Wilson's Disease
A Neurology Perspective

Diagnosis

Motor abnormalities which are not clearly and unequivocally explained by a particular diagnosis should prompt the neurologist to consider Wilson's Disease. Neurologic abnormalities are almost always motor and not sensory disturbances. Kayser-Fleischer rings are invariably present when there are neurologic signs. While they may be visible to the naked eye, they are best found with a slit-lamp examination of Descemet's membrane by an ophthalmologist.

Common Signs

• Tremors or chorea - coordination difficulties such as with handwriting
• Gait disturbance
• Balance disorders
• Stiffness or rigidity (Dystonia)
• Abnormal reflexes
• Abnormal speech
• Drooling
• Difficulty swallowing
• Abnormal ocular responses (uncommon)
• Psychiatric abnormalities which run the entire gamut including depression, psychoses, and antisocial behavior resulting in confinement or imprisonment
• Hemolytic anemia
• Liver disease or liver function abnormalities
• Parkinsonism-like symptoms

The majority of patients become symptomatic during their teens, 20s, and 30s. The basal ganglia and putamen are the most commonly affected areas of the brain, and the abnormalities can often be diagnosed by MRI. Cerebellum, cortex, and white matter may also be involved. There are also findings on PET scan involving decreased glucose consumption.

Diagnostic Tests

Diagnostic tests include:

• 24-hour urine copper levels greater than 100 µg/24 hours
• Serum ceruloplasmin depression to less than 20 mg % (in 95% of patients)
• 20% of heterozygotes (carriers) also have low ceruloplasmin levels
• Kayser-Fleischer rings are invariably present with neurologic or psychiatric symptoms. A slit-lamp exam is required to confirm their presence.
• Liver biopsy revealing greater than 250 µg/g dry weight of copper. There are also characteristic microscopic changes including glycogen nuclei, microvesicular and macrovesicular fatty changes, steatosis, and fibrosis. Fulminant Wilsonian hepatitis results in Mallory bodies and submassive necrosis.

Cytochemical testing results with rhodanine, rubeanic acid, orcein, and Victoria blue are significant only when positive. The electron microscope shows characteristic mitochondrial changes with pleiotropism, increased matrix density, matrical inclusion, widening of intermembranous and intracristal spaces. Less-specific changes include lysosomal density due to copper accumulation.

Genetic Diagnosis

Because of the many possible mutations involved in Wilson's disease, molecular genetic diagnosis is beneficial primarily in families where the particular gene responsible is known.

Therapy Overview

Wilson's disease is a very treatable condition. With proper drug therapy, disease progression can be halted, and often symptoms can be improved. The treatment goal is to first remove the excess accumulated copper in the body and then to prevent its reaccumulation. Therapy must be lifelong.

Galzin (zinc acetate) capsules are indicated for maintenance therapy in patients who have undergone initial treatment with a chelating agent. Galzin works by a different mechanism of action from chelating agents, it blocks absorption of copper from the intestine. In addition, Galzin has a different safety profile from chelating therapies.

Clinical experience with zinc acetate has been limited. The following adverse reactions have been reported in patients with Wilson's disease on zinc therapy: gastric irritation, and elevations of serum alkaline phosphatase, amylase and lipase lasting from weeks to months. The levels usually return to high normal within the first year or two of zinc therapy.

Other drugs approved for use in Wilson's disease act by chelation or binding of copper, causing its increased urinary excretion. Other therapies are under investigation for initial treatment of Wilson's disease in the hope that they will not cause worsening of neurologic symptoms, as may occur with penicillamine. Patients with severe hepatitis may require liver transplant.

Whichever treatment strategy is chosen, physicians and their Wilson's disease patients must keep in mind that continued compliance with therapy is essential.
Discontinuation of treatment will lead to recurrence and worsening of Wilson's disease symptoms.