Wilson Disease (ATP7B)

Genetic Region: ATP7B

ATP7B

ATP7B

Wilson disease is caused by mutations in the ATP7B gene, located on the long arm of chromosome 13 (q14.3). This gene encodes an enzyme called copper-transporting ATPase, which plays a key role in copper metabolism. The enzyme’s function is to transport copper into and out of cells, and help eliminate excess copper via bile.

The ATP7B protein has the following structure:

8 transmembrane domains for copper transport across cell membranes

3 intracellular domains that bind and hydrolyze ATP

6 metal-binding domains (MBDs) for copper binding

C-terminal regulatory domain

Mutations in this gene impair copper excretion, causing copper to build up to toxic levels in the liver, brain, kidneys, and eyes.す。

Disorder Overview

Wilson disease, also known as hepatolenticular degeneration, is a genetic disorder of copper metabolism. Normally, copper is utilized in various enzymes, but any excess copper is toxic. Healthy individuals process and excrete excess copper through bile. In Wilson disease, this system fails, causing copper to accumulate in the liver, brain, eyes, and kidneys.

Symptoms may not appear in infants, but they usually develop between the ages of 5 and 35, although onset can occur at any age. Initially, the disease may present as liver dysfunction, but neurological or psychiatric symptoms may also be the first signs.

A distinctive sign of Wilson disease is the Kayser-Fleischer ring, a green-brown ring around the cornea of the eye, which is a key diagnostic clue.

Epidemiology

Wilson disease is rare, with a global incidence of approximately 1 in 30,000 to 50,000 people. However, in specific regions such as Japan, China, and Sardinia, the frequency can be as high as 1 in 10,000 people. Recent genetic studies suggest that the number of carriers (those who carry one copy of the mutated gene) is higher than the number of diagnosed cases.

Etiology

The cause of Wilson disease is mutations in the ATP7B gene, leading to an inability to properly regulate copper in the body. The main mechanisms affected are:

Impaired synthesis of ceruloplasmin, a protein that transports copper in the blood

Failure to excrete copper through bile, leading to copper buildup in the liver

The release of toxic, unbound copper into the bloodstream, which then damages organs such as the brain and kidneys

Symptoms

原因は、ATP7B遺伝子の両方に変異があることです。この遺伝子の異常によって：

1. セロロプラスミン（ceruloplasmin）という血液中の銅を運ぶタンパク質がうまく作られない
2. 銅が胆汁中に排出されずに肝臓にたまり
3. その結果、肝臓から全身に毒性をもつ「遊離銅（non-ceruloplasmin-bound copper）」が放出され、脳や腎臓、角膜などに障害になる

症状 | Symptoms

The symptoms of Wilson disease are varied, depending on where copper accumulates in the body:

Liver (most commonly affected)

Hepatitis, cirrhosis, liver failure

Ascites (fluid buildup in the abdomen) and jaundice (yellowing of skin and eyes)

Hemolytic anemia (destruction of red blood cells) in acute liver failure

Rarely, liver cancer

Neurological Symptoms

Tremors, muscle rigidity

Speech difficulties, swallowing issues

Dystonia (abnormal muscle movements)

Ataxia (unsteady movements)

Parkinson-like symptoms (slowed movements, expressionless face)

Seizures, cognitive impairment (memory and concentration problems)

Psychiatric Symptoms

Mood swings, irritability

Depression, anxiety, insomnia

Mental health issues often appear in adolescence or early adulthood

Eye Findings

Kayser-Fleischer ring: Green or brown ring around the cornea

Sunflower cataract: Rare lens opacity that resembles a sunflower in shape

Kidney and Endocrine Issues

Proteinuria, aminoaciduria, glycosuria (kidney dysfunction)

Hypoparathyroidism (low calcium levels)

Bone and Blood Issues

Osteoporosis, joint pain

Hemolytic anemia (non-autoimmune type)

Decreased platelets and white blood cells (due to spleen enlargement)

Testing & Diagnosis

The diagnosis of Wilson disease involves a combination of tests:

Blood Tests

Ceruloplasmin levels: Normally <20 mg/dL, although this is not always conclusive

Serum copper levels: Free copper calculation is key for diagnosis

Formula: Free Cu = Total Copper – (3.15 × Ceruloplasmin)

Free copper levels >25 µg/dL indicate active disease

Urine Tests

24-hour urinary copper excretion: >100 µg/day is diagnostic

Imaging

MRI: Abnormal signals in the brain, especially the basal ganglia and thalamus

Slit-lamp examination: Detection of the Kayser-Fleischer ring

Genetic Testing

Full exonic analysis of the ATP7B gene (NGS) is recommended

Genetic counseling is advised for family members

Liver Biopsy (if necessary)

Copper content >250 µg/g (dry weight) is diagnostic

New Diagnostic Methods

Mass spectrometry of ATP7B peptides: A promising future diagnostic tool, especially for detecting early-stage disease

Treatment & Management

The goal of treatment is to remove excess copper and prevent further accumulation. Long-term treatment and follow-up are required.

Medications

D-penicillamine: Chelates copper for excretion via urine (used in early stages)

Trientine: Similar to penicillamine, but preferred for those unable to tolerate penicillamine

Zinc salts: Inhibit copper absorption in the gut (used for maintenance)

Tetrathiomolybdate: Prevents copper binding to albumin (experimental)

Neuro-psychiatric Management

Tremors: Propranolol, clonazepam

Dystonia/Parkinsonism: Anticholinergics, levodopa

Psychiatric symptoms: Antipsychotics, antidepressants as needed

Surgical Treatment

Deep brain stimulation (DBS): Effective for severe dystonia and tremors

Liver transplant: Considered for acute liver failure or advanced cirrhosis

Diet and Lifestyle

Avoid copper-rich foods (e.g., liver, shellfish, chocolate, nuts)

Avoid copper-containing water and supplements

Regular follow-up every 6-12 months is crucial

Prognosis

With early diagnosis and ongoing treatment, patients can lead healthy lives. However, neurological symptoms may not fully reverse, even with treatment. Stopping treatment or non-compliance (especially during adolescence) significantly increases the risk of disease relapse.

Liver transplants restore liver function, but not all symptoms improve.

Helpful Terms

• Copper: An essential metal for human health, but toxic in excess
• Ceruloplasmin: A protein that carries copper in the blood
• Autosomal Recessive Inheritance: Both parents must pass on a mutated gene for the disease to develop
• Chelating Agent: A medication that binds to toxic metals like copper and helps remove them from the body
• Kayser-Fleischer Ring: A green or brown ring in the eye cornea due to copper buildup
• Dystonia: Involuntary muscle movements
• Cirrhosis: Scarring of the liver that impairs its function
• Immuno-SRM: A diagnostic technique for detecting proteins in the blood with high precision
• ATP7B: The gene responsible for copper transport

References

• Yang, Guo-Min, et al. ‘Structures of the Human Wilson Disease Copper Transporter ATP7B’. Cell Reports, vol. 42, no. 5, May 2023, p. 112417. DOI.org (Crossref), https://doi.org/10.1016/j.celrep.2023.112417.
• Bitter, Ryan M., et al. ‘Structure of the Wilson Disease Copper Transporter ATP7B’. Science Advances, vol. 8, no. 9, Mar. 2022, p. eabl5508. DOI.org (Crossref), https://doi.org/10.1126/sciadv.abl5508.
• Collins, Christopher J., et al. ‘Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease’. Gastroenterology, vol. 160, no. 7, June 2021, pp. 2367-2382.e1. DOI.org (Crossref), https://doi.org/10.1053/j.gastro.2021.02.052.
• Ovchinnikova, Elena Vasilievna, et al. ‘Epidemiology of Wilson’s Disease and Pathogenic Variants of the ATP7B Gene Leading to Diversified Protein Disfunctions’. International Journal of Molecular Sciences, vol. 25, no. 4, Feb. 2024, p. 2402. DOI.org (Crossref), https://doi.org/10.3390/ijms25042402.
• Ganaraja VH, Holla VV, Pal PK. Current Management of Neurological Wilson’s Disease. Tremor Other Hyperkinet Mov (N Y). 2025 May 5;15:17. doi: 10.5334/tohm.938. PMID: 40351566; PMCID: PMC12063596.
• Kasztelan-Szczerbinska, Beata, and Halina Cichoz-Lach. ‘Wilson’s Disease: An Update on the Diagnostic Workup and Management’. Journal of Clinical Medicine, vol. 10, no. 21, Oct. 2021, p. 5097. DOI.org (Crossref), https://doi.org/10.3390/jcm10215097.
• Pop, Tudor Lucian, and Alina Grama. ‘New Developments in the Management of Wilson’s Disease in Children’. Global Pediatrics, vol. 8, June 2024, p. 100142. DOI.org (Crossref), https://doi.org/10.1016/j.gpeds.2024.100142.
• Perez G, Barber GP, Benet-Pages A, Casper J, Clawson H, Diekhans M, Fischer C, Gonzalez JN, Hinrichs AS, Lee CM, Nassar LR, Raney BJ, Speir ML, van Baren MJ, Vaske CJ, Haussler D, Kent WJ, Haeussler M. The UCSC Genome Browser database: 2025 update. Nucleic Acids Res. 2025 Jan 6;53(D1):D1243-D1249. doi: 10.1093/nar/gkae974. PMID: 39460617; PMCID: PMC11701590.

キーワード｜Keywords

^{ウィルソン病, Wilson disease, ATP7B, 常染色体劣性遺伝, 銅代謝異常, 肝レンズ核変性症, セロロプラスミン, カイザー・フライシャー輪, 神経症状, 精神症状, 肝硬変, 急性肝不全, キレート療法, 亜鉛療法, トリエンチン, D-ペニシラミン, 遺伝子検査, 質量分析, 遊離銅, 交換可能銅, バイオマーカー, 脳MRI, 小児肝疾患, 希少疾患, 複雑な症状, ATPアーゼ, 構造解析, 銅輸送, p.H1069Q, p.R778L, 神経ウィルソン病, 銅輸送経路, 肝移植, 遺伝カウンセリング, ペプチド診断, 免疫SRM, 臨床スコアリング, 遺伝子治療}