Genotype-phenotype correlation in Wilson disease (WD) is intriguing. This is well-illustrated by several reports of homozygotic WD twins presenting with totally different phenotypes, as well as contrasting response to therapy.

The ATP7B gene, the gene underlying WD, can be affected by thousands of mutations that may lead to the inactivation of the ATP7B transporter in hepatocytes and consequent impairment of copper homeostasis. Copper intoxication leads to tissue damage, which is responsible for clinical manifestations in WD.

“Copper intoxication is dependent on duration of exposure to and the amount of toxic copper which is penetrated into the tissue of an organ. However, damage of an organ in WD is not only dependent on the transport of copper to the organ, but also on the ability of the organ to regenerate,” explained Samadzadeh et al in Genes.

Moreover, evidence suggests that difference in time to diagnosis, nutrition, and lifestyle might contribute to the wide variability of phenotypes. The situation becomes even more complex after initiating WD-specific therapy as patients can be treated with different drugs, as well as different doses of a certain drug.

History: Monozygotic Sisters With Distinct Phenotypes

Two monozygotic sisters lived without evidence of the disease until the age of 22 years. After getting divorced, sister 1 developed neuropsychiatric symptoms and Kayser-Fleischer rings, which led to the diagnosis of WD. She initiated treatment with d-penicillamine (DPA).

Both sisters underwent genetic testing, which confirmed the diagnosis of WD. Sister 1 experienced a rapid deterioration in a 4-months period, even with increased DPA dose, while sister 2 remained asymptomatic at first clinical visit.

Despite being clinically asymptomatic, sister 2 had abnormal liver values and started DPA therapy up to 600 mg. Then, to prepare for pregnancy, DPA dose was increased and then reduced after the positive test. She remained asymptomatic during pregnancy.

Sister 1, the severely affected sister, was almost anarthric and had severe difficulties in swallowing, severe juvenile parkinsonian syndrome with considerable slowness of movement, severe stance and gait ataxia, vertical gaze palsy, and hypersalivation. She needed a percutaneous endoscopic gastrostomy and was dependent on a wheelchair or an accompanying person. She also suffered from mild anxiety disorder.

DPA dose was increased up to 600 mg, 3 times daily. Her condition improved initially, but 6 months after she experienced general deterioration after 6 months. In addition, she developed nephrotic syndrome as DPA side effect, which prompted a therapy switch to trientine tetrahydrochloride (Cuvrior™). Her condition improved, and she was able to walk a few steps without help. However, after a long-distance 2-month trip, she was admitted to the hospital due to fever and cough and eventually died of bronchopneumonia.

Can Epigenetics Explain the Difference?

Several authors have been suggesting that the explanation for such genotype-phenotype discordance could lay on epigenetics. “Although ATP7B mutations define WD, they do not explain the phenotypic variations and diverse clinical presentations, and no firm correlations between genotype and phenotype exist. For this reason, environmental factors and epigenetic phenomena are thought to contribute to WD pathogenesis,” Dev and Hamilton wrote in Cellular and Molecular Gastroenterology and Hepatology.

Accordingly, studies in rodent models have shown downregulation of the S-adenosylhomocysteine hydrolase activity, an enzyme involved in methionine metabolism, in the presence of hepatic copper accumulation. Moreover, a mouse model with a spontaneous point mutation in the copper transporter showed dysregulation of methionine metabolism and global DNA hypomethylation in hepatocytes, which may affect the regulation of genes involved in liver damage. These and other findings suggest a possible role for epigenetics in determining WD phenotype.


Samadzadeh S, Kruschel T, Novak M, et al. Different response behavior to therapeutic approaches in homozygotic Wilson’s disease twins with clinical phenotypic variability: case report and literature review. Genes. Published online July 7, 2022. doi:10.3390/genes13071217

Dev S, Hamilton JP. Wilson disease: epigenetic factors contribute to genetic mutations to affect the disease. Cell Mol Gastroenterol Hepatol. Published online August 2, 2021. doi:10.1016/j.jcmgh.2021.07.010