmed publisher
    ..5%) vs. 36 (48.0%)), and more frequently presented with hepatic WND (44 (41.9%) vs. 22 (29.3%)), compared with subjects MTHFR 677T(-). We postulate that MTHFR polymorphism contributes to the phenotypic variability of WND. ..
  20. van den Berghe P, Klomp L. New developments in the regulation of intestinal copper absorption. Nutr Rev. 2009;67:658-72 pubmed publisher
  21. Prashanth L, Sinha S, Taly A, A Mahadevan -, Vasudev M, Shankar S. Spectrum of epilepsy in Wilson's disease with electroencephalographic, MR imaging and pathological correlates. J Neurol Sci. 2010;291:44-51 pubmed publisher
    ..This is the largest series regarding epilepsy in WD. Seizures are not uncommon and could occur at any stage. Deafferentation of white matter tracts from cortex may contribute for seizure in WD. ..
  22. Gray L, Peng F, Molloy S, Pendyala V, Muchenditsi A, Muzik O, et al. Urinary copper elevation in a mouse model of Wilson's disease is a regulated process to specifically decrease the hepatic copper load. PLoS ONE. 2012;7:e38327 pubmed publisher
    ..These results demonstrate that the body regulates copper export through more than one mechanism; better understanding of urinary copper excretion may contribute to an improved diagnosis and monitoring of WD. ..
  23. Gupta A, Chattopadhyay I, Mukherjee S, Sengupta M, Das S, Ray K. A novel COMMD1 mutation Thr174Met associated with elevated urinary copper and signs of enhanced apoptotic cell death in a Wilson Disease patient. Behav Brain Funct. 2010;6:33 pubmed publisher
    ..Two other changes were also identified in the gene. We have examined genotype-phenotype correlation between the detected changes and the atypical presentation of the WD patient. ..
  24. Merle U, Weiss K, Eisenbach C, Tuma S, Ferenci P, Stremmel W. Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease. BMC Gastroenterol. 2010;10:8 pubmed publisher
    ..Measurement of serum ceruloplasmin oxidase might help to predict presence of truncating ATP7B mutations and might facilitate the mutation analysis. ..
  25. Huster D, Hermann W, Bartels M. [Acute Wilson disease]. Internist (Berl). 2011;52:815-22 pubmed publisher
  26. Lalioti V, Muruais G, Tsuchiya Y, Pulido D, Sandoval I. Molecular mechanisms of copper homeostasis. Front Biosci (Landmark Ed). 2009;14:4878-903 pubmed
    ..In mammalians liver is the major captor, distributor and excreter of Cu. Mutations in the P-type ATPases that interfere with their functioning and traffic are cause of the life-threatening Wilson (ATP7B) and Menkes (ATP7A) diseases...
  27. Brewer G, Askari F, Dick R, Sitterly J, Fink J, Carlson M, et al. Treatment of Wilson's disease with tetrathiomolybdate: V. Control of free copper by tetrathiomolybdate and a comparison with trientine. Transl Res. 2009;154:70-7 pubmed publisher
  28. Tsubota A, Matsumoto K, Mogushi K, Nariai K, Namiki Y, Hoshina S, et al. IQGAP1 and vimentin are key regulator genes in naturally occurring hepatotumorigenesis induced by oxidative stress. Carcinogenesis. 2010;31:504-11 pubmed publisher
    ..These findings enhance our understanding of the multistep hepatotumorigenesis and identification of target molecules for novel treatments. ..
  29. Lee B, Kim J, Lee S, Jin H, Kim K, Lee J, et al. Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort. Liver Int. 2011;31:831-9 pubmed publisher
    ..The presenting phenotype strongly affects the clinical outcome of WD, and is related to the ATP7B mutation type and location, providing an evidence for genotype-phenotype correlations in WD. ..
  30. Pestana Knight E, Gilman S, Selwa L. Status epilepticus in Wilson's disease. Epileptic Disord. 2009;11:138-43 pubmed publisher
  31. Litwin T, Gromadzka G, Członkowska A. Apolipoprotein E gene (APOE) genotype in Wilson's disease: impact on clinical presentation. Parkinsonism Relat Disord. 2012;18:367-9 pubmed publisher
    ..H1069Q homozygous patients. Further studies are needed to understand the mechanisms of these gender-dependent phenotypic effects. ..
  32. Burkhead J, Gray L, Lutsenko S. Systems biology approach to Wilson's disease. Biometals. 2011;24:455-66 pubmed publisher
    ..A systems biology approach promises to generate a comprehensive view of WD onset and progression, thus helping with a more fine-tune treatment and monitoring of the disorder. ..
  33. Johncilla M, Mitchell K. Pathology of the liver in copper overload. Semin Liver Dis. 2011;31:239-44 pubmed publisher
    ..Copper and copper-associated protein accumulation may also be seen in chronic biliary obstructive processes. ..
  34. Pfeiffer R. Wilson's disease. Handb Clin Neurol. 2011;100:681-709 pubmed publisher
    ..Appropriate diagnostic evaluations to confirm the diagnosis and institute treatment can be confusing. In this chapter, the clinical manifestations, diagnostic evaluation, and treatment approaches for Wilson's disease are discussed. ..
  35. Wang Y, Hodgkinson V, Zhu S, Weisman G, Petris M. Advances in the understanding of mammalian copper transporters. Adv Nutr. 2011;2:129-37 pubmed publisher
    ..Herein, we review recent studies of the biochemical and cell biological characteristics of CTR1, ATP7A, and ATP7B, as well as emerging roles for Cu in new areas of physiology. ..
  36. Nicastro E, Loudianos G, Zancan L, D Antiga L, Maggiore G, Marcellini M, et al. Genotype-phenotype correlation in Italian children with Wilson's disease. J Hepatol. 2009;50:555-61 pubmed publisher
    ..Urinary copper excretion appears to be correlated to the age at diagnosis rather than genotype. ..
  37. Walshe J. Monitoring copper in Wilson's disease. Adv Clin Chem. 2010;50:151-63 pubmed
    ..Lack of compliance is revealed by a reversal of this trend. This chapter critically reviews current testing methods and describes other approaches that may be helpful. ..
  38. Lin C, Er T, Tsai F, Liu T, Shin P, Chang J. Development of a high-resolution melting method for the screening of Wilson disease-related ATP7B gene mutations. Clin Chim Acta. 2010;411:1223-31 pubmed publisher
    ..L776L) in 50 normal Taiwanese individuals. We estimate that the carrier frequency of WD in the Taiwanese population as probably 0.03. HRM analysis is accepted as a rapid, accurate and low-cost method to screen ATP7B gene mutations. ..
  39. Walshe J. The pattern of urinary copper excretion and its response to treatment in patients with Wilson's disease. QJM. 2011;104:775-8 pubmed publisher
    ..After 1 and 2 years of treatment, there is significant decrease in copper excretion in both basal and after penicillamine challenge. This presumably indicates a reduction in the body load of copper. ..
  40. Manolaki N, Nikolopoulou G, Daikos G, Panagiotakaki E, Tzetis M, Roma E, et al. Wilson disease in children: analysis of 57 cases. J Pediatr Gastroenterol Nutr. 2009;48:72-7 pubmed publisher
    ..Chelating therapy was well tolerated, and the outcome was satisfactory. WD in children may be obscure and requires extensive investigation to establish the diagnosis. Genetic analysis is needed in equivocal cases. ..
  41. Bennett J, Hahn S. Clinical molecular diagnosis of Wilson disease. Semin Liver Dis. 2011;31:233-8 pubmed publisher
    ..In this article, the authors review the sensitivity, limitations, and pitfalls of ATP7B sequencing in the diagnosis of Wilson disease. ATP7B sequencing should be standard practice in the diagnosis of Wilson disease. ..
  42. Litwin T, Gromadzka G, Członkowska A. Gender differences in Wilson's disease. J Neurol Sci. 2012;312:31-5 pubmed publisher
    ..We speculate these differences may be due to the protective effect of estrogens and iron metabolism differences. ..
  43. Zischka H, Lichtmannegger J, Schmitt S, Jägemann N, Schulz S, Wartini D, et al. Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease. J Clin Invest. 2011;121:1508-18 pubmed publisher
    ..Together, these findings suggest that the mitochondrion constitutes a pivotal target of copper in WD. ..
  44. Ralle M, Huster D, Vogt S, Schirrmeister W, Burkhead J, Capps T, et al. Wilson disease at a single cell level: intracellular copper trafficking activates compartment-specific responses in hepatocytes. J Biol Chem. 2010;285:30875-83 pubmed publisher
    ..These observations suggest new stage-specific as well as general biomarkers for WD. The model for the dynamic role of copper in WD is proposed. ..
  45. Cope Yokoyama S, Finegold M, Sturniolo G, Kim K, Mescoli C, Rugge M, et al. Wilson disease: histopathological correlations with treatment on follow-up liver biopsies. World J Gastroenterol. 2010;16:1487-94 pubmed
    ..6 fibrosis units between the second and third biopsy. The inability of clinical tools to detect fibrosis progression in WD suggests that a liver biopsy with hepatic copper quantification every 3 years should be considered. ..
  46. Merle U, Eisenbach C, Weiss K, Tuma S, Stremmel W. Serum ceruloplasmin oxidase activity is a sensitive and highly specific diagnostic marker for Wilson's disease. J Hepatol. 2009;51:925-30 pubmed publisher
    ..Our data suggest that the enzymatic ceruloplasmin assay is superior to the immunologic assay in diagnosing Wilson's disease and should become the preferred method. ..
  47. Kodama H, Fujisawa C, Bhadhprasit W. Pathology, clinical features and treatments of congenital copper metabolic disorders--focus on neurologic aspects. Brain Dev. 2011;33:243-51 pubmed publisher
    ..Neurologic worsening in patients treated with tetrathiomolybdate has been reported to be lower than rates of neurologic worsening when treating with other chelating agents...
  48. Schilsky M, Oikonomou I. Inherited metabolic liver disease. Curr Opin Gastroenterol. 2005;21:275-82 pubmed
  49. Sinha S, Taly A, Prashanth L, Ravishankar S, Arunodaya G, Vasudev M. Sequential MRI changes in Wilson's disease with de-coppering therapy: a study of 50 patients. Br J Radiol. 2007;80:744-9 pubmed
    ..Patients with extensive changes, white-matter involvement and severe diffuse atrophy had a poor prognosis In conclusion, the majority of patients with WD showed variable improvement in clinical and MRI features when treated. ..
  50. Bohrer D, do Nascimento P, Ramirez A, Mendonça J, De Carvalho L, Pomblum S. Comparison of ultrafiltration and solid phase extraction for the separation of free and protein-bound serum copper for the Wilson's disease diagnosis. Clin Chim Acta. 2004;345:113-21 pubmed
    ..Advantages of SPE are small sample volume (50 microl), separation carried out in 10 min, and the use of the same column for several analyses. ..
  51. Gitlin J. Wilson disease. Gastroenterology. 2003;125:1868-77 pubmed
  52. Panagiotakaki E, Tzetis M, Manolaki N, Loudianos G, Papatheodorou A, Manesis E, et al. Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A. 2004;131:168-73 pubmed
    ..Our results on the effect of predicted nonsense and frameshift mutations are especially important for early medical intervention in presymptomatic infants and children with these genotypes. ..
  53. Zhuang X, Mo Y, Jiang X, Chen S. Analysis of renal impairment in children with Wilson's disease. World J Pediatr. 2008;4:102-5 pubmed publisher
    ..was undertaken to find the clinical features of renal impairment in children with Wilson's disease or hepatolenticular degeneration (HLD)...