Details of Disease

General Information of Disease (ID: DISVS9H7)

• Disease Name: Wilson disease
• Synonyms: hepatolenticular Degeneration; Wnd; WD; cerebral pseudosclerosis; Westphal pseudosclerosis; Wilson's disease; Westphal-Strumpell syndrome; hepatolenticular degeneration; Wilson disease
• Disease Class: 5C64: Mineral absorption/transport disorder
• Definition: A very rare inherited multisystemic disease presenting non-specific neurological, hepatic, psychiatric or osseo-muscular manifestations due to excessive copper deposition in the body.
• Disease Hierarchy:
  DISXHPKM: Copper metabolism disorder
  DIS0HB59: Inborn metal metabolism disorder
  DISVS9H7: Wilson disease
• ICD Code:
  ICD-11: ICD-11: 5C64.00
  Expand ICD-11: '5C64.00
• Disease Identifiers:
  MONDO ID: MONDO_0010200
  MESH ID: D006527
  UMLS CUI: C0019202
  OMIM ID: 277900
  MedGen ID: 42426
  Orphanet ID: 905
  SNOMED CT ID: 190823004

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 4 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Penicillamine	DM40EF6	Approved	Small molecular drug	[1]
TRIENTINE	DMD2WPG	Approved	Small molecular drug	[2]
Trientine Hydrochloride	DM0KCV1	Approved	Small molecular drug	[3]
Zinc Acetate	DM3X357	Approved	Small molecular drug	[3]

This Disease is Treated as An Indication in 3 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
VTX-801	DMQU7HQ	Phase 2	Gene therapy	[4]
WTX-101	DMQK032	Phase 2	NA	[5]
UX701	DMD1T2D	Phase 1/2	Gene therapy	[6]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 16 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
AHCY	TTE2KUJ	moderate	Genetic Variation	[7]
APOE	TTKS9CB	Strong	Genetic Variation	[8]
ARSA	TTYQANR	Strong	Genetic Variation	[9]
GALNS	TTT9YPO	Strong	Biomarker	[10]
GCH1	TTLSWP6	Strong	Biomarker	[11]
HAMP	TTRV5YJ	Strong	Biomarker	[12]
HMGCR	TTPADOQ	Strong	Biomarker	[13]
LOX	TTQHNAM	Strong	Biomarker	[14]
LOXL2	TTFSUHX	Strong	Biomarker	[14]
MTF1	TTTQDEO	Strong	Genetic Variation	[15]
PNPLA3	TTEUAEH	Strong	Genetic Variation	[16]
PPP3CA	TTA4LDE	Strong	Biomarker	[12]
PRNP	TTY5F9C	Strong	Genetic Variation	[17]
SMPD1	TTJTM88	Strong	ModifyingMutation	[18]
SNCA	TT08OSU	Strong	Biomarker	[12]
ANXA5	TT2Z83I	Definitive	Biomarker	[19]

This Disease Is Related to 6 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
ATP7A	DT0LT17	Limited	Biomarker	[20]
SLC31A1	DTP8L4F	Limited	Biomarker	[21]
SLC31A2	DT8Q56F	Strong	Biomarker	[22]
SLC39A14	DTZ6IJW	Strong	Biomarker	[23]
SLC39A8	DTLPQGT	Strong	Genetic Variation	[23]
ATP7B	DT206GF	Definitive	Autosomal recessive	[24]

This Disease Is Related to 4 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
GPT	DER5HFI	Limited	Genetic Variation	[25]
ASMT	DEHGR57	Strong	Biomarker	[12]
CYP27B1	DE3FYEM	Strong	Biomarker	[26]
FXN	DEXVHDB	Strong	Genetic Variation	[27]

This Disease Is Related to 30 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
MBD6	OTDHBSFS	Limited	Biomarker	[8]
A2M	OTFTX90K	Strong	Biomarker	[12]
AFM	OTPOR8IO	Strong	Biomarker	[28]
AMELX	OTIN26MM	Strong	Biomarker	[29]
ANKS1B	OT26DGM9	Strong	Biomarker	[12]
BHMT	OTYB6PXZ	Strong	Biomarker	[12]
CAMK2A	OTJGX19T	Strong	Biomarker	[12]
CCDC115	OT04AZNZ	Strong	Genetic Variation	[30]
CCS	OTXHT3QO	Strong	Altered Expression	[31]
CHMP2B	OTZA7RJB	Strong	Genetic Variation	[32]
DNAJC5	OTCZDXAL	Strong	Biomarker	[33]
FNDC3A	OTUX3S2I	Strong	Genetic Variation	[34]
GTF2A1L	OTDQHVAI	Strong	Biomarker	[28]
HFE	OTDD93KB	Strong	Genetic Variation	[35]
INO80	OTJBMS8T	Strong	Genetic Variation	[8]
MBD1	OTD19VO6	Strong	Biomarker	[36]
MT1X	OT9AKFVS	Strong	Biomarker	[37]
NDUFAB1	OTF906UR	Strong	Biomarker	[38]
NDUFB7	OT2CHQQ1	Strong	Biomarker	[12]
PAGR1	OTXR5PQ8	Strong	Biomarker	[10]
PANK2	OTFBW889	Strong	Biomarker	[39]
PDCD10	OTCHJTSF	Strong	Genetic Variation	[40]
PNOC	OTJEAADN	Strong	Altered Expression	[41]
PPP3CB	OTEGNEHW	Strong	Biomarker	[12]
PRC1	OTHD0XS0	Strong	Biomarker	[42]
PROP1	OT8GF6N8	Strong	Genetic Variation	[43]
SDHAF2	OT0UG9H5	Strong	Biomarker	[12]
STON1	OT2HPUAI	Strong	Biomarker	[28]
TIMP1	OTOXC51H	Strong	Biomarker	[44]
ATP7B	OTPWLNCO	Definitive	Autosomal recessive	[24]

References

• [1] Penicillamine FDA Label
• [2] Trientine FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] ClinicalTrials.gov (NCT04537377) A Phase I/II, Multicenter, Non-randomized, Open Label, Adaptive Design, 5-year Follow-up, Single Dose-escalation Study of VTX-801 in Adult Patients With Wilson's Disease. U.S.National Institutes of Health.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] ClinicalTrials.gov (NCT04884815) A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Seamless, Adaptive, Safety, Dose-Finding, and Phase 3 Clinical Study of UX701 AAV-Mediated Gene Transfer for the Treatment of Wilson Disease. U.S.National Institutes of Health.
• [7] Epigenetic changes of the thioredoxin system in the tx-j mouse model and in patients with Wilson disease.Hum Mol Genet. 2018 Nov 15;27(22):3854-3869. doi: 10.1093/hmg/ddy262.
• [8] Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype.Liver Int. 2019 Jan;39(1):177-186. doi: 10.1111/liv.13967. Epub 2018 Oct 8.
• [9] Wilson's disease with Leu492Ser mutation and arylsulfatase A pseudodeficiency: just a coincidence?.Neurol Sci. 2004 Apr;25(1):18-20. doi: 10.1007/s10072-004-0220-z.
• [10] Comparative assessment of clinical rating scales in Wilson's disease.BMC Neurol. 2017 Jul 21;17(1):140. doi: 10.1186/s12883-017-0921-3.
• [11] Treatable inherited rare movement disorders.Mov Disord. 2018 Jan;33(1):21-35. doi: 10.1002/mds.27140. Epub 2017 Sep 1.
• [12] The early molecular processes underlying the neurological manifestations of an animal model of Wilson's disease.Metallomics. 2013 May;5(5):532-40. doi: 10.1039/c3mt20243g. Epub 2013 Mar 21.
• [13] Abnormal hepatobiliary and circulating lipid metabolism in the Long-Evans Cinnamon rat model of Wilson's disease.Life Sci. 2007 Mar 27;80(16):1472-83. doi: 10.1016/j.lfs.2007.01.017. Epub 2007 Jan 20.
• [14] Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J Hepatol. 2005 Sep;43(3):499-507. doi: 10.1016/j.jhep.2005.02.052.
• [15] An MTF1 binding site disrupted by a homozygous variant in the promoter of ATP7B likely causes Wilson Disease.Eur J Hum Genet. 2018 Dec;26(12):1810-1818. doi: 10.1038/s41431-018-0221-4. Epub 2018 Aug 7.
• [16] Hepatic steatosis in Wilson disease--Role of copper and PNPLA3 mutations.J Hepatol. 2015 Jul;63(1):156-63. doi: 10.1016/j.jhep.2015.01.034. Epub 2015 Feb 9.
• [17] Influence of Apolipoprotein E polymorphism on susceptibility of Wilson disease.Ann Hum Genet. 2018 Mar;82(2):53-59. doi: 10.1111/ahg.12223. Epub 2017 Oct 23.
• [18] Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide.Nat Med. 2007 Feb;13(2):164-70. doi: 10.1038/nm1539. Epub 2007 Jan 28.
• [19] Proteomic analysis of the hepatic tissue of Long-Evans Cinnamon (LEC) rats according to the natural course of Wilson disease.Proteomics. 2011 Sep;11(18):3698-705. doi: 10.1002/pmic.201100122. Epub 2011 Aug 9.
• [20] Mechanistic and Structural Basis for Inhibition of Copper Trafficking by Platinum Anticancer Drugs. J Am Chem Soc. 2019 Jul 31;141(30):12109-12120.
• [21] Probing functional roles of Wilson disease protein (ATP7B) copper-binding domains in yeast.Metallomics. 2017 Jul 19;9(7):981-988. doi: 10.1039/c7mt00101k.
• [22] Non-Indian childhood cirrhosis.Eur J Med Res. 1999 Jul 28;4(7):293-7.
• [23] Inherited disorders of transition metal metabolism: an update.J Inherit Metab Dis. 2017 Jul;40(4):519-529. doi: 10.1007/s10545-017-0030-x. Epub 2017 Mar 16.
• [24] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [25] Familial screening of children with Wilson disease: Necessity of screening in previous generation and screening methods.Medicine (Baltimore). 2018 Jul;97(27):e11405. doi: 10.1097/MD.0000000000011405.
• [26] Metabolism of 25-hydroxyvitamin D in copper-laden rat: a model of Wilson's disease.Am J Physiol. 1988 Feb;254(2 Pt 1):E150-4. doi: 10.1152/ajpendo.1988.254.2.E150.
• [27] Mitochondria.J Neurol Neurosurg Psychiatry. 2003 Sep;74(9):1188-99. doi: 10.1136/jnnp.74.9.1188.
• [28] Plasmapheresis Combined with Continuous Plasma Filtration Adsorption Rescues Severe Acute Liver Failure in Wilson's Disease before Liver Transplantation.Blood Purif. 2019;47(1-3):120-125. doi: 10.1159/000493909. Epub 2018 Oct 25.
• [29] Tryptophan-kynurenine profile in pediatric autoimmune hepatitis.Immunol Res. 2019 Feb;67(1):39-47. doi: 10.1007/s12026-019-9068-1.
• [30] CCDC115-CDG: A new rare and misleading inherited cause of liver disease.Mol Genet Metab. 2018 Jul;124(3):228-235. doi: 10.1016/j.ymgme.2018.05.002. Epub 2018 May 9.
• [31] Mutation analysis of copper transporter genes in patients with ethylmalonic encephalopathy, mitochondriopathies and copper deficiency phenotypes.J Inherit Metab Dis. 2003;26(1):55-66. doi: 10.1023/a:1024027630589.
• [32] Polymorphisms of metal transporter genes DMT1 and ATP7A in Wilson's disease.J Trace Elem Med Biol. 2014 Jan;28(1):8-12. doi: 10.1016/j.jtemb.2013.08.002. Epub 2013 Aug 25.
• [33] Different cortical excitability profiles in hereditary brain iron and copper accumulation.Neurol Sci. 2020 Mar;41(3):679-685. doi: 10.1007/s10072-019-04147-0. Epub 2019 Nov 26.
• [34] Mutation analysis of ATP7B gene in Turkish Wilson disease patients: identification of five novel mutations. Eur J Med Genet. 2013 Apr;56(4):175-9. doi: 10.1016/j.ejmg.2013.01.003. Epub 2013 Jan 17.
• [35] Iron metabolism and the role of HFE gene polymorphisms in Wilson disease.Liver Int. 2012 Jan;32(1):165-70. doi: 10.1111/j.1478-3231.2011.02661.x. Epub 2011 Oct 17.
• [36] Copper relay path through the N-terminus of Wilson disease protein, ATP7B.Metallomics. 2019 Sep 1;11(9):1472-1480. doi: 10.1039/c9mt00147f. Epub 2019 Jul 19.
• [37] The effect of zinc and D-penicillamine in a stable human hepatoma ATP7B knockout cell line. PLoS One. 2014 Jun 3;9(6):e98809. doi: 10.1371/journal.pone.0098809. eCollection 2014.
• [38] ACP Best Practice No 163. Wilson's disease: acute and presymptomatic laboratory diagnosis and monitoring.J Clin Pathol. 2000 Nov;53(11):807-12. doi: 10.1136/jcp.53.11.807.
• [39] Neuropathology and pathogenesis of extrapyramidal movement disorders: a critical update-I. Hypokinetic-rigid movement disorders.J Neural Transm (Vienna). 2019 Aug;126(8):933-995. doi: 10.1007/s00702-019-02028-6. Epub 2019 Jun 18.
• [40] Hereditary Multiple Cerebral Cavernous Malformations Associated with Wilson Disease and Multiple Lipomatosis.World Neurosurg. 2017 Sep;105:1034.e1-1034.e6. doi: 10.1016/j.wneu.2017.06.002. Epub 2017 Jun 8.
• [41] Elevated plasma nociceptin level in patients with Wilson disease.Brain Res Bull. 2002 Jul;58(3):311-3. doi: 10.1016/s0361-9230(02)00795-5.
• [42] Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers.Epigenetics Chromatin. 2019 Feb 1;12(1):10. doi: 10.1186/s13072-019-0255-z.
• [43] Exome-based search for recurrent disease-causing alleles in Russian population.Eur J Med Genet. 2019 Jul;62(7):103656. doi: 10.1016/j.ejmg.2019.04.013. Epub 2019 Apr 24.
• [44] Elevated copper impairs hepatic nuclear receptor function in Wilson's disease.J Clin Invest. 2015 Sep;125(9):3449-60. doi: 10.1172/JCI78991. Epub 2015 Aug 4.