Early Treatment May Protect Cognitive Function in Wilson Disease, With Michael Schilsky, MD

New 5-year data from the Wilson Disease Registry indicate patients without severe neurologic involvement can show meaningful cognitive gains after early detection and therapy.

Michael Schilsky, MD, a professor of medicine and medical director of adult liver transplant at Yale-New Haven Transplantation Center, presented the findings at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025, and reported patients with abnormal baseline cognition saw significant MoCA improvement over time when treated early in the disease course.

WD is a rare inherited multisystem disorder affecting approximately 1 in 30,000 individuals worldwide. The disease primarily impacts hepatic and neurological function and stems from pathogenic mutations in the ATP7B gene, which impairs the liver’s ability to excrete excess copper. Copper accumulation damages the liver and brain, and without daily treatment, the disease is fatal.

In patients, early signs of excess copper may present as neurologic (40-45%), hepatic (50-60%), or psychiatric (10-20%) symptoms. Although the liver is affected first, neurological symptoms are the initial presentation in about 40% of patients. Before diagnosis, 20% of patients have already seen a psychiatrist, and some report psychological or behavioral changes such as depression, anxiety, impulsivity, and aggression.

“When you see patients with severe neurologic impairment or other mental health concerns, the key questions become: How intact are they, and what is the effect of therapy?” said Schilsky in an interview with HCPLive. “It was important to examine this prospectively. Using a multinational, multicenter registry that collected detailed data, we evaluated cognition, quality of life, neurologic function, and liver function to understand baseline cognition and how it changes over time.”

The study conducted a cross-sectional and longitudinal analysis using the Montreal Cognitive Assessment (MoCA) and the Unified Wilson’s Disease Rating Scale (UWDRS), a disease-specific tool evaluating neurologic symptoms. With a possible score of 30, a MoCA score of ≥ 26 is considered normal and <26 is considered abnormal, indicating cognitive impairment. Participants were classified by phenotype at diagnosis: asymptomatic (21%), hepatic (30%), or neurologic (37%).

The cohort included 138 patients with a mean baseline MoCA score of 26.3. A total of 44 patients (32%) had MoCA scores <26 (mean 22.9, 3), distributed as 21% asymptomatic, 30% hepatic, and 37% neurologic.

Investigators found a negative correlation between MoCA and UWDRS at baseline (r = -0.47, P = <.001, Pearson), and patients with MoCA <26 had significantly higher UWDRS scores (P = .0003).

Over 2-3 years, investigators observed an average 1-point increase in MoCA (P = .001), suggesting cognitive improvement with treatment. In a longitudinal follow-up at 2, 3, 4, and 5 years (P < .01), only patients with baseline MoCA <26 showed significant improvements in cognitive function. Phenotype-adjusted analysis revealed the hepatic group experienced a 0.6-1.8 MoCa increase from baseline.

Patients with less severe neurologic disease showed less Central Nervous System injury at baseline, which was associated with a greater likelihood of cognitive improvement over time.

“Overall, cognition is preserved in most patients and remains stable with treatment,” said Schilsky. “And importantly, with treatment, patients without severe neurologic impairment are likely to improve.”

References

1. Schilsky, M, Ulcay A, Maras H, et al. Cognitive function in patients with Wilson disease: prospective analysis from the Wilson Disease Registry study. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

2. Disease W. Wilson Disease - Wilson Disease Association. Wilson Disease Association. Published August 13, 2021. Accessed November 14, 2025. https://wilsondisease.org/do-i-have-wilson-disease/?gad_source=1&gad_campaignid=16684019432&gbraid=0AAAAADN9hfNH0Qklo1N7KKX3qO0womQLJ&gclid=CjwKCAiAw9vIBhBBEiwAraSATuJdNxoP57_7zjL0DUUF0B9EceR3whBrdSIFmutmQSsj2E3BL4nQkhoC-xwQAvD_BwE