Clinical Vignette

Approximately 1 year ago, an 18-year-old woman began to have peculiar tremors of her arms and hands as well as difficulty with her speech becoming soft and slurred. This followed an insidiously progressive course to the point of being embarrassing when she was so poorly understood that family and colleagues sometimes found comprehension quite difficult as she started college. Concomitantly, she became irritable and had variable mood swings, at times leading to profound depression. On other occasions, she was belligerent. Within months, she took a medical leave of absence from school.

After initially being thought to be suffering from academic stress leading to profound somatization, she was referred to another neurologist. In addition to a poorly defined rather gross tremor of her arms and hands, a mildly masked bradykinetic facies and dysarthric speech were recognized. Ophthalmic examination demonstrated a gold/brown-pigmented ring at the limbus of his cornea. This was clearly visible with her blue irises. This proved to be a classic Kayser–Fleischer ring. She was mildly jaundiced.

Laboratory investigation demonstrated mildly abnormal general liver function tests (LFTs). Serologies were negative for hepatitis A, B, and C. Her serum ceruloplasmin level was low, and a 24-hour urine copper excretion level was increased. Magnetic resonance imaging (MRI) demonstrated variable degrees of cerebral cortical, brainstem, and cerebellar atrophy. Signal abnormalities were also noted in her putamen, caudate, midbrain, and pons. There was characteristic T2-W globus pallidal hypointensity with T1-W striatal hyperintensity.

Wilson disease (WD) was diagnosed, and she was started on penicillamine. Within 6 weeks, increased bradykinesia, rigidity, and mutism developed. However, these symptoms gradually cleared over the next 6 months. Twelve months later, the patient’s speech had returned to normal, and her behavior had improved, although she still showed some depressive symptoms. Zinc acetate was started as a long-term therapy.

History

WD is a rare hereditary disorder of copper metabolism, biochemically characterized by abnormal accumulation of this essential trace metal in both the liver and the brain, leading respectively to cirrhosis and neuronal degeneration. WD has an autosomal recessive inheritance with a prevalence of approximately 1 case in 30,000 live births and a carrier rate of 1 in 90. Clinical presentations are quite variable. These include primarily neurologic, neuropsychiatric, or hepatic disturbances; less common are acute hemolytic crisis, arthralgias, nephrolithiasis, and cardiac arrhythmias.

This association between cirrhosis and progressive lenticular degeneration was first described by Kinnier Wilson in 1912. Subsequently excess copper deposits were demonstrated in both the liver and basal ganglia in a patient dying of WD. The finding of reduced serum ceruloplasmin level was recognized a few years later. Treatment was initially attempted using dimercaptopropanol (British Anti-Lewisite [BAL]) in 1951; the much more effective penicillamine treatment was introduced 5 years later. WD thus became the first inherited metabolic disorder with specific treatments. More recently, orthotopic liver transplantation performed for patients with WD has cured the disease in some instances, thus revolutionizing its treatment.

Genetics

The genetic defect of WD is the ATP7B gene located on the long arm of chromosome 13. ATP7B binds copper and transports it across cellular membranes using ATP as an energy source. In WD, this defect leads to reduced copper binding to apoceruloplasmin, which normally forms ceruloplasmin. It also leads to decreased secretion of copper into the bile ducts. DNA analysis from patients with WD shows more than 100 mutations, thus complicating the opportunity for DNA diagnosis. Similarly, it is difficult to make a correlation between the various mutations and specific clinical features. Only a few patients are homozygous for the same mutation. The most frequently observed point mutation, H1069Q, results from the substitution of a histidine to a glutamine. This is present in nearly 30% of Wilson patients of European descent.

Hepatic Copper Metabolism

Copper facilitates electron transfer in critical metabolic pathways involving cellular respiration, iron homeostasis, pigment formation, neurotransmitter production, peptide biosynthesis, connective tissue biosynthesis, and antioxidant defense. Within the brain, copper is found in particularly high concentrations in catecholamine-containing neurons. It is a component of the dopamine β-hydroxylase enzyme complex.

Copper balance is maintained entirely by gastrointestinal absorption and biliary excretion; urinary copper excretion cannot adequately compensate for reduced biliary excretion. Approximately 60% of dietary copper is absorbed in the proximal small intestine, most of which enters hepatoportal circulation, where it is rapidly taken up by hepatocytes. These cells regulate copper homeostasis by excretion of copper into the bile. This system is dependent on the degree of copper concentration as sensed by the ATP7B receptor that is located on the trans-Golgi network and the cytoplasmic vesicular compartment near the canalicular membrane. The absence or decreased function of ATP7B results in dysfunction of biliary copper excretion and consequently leads to copper accumulation within the liver.

Ceruloplasmin is a protein synthesized by hepatocytes and is the major carrier of copper in the bloodstream. Copper is thought to be incorporated into this protein via the ATP7B pathway. In WD, absent or diminished function of the ATP7B leads to reduced binding of ceruloplasmin to copper, thereby lowering circulating levels of ceruloplasmin.

Excess copper accumulation results in generation of free radicals, lipid peroxidation of membranes and DNA, and inhibition of protein synthesis leading to hepatocellular injury and necrosis. Release of free copper, from injured hepatocytes, into circulation is thought to be responsible for causing extrahepatic deposition of copper in the brain, kidneys, eyes, and joints.

Clinical Presentation

WD patients have quite variable clinical presentations. Because WD is such an extremely rare disorder, and lacks a precise, stereotyped clinical presentation, these patients are often not diagnosed until long after the onset of their symptomatology. As with the above vignette, there are legendary recitals of individuals being told, not once but a number of times, that they are not organically ill and that a psychiatric evaluation is in order, only to later visit a dedicated physician who takes a careful history and closely examines the patient, often recognizing the classic and diagnostic Kayser–Fleischer (KF) ring and thus making the WD diagnosis.

One might suspect that as the liver is the primary site of both the abnormal copper storage, as well the specific genetic defect, the earliest signs of WD will be identified as having a hepatic origin. However, hepatic involvement is often clinically and laboratory-wise a subtle disorder because the copper accumulates very slowly. Eventually, subclinical cirrhosis develops. Concomitantly, as hepatocytic injury ensues, copper is released into the systemic circulation and subsequently is deposited within various other organs.

The subcortical nervous system is particularly sensitive to the free-ranging excess copper. Approximately 60% of WD patients present with a neurologic disorder (Box 37-1). Often they do not present until young adulthood with a variety of neurologic manifestations, including dysarthria, tremor, dysphagia, bradykinesia, and behavioral disturbance. Speech manifestations

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