Wilson’s Disease
Pathophysiology:
-Autosomal recessive disorder of impaired copper excretion, due to mutation on chromosome 13
(MANY different types of gene mutations). Get defective copper transport with normal absorption,
causing increased circulating copper that accumulates in brain and liver, causing damage to the
tissue.
-Peak incidence around 17 years, but can present as late as 60’s (and maybe even later).
-Neuropathology: Diffuse atrophy, enlarged ventricles, particularly putamen/caudate and frontal lobes.
Opalaski cells in the globus pallidus are a classic finding.
Signs/Symptoms:
A) Hepatic (hepatitis, cirrhosis, fulminant liver failure)
B) Psychiatric (frontal lobe behavior/personality changes, depression)
C) Neurologic:
-Classically presents as either akinetic rigidity, generalized dystonia, or postural/intention tremor with
ataxia, titubation, and dysarthria.
-Dysarthria (97%; usually early)
-Tremor (20-60% get action or rest tremor; classically the “wing beating” tremor of deltoids)
-Parkinsonism (20-60%), Dystonia (10-60%; classically can see risus sardonicus or vocal cord
dystonia)
chorea, seizures (6%), ataxia (30%), drooling, hyperreflexia.
-Ophthalmologic: Kayser-Fleischer rings (100% who also have neuro symptoms), eye
movement abnormalities.
-Untreated, becomes a severe dystonic akenetic mute state with retained cognition
DDX:
-Essential tremor, early onset Parkinsons, generalized dystonia, Huntington’s, SCAs.
Diagnosis:
-Serum ceruloplasmin (90% sensitive), 24 hour urine copper (<50 is not Wilson’s).
-Slit lamp exam for KF rings.
-MRI brain: high T2 signal in the lentiform and caudate nuclei, thalamus, brain stem, and white
matter. Basal ganglia with giant panda sign.
-Gold standard: Liver biopsy with quantitative copper levels (not necessary for diagnosis, though can
be useful if clinical question remains)
Treatment:
1) Chelation: Goal is 24 hour urine copper level 250-500, monitored at least yearly.
A) Zinc acetate (first line, particularly if asymptomatic): 50-200mg TID. Best option; minimal
side effects and no evidence of neurologic worsening due to treatment, BUT takes 4-8 months
to kick in (during which time neurologic worsening from the elevated copper can continue).
B) Trientine (second line due to side effects, use if very symptomatic): 250mg daily or 250mg
BID
-Also give pyridoxine 25mg/day.
-Works fast, BUT can cause major neurologic worsening early in treatment (50% have
worsening, 50% of those who worsen never get back to their pre-penicillamine baseline, and
up to 30% of treated patients can becomes disabled or die). Hypothesized to be due to
mobilized large hepatic copper stores getting into blood and affecting brain.
-Worsening tends to occur in the first 4 weeks of treatment. No way to predict who will get side
effects, which can include allergy, marrow suppression, neurologic worsening.
-Improvement in neurologic symptoms tends to occur beginning in 3-6 months.
-Avoid eating liver, chocolate, nuts, coffee, and shellfish during the initial de-coppering phase, as
these are foods high in copper.
-Maintenance chelation is required life-long.
-If symptoms worsen despite treatment, recheck 24 hour urine copper, and consider if medication
non-compliance could be a factor.
2) GI referral; also consider referrals to psych, SLP.
3) Liver transplant: curative, but often not necessary.
4) Screen 1st degree relatives, cousins, nephews/nieces as well. Place on zinc therapy if positive.
Prognosis for neurologic recovery:
-Hard to predict. Appropriate treatment prevents further worsening, but may not reverse existing
damage/symptoms.
-Dysarthria + tremor types do best (82% chance to become symptom-free or have minor symptoms),
followed by chorea (75%), parkinsonism (65%), and dystonia (53%)
RESOURCES: Neurologic Wilson’s disease. Matthew T. Lorincz. Annals of the New York
Academy of Sciences (2010)