As the disease progresses, the “classic syndrome” evolves: dysphagia and drooling, rigidity and slowness of movements of the limbs; flexed limb postures; fixity of facial muscles with mouth constantly agape, giving an appearance of grinning or a “vacuous smile”; dysarthria or virtual anarthria (bulbar extrapyramidal syndrome); and a tremor in repose that increases when the limbs are outstretched to a coarse, “wing-beating” movement. Slowed saccadic eye movements and limitation of upgaze are also characteristic. A notable feature is the tendency for the motor disorders to be concentrated in the bulbar musculature and to spread caudally. Thus, the syndrome differs from typical parkinsonism. Usually, elements of cerebellar ataxia and intention tremor of variable degree are added at some stage of the disease. Approximately 6 percent of patients develop seizures (Dening et al). Gradually the disability increases because of increasing rigidity and tremor. The patient becomes mute, immobile, extremely rigid, dystonic, and slowed mentally, the latter usually being a late and variable effect.
With progression of the neurologic disease, the Kayser-
Fleischer rings become more evident (see Fig. 36-7). They take the form of a crescentic rusty-brown discoloration of the deepest layer of the cornea (Descemet membrane). In the purely hepatic stage of the disease, the rings may not be evident (in 25 percent of cases), but they are virtually always present (if properly sought) once the neurologic signs become manifest. A slit-lamp examination may be necessary for their early detection, particularly in brown-eyed patients, but in the majority of patients with neurologic signs the rings can be visualized with the naked eye or with the aid of an indirect ophthalmoscope focused on the limbus.
The diagnosis is virtually certain when there is a similar syndrome in a sibling or when an extrapyramidal motor disorder of this type is conjoined with liver disease and the corneal rings. Variants of the above syndrome that the authors have seen are an early choreoathetosis (like Sydenham chorea); prominent dystonic postures; a cerebellar ataxia with minimal rigidity; a syndrome of coarse action or action and intention tremor resembling that of dentatorubral degeneration; an immobile mute state with profound rigidity; and a dementia, character change, or psychosis with relatively few extrapyramidal signs. Action myoclonus as a prominent early manifestation has also been described. The parkinsonian features do not respond to l-dopa treatment.
Laboratory findings Although the diagnosis is currently established by sequencing the ATP7B gene for specific mutations, in both the typical and variant forms of the disease, the finding of a low serum ceruloplasmin level (less than 20 mg/dL in 80 to 90 percent of patients), low serum copper (3 to 10 mM/L; normal 11 to 24 mM/L), and increased urinary copper excretion (more than 100 mg Cu/24 h) serve to make the diagnosis likely. Because 90 percent of copper is carried by ceruloplasmin and the latter is generally reduced in Wilson disease, serum copper values alone may be misleadingly normal. In the past, the reliable findings early in the course of high copper content in a biopsy of liver tissue (more than 200 µg Cu/g dry weight) and a failure to incorporate labeled 64Cu into ceruloplasmin were used. The latter test, however, fails to dependably differentiate asymptomatic carriers from affected individuals. Measurement of increased cupruresis after the administration of penicillamine was also not been shown to be more sensitive than an unenhanced 24-h urine collection for copper.