WILSON DISEASE

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CHAPTER 108 WILSON DISEASE

Wilson Disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. The gene product, a P-type adenosine triphosphatase (ATPase), is necessary for both the incorporation of copper into ceruloplasmin and its excretion into bile. The disease is associated with increased hepatic copper storage which leads to a clinically heterogeneous illness marked by cirrhosis of the liver and degenerative changes in the basal ganglia.

During the second half of the 19th century, a condition termed pseudosclerosis was distinguished from multiple sclerosis by the lack of ocular signs. In 1902, Kayser observed green corneal pigmentation in one such patient.1 Fleischer, who had also noted the green pigmentation of the cornea in 1903, commented on the association of the corneal rings with pseudosclerosis.2 In 1912, Wilson provided the classic description of the disease and its pathological anatomy but failed to mention the abnormal corneal pigmentation.3

CLINICAL FEATURES

Wilson disease is a progressive condition with a tendency toward temporary clinical improvement and arrest of symptoms.4 The presenting symptoms can be neurological, hepatic, psychiatric, or, less frequently, hematological. Symptoms at onset are listed in Table 108-1.

TABLE 108-1 Clinical Manifestations at Onset of Wilson’s Disease

Symptoms Percentage*
Hepatic or Hematologic Abnormalities 35
Behavioral Abnormalities 25
Neurological Abnormalities 40
“Pseudosclerotic” form: one or more of the following: 40
Resting or intentional tremor  
Dysarthria or scanning speech
Diminished dexterity or mild clumsiness
Unsteady gait
Tremor alone 33
Dysarthria alone 5
“Dystonic” form: One or more of the following: 60
Hypophonic speech or mutism  
Drooling
Rigid mouth, arms, or legs
Seizures 1
Chorea or small-amplitude twitches <1

Table prepared with the assistance of Drs. I. H. Scheinberg and I. Sternlieb, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York.

* Percentages are approximate.

In the experience of Gow and colleagues,5 of symptomatic patients aged 7 to 58 years, 22% presented with fulminant hepatic failure, 54% presented with liver abnormalities, 10% with neurological features, and 4% with hemolysis. In 10% of patients, hepatic and neurological symptoms were concurrent.

In a fair number of cases, primarily in young children, initial symptoms are hepatic, such as jaundice or portal hypertension, and the disease can assume a rapidly fatal course without any detectable neurological abnormalities.6,7 In many of these patients, an attack of what appears to be acute viral hepatitis heralds the onset of Wilson disease.8 The manifestation with hepatic symptoms is common among affected children in the United States. In the series of Werlin and associates,9 who surveyed patients in the Boston area, the primary mode of manifestation was hepatic in 61% of patients younger than 21 years. In about 10% of affected children in the United States, Wilson disease manifests as an acute or intermittent, Coombs’ test–negative, nonspherocytic anemia that is accompanied by leukopenia and thrombocytopenia.9

When neurological symptoms predominate, the manifestations are so varied that it is impossible to describe a characteristic clinical picture. As a rule, the appearance of neurological symptoms is delayed until 10 to 20 years of age, and the disease progresses at a slower rate than in the hepatic form. Symptoms of basal ganglia damage usually predominate, but cerebellar symptoms are occasionally in the foreground. Tremors and rigidity are the most common early signs. The tremor may be of the intention type, or it may be the alternating resting tremor of parkinsonism. More commonly, especially when the disease is in its more advanced stages, the tremor is localized to the arms and is best described by the term wing beating. The tremor is often absent when the arms are at rest; it develops after a short latent period when the arms are extended. The beating movements may be confined to the muscles of the wrist, but it is more common for the arm to be thrown up and down in a wide arc. The movements increase in severity; at times, they reach a point at which the patient is thrown off balance. The tremor may affect both arms but is usually more severe in one.

Rigidity and spasms of the muscles are often present. In some instances, typical parkinsonian rigidity involves all muscles. Torticollis, tortipelvis, and other dystonic postures are not uncommon. Many patients have a fixed open-mouth smile with drooping of the lower jaw and excess salivation. Spasticity of the laryngeal and pharyngeal muscles can lead to dysarthria and dysphagia. A nearly pure Parkinson-like syndrome with progressive choreoathetosis or hemiplegia has also been described.10

Tendon reflexes are increased, but extensor plantar responses are exceptional. In essence, Wilson disease is a disorder of motor function; despite often widespread cerebral atrophy, there are no sensory symptoms or reflex alterations.

When Wilson disease manifests during childhood, the first signs are usually bulbar; these can include indistinct speech and difficulty in swallowing. A rapidly progressive dystonic syndrome is not unusual. Such patients can present with acute dystonia, rigidity, and fever, with an occasional elevation of serum creatine phosphokinase level.11

Behavioral and personality disorders were noted in Wilson’s original description of the disease.3 These are almost invariable and predominate in about one third of patients.12,13 They include impaired school or work performance, depression, mood swings, and frank psychosis. Of patients who show primarily neurological symptoms, about two thirds have had psychiatric problems before the diagnosis of Wilson disease is made. Minor intellectual impairment can also be observed, but seizures and mental deterioration are not prominent features of the disease.

The intracorneal ring-shaped pigmentation, first noted by Kayser and Fleischer,1,2 might be evident to the naked eye or might appear only on slit-lamp examination. The color of the Kayser-Fleischer ring varies from yellow to green to brown. It is the consequence of copper deposition close to the endothelial surface of Descemet’s membrane. The ring can be complete or incomplete. It occurs in 79% of patients who present with hepatic symptoms and in all patients who present with cerebral or a combination of cerebral and hepatic symptoms.5,7 “Sunflower” cataracts are less commonly encountered, as are azure lunulae of the fingernails.14 Hypercalciuria and nephrocalcinosis are not uncommon and can be presenting signs of Wilson disease.15

Without treatment, death ensues within 1 to 3 years after the onset of neurological symptoms and is usually a result of hepatic insufficiency.

NEUROIMAGING

Computed tomographic scans usually reveal ventricular dilatation and diffuse atrophy of the cortex, cerebellum, and brainstem. About half the patients have symmetrical hypointensities in the head of the caudate, pallidum, substantia nigra, and red nuclei. The histopathology of Wilson disease suggests that these hypointensities are secondary to the presence of protein-bound copper in the thalamus and basal ganglia. Cortical atrophy and focal lesions in cortical white matter are also noted. Increased CT density resulting from copper deposition is not observed.

T2-weighted magnetic resonance imaging demonstrates symmetrical areas of increased signal intensity in the putamen, particularly in its outer rim; in the thalami; in the head of the caudate nucleus; and in the globus pallidus (Fig. 108-1). In the series of King and coworkers, the midbrain was abnormal in 77% of patients with Wilson disease.16 Involvement included primarily the tegmentum but also included the substantia nigra and the mesencephalic tectum. Abnormalities are also seen in the pons and the cerebellum. These areas are hypointense on T1-weighted images.17 Correlation with the clinical picture is not good in that magnetic resonance imaging can produce normal findings in patients with neurological symptoms and abnormal findings in patients with no neurological symptoms.16,18

Positron emission tomography demonstrates a widespread depression of glucose metabolism; the greatest focal hypometabolism is observed in the lenticular nucleus. This abnormality precedes any alteration visible on computed tomography19 and improves with chelation therapy.20 In addition, a reduction in dopamine D2 receptor binding and loss of striatal dopamine transporters have been documented.21,22

DIAGNOSIS

When Wilson disease manifests with neurological manifestations, the diagnostic features include progressive extrapyramidal symptoms, which commence after the first decade of life; abnormal liver function; aminoaciduria; cupriuria; and absence or decreased serum levels of ceruloplasmin. In the experience of Gow and colleagues5 and of Steindl and coworkers,23 the diagnosis is more difficult to establish in patients who present with hepatic symptoms, particularly those who present in fulminant hepatic failure.

The presence of a Kayser-Fleischer ring is the single most important diagnostic feature; its absence in a patient with neurological symptoms virtually rules out the diagnosis of Wilson disease. The ring is not seen in the majority of presymptomatic patients, nor is it seen in 33% of patients who present with hepatic symptoms.5

Absence or low serum level of ceruloplasmin is of lesser diagnostic importance; approximately 5% to 20% of patients with Wilson disease have normal levels of the copper protein. Ceruloplasmin levels are abnormally low in about 10% of persons heterozygous for the Wilson disease gene. Because gene carriers constitute about 1% of the population, there are 40 times more gene carriers with low ceruloplasmin values than patients with Wilson disease and low ceruloplasmin values. In affected families, the differential diagnosis between heterozygous and presymptomatic homozygous patients is of utmost importance, inasmuch as it is generally accepted that presymptomatic homozygous patients should be treated preventively.24

Several workers have stressed the diagnostic value of measuring 24-hour urine copper concentrations.25

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