Erum Naqvi obtained her Ph.D. in Molecular Medicine from Hannover Medical School (Germany) after completing her Masters in Biomedical Science and Bachelors in Microbiology from University of Delhi (India). She has several years of experience as a science writer.
Wilson disease is a rare inherited disorder caused by mutations in the ATP7B gene, which encodes a transmembrane copper-transporting ATPase. The abnormal ATPase causes copper to accumulate in vital organs such as the liver and brain, among others. The severity and symptoms vary among patients and within families depending on a combination of multiple genetic, epigenetic, hormonal, and environmental factors. Wilson disease is diagnosed mainly in individuals between the ages of 5 and 35 years. If diagnosed early, it is treatable.1,2
Liver dysfunction is the first clinical symptom in approximately 40% to 60% of patients with Wilson disease. The liver-related clinical manifestations may range from subtle, asymptomatic morphological changes or an acute, self-limited hepatitis-like illness to autoimmune-like hepatitis, recurrent jaundice (in the presence of hemolysis), cirrhosis with or without portal hypertension, and even acute liver failure. The probability that liver dysfunction will develop and its severity seem to depend on age and gender; a presentation with acute liver failure is more frequent in female than in male patients, and adult patients are more likely to have liver cirrhosis than are pediatric patients.2
Mild to moderate fatty liver on liver imaging or liver biopsy is usually the first finding in children and young adults with Wilson disease. Without treatment, these patients go on to acquire chronic liver disease with portal hypertension, hepatosplenomegaly, ascites, a low serum albumin concentration, and coagulopathy.
The most severe form of liver involvement, acute liver failure, occurs predominantly in young female patients with Wilson disease. Liver failure is often associated with hemolytic anemia, severe coagulopathy, encephalopathy, and often rapidly progressive renal failure. Whereas the bilirubin level is highly elevated, the serum activity of aminotransferases is only moderately increased.2
To assess the severity of liver disease, computed tomography and magnetic resonance imaging are commonly performed at diagnosis and at follow-up. The most common findings are fatty infiltration, contour irregularity, and right lobe atrophy.2
Neurological problems are the second most frequent clinical manifestation of Wilson disease after hepatic manifestations. The mean age at symptom onset is reported to be 20 to 30 years3; however, the youngest patient with a neurological presentation of Wilson disease was 6 years old, and the oldest was 72 years. The main neurological symptoms include various movement disorders associated with a wide spectrum of involuntary movements; these often overlap. The most common neurological features include tremor, dystonia, parkinsonism, dysarthria (difficulty speaking and poor articulation), gait and posture disturbances, drooling, and dysphagia. The disturbances may severely affect the activities of daily living.2-4
Tremor, which can be resting, postural, or kinetic, is a characteristic and frequent symptom reported in up to 55% of patients with a neurological presentation of Wilson disease. It may begin as unilateral or bilateral tremor with involvement mainly of the distal upper extremities. With time, the legs, head, or even the entire body may be affected, often bilaterally.2-4
In approximately 11% to 65% of patients with Wilson disease, dystonia is reported as the first symptom. It can be focal (involving one body part), segmental (involving one segment), multisegmental (involving multiple segments), or generalized. The most characteristic dystonic presentation of Wilson disease is risus sardonicus, which is an abnormal facial expression resembling a fixed smile that is due to dystonia of the risorius muscle. In patients who do not receive treatment, symptoms usually progress to generalized dystonia, contractures, and a terminal dystonic state.2
Parkinsonism occurs in 19% to 62% of patients with Wilson disease. It usually presents as symmetrical bradykinesia, rigidity, hypomimia, and gait and posture disturbances, in addition to dysarthria, dysphagia, and drooling. Ataxia (ataxic gait and posture, impaired coordination, intentional tremor, dysarthria) occurs in 30% of patients. Gait and posture disturbances are reported in 44% to 75% of patients with a neurological presentation of Wilson disease, and 57% have impaired handwriting, often an early sign of the disease. Dysarthria, reported in up to 97% of patients with neurological Wilson disease, seems to be the most frequent neurological symptom. In some cases, dysarthria may become so severe and persistent that verbal communication is impossible for the rest of the patient’s life.2
Dysphagia, or difficulties with any phase of swallowing (oral preparation, oral transit, swallowing), and drooling are reported in up to 50% of patients with neurological Wilson disease. Dysphagia varies from mild to severe and may lead to general health complications, including broncho-aspiration, pneumonia, malnutrition, and weight loss. Drooling is a classic neurological symptom of Wilson disease; it is observed in almost 68% of patients with neurological Wilson disease, occurring as a result of dysphagia or orofacial dystonia.2,4
Epilepsy resulting in generalized seizures may occur in 6.2% to 8.3% of patients with Wilson disease. Other neurological symptoms have also been reported, including olfactory dysfunction, neuropathy (due to liver failure or treatment-induced copper deficiency), restless leg syndrome (RLS), rapid eye movement (REM) sleep behavior disorder and other sleep abnormalities, tics, myoclonus, headache, pyramidal signs, oculomotor impairment, and taste dysfunction.2,4,5
Psychiatric symptoms have been reported as the initial manifestation of Wilson disease in approximately 30% of patients. These vary widely from patient to patient, from major depressive disorder to bipolar disorder; the diagnosis is often missed or delayed, or the symptoms are often misdiagnosed as substance abuse. They may occur before, concurrently with, or after the diagnosis and treatment of Wilson disease. The symptoms may start in childhood as declining academic performance, inappropriate behavior, or impulsiveness. The most common psychiatric manifestations of Wilson disease are mood disturbances. Depression develops in approximately 20% to 60% of patients, and the rate of suicidal attempts is high, ranging between 4% and 16%. Depression may develop in response to the chronic disease or to physical incapacity due to neurological deficits. Bipolar disorder is reported in approximately 14% to 18% of patients with Wilson disease.2,6,7
Psychosis may also occur in patients with Wilson disease, predominantly in those with neurological symptoms. Patients usually have an initial diagnosis of schizophrenia or schizoaffective and delusional disorder.2,6
Other psychiatric disturbances frequently associated with Wilson disease include behavioral and personality disorders. The most common manifestations are irritability, aggression, and antisocial behavior. Other reported psychiatric conditions are catatonia, anorexia nervosa, bulimia, obsessive-compulsive disorder, and attention-deficit hyperactivity disorder.2,6
Ophthalmological manifestations include Kayser-Fleischer ring and sunflower cataract, which are caused by the pathological accumulation of copper in the eyes. Kayser-Fleischer rings are caused by the accumulation of copper in the Descemet membrane and appear as a golden, brown, or green coloration at the periphery of the cornea. These rings are an important diagnostic feature that occur in almost 100% of patients with neurological Wilson disease, 40% to 50% with hepatic Wilson disease, and 20% to 30% with presymptomatic Wilson disease. Sunflower cataract appears as a central disc with radiating petal-like fronds located under the lens capsule and occurs rarely (2%-20% of cases). The most recent ophthalmological studies suggest that the retina and optic nerve may also be affected in Wilson disease.2,8,9
In young female patients, Wilson disease may affect the menstrual cycle, preventing either menarche or menopause. Menstrual problems are due to hormonal disturbances associated with liver disease in Wilson disease. Other common problems include menstrual irregularity, loss of menstruation (amenorrhea), miscarriages, and infertility.10
Some other symptoms reported may include kidney stones and renal tubular damage, premature arthritis, and other forms of joint and bone involvement, including thinning of the bones (osteoporosis), the development of bony outgrowths (osteophytes) at large joints, and reduced joint spaces in the spine and extremities.10
- Wilson’s disease – symptoms and causes. Mayo Clinic. Accessed September 27, 2022.
- Członkowska A, Litwin T, Dusek P, et al. Wilson disease. Nat Rev Dis Primers. 2018;4(1):21. doi:10.1038/s41572-018-0018-3
- Pfeiffer RF. Wilson’s disease. Semin Neurol. 2007;27(2):123-132. doi:10.1055/s-2007-971173
- Litwin T, Dzieżyc K, Karliński M, Szafrański T, Członkowska A. Psychiatric disturbances as a first clinical symptom of Wilson’s disease – case report. Psychiatr Pol. 2016;50(2):337-344. doi:10.12740/PP/45218
- Machado A, Chien HF, Deguti MM, et al. Neurological manifestations in Wilson’s disease: report of 119 cases. Mov Disord. 2006;21(12):2192-2196. doi:10.1002/mds.21170
- Zimbrean PC, Schilsky ML. Psychiatric aspects of Wilson disease: a review. Gen Hosp Psychiatry. 2014;36(1):53-62. doi:10.1016/j.genhosppsych.2013.08.007
- Carta MG, Sorbello O, Moro MF, et al. Bipolar disorders and Wilson’s disease. BMC Psychiatry. 2012;12:52. doi:10.1186/1471-244X-12-52
- Członkowska A, Litwin T. Wilson disease – currently used anticopper therapy. Handb Clin Neurol. 2017;142:181-191. doi:10.1016/B978-0-444-63625-6.00015-X
- Langwińska-Wośko E, Litwin T, Szulborski K, Członkowska A. Optical coherence tomography and electrophysiology of retinal and visual pathways in Wilson’s disease. Metab Brain Dis. 2016;31(2):405-415. doi:10.1007/s11011-015-9776-8
- Wilson disease. NORD (National Organization for Rare Disorders). Accessed September 27, 2022.
Reviewed by Harshi Dhingra, MD, on 8/29/2022.