Young Girl With Clumsiness, Dystonia, and Speech Difficulty

Sidra Aurangzeb, MBBS; Muhammad Tariq, MRCP, FRCP, FRCPE


June 24, 2015

KF rings are formed by the deposition of copper in the Descemet membrane in the limbus of the cornea. The color may range from greenish-gold to brown, and the rings form bilaterally, initially appearing at the superior pole of the cornea, then the inferior pole and, ultimately, circumferentially. Rings may be readily visible to the naked eye or with an ophthalmoscope set at +40. If the ring is not detected by clinical inspection, the cornea should be examined under a slit lamp by an experienced ophthalmologist.

KF rings are observed in up to 90% of individuals with symptomatic Wilson disease, 95% of patients with neurologic symptoms of Wilson disease, 50%-60% of patients without neurologic symptoms, and only 10% of asymptomatic siblings.

Although KF rings are a useful diagnostic sign, they are no longer considered pathognomonic for Wilson disease. They may also be observed in patients with carotenemia, arcus senilis, chronic active hepatitis, chronic cholestasis, chronic jaundice, cryptogenic cirrhosis, intraocular foreign body of < 85% copper, multiple myeloma, primary biliary cirrhosis, and trypanosomiasis.[2,3,4]

Neurologic symptoms usually develop in patients who are in their mid-teenage years or 20s. The hallmark of neurologic Wilson disease is a progressive movement disorder characterized by dysarthria, dysphagia, apraxia, drooling, and a tremor/rigidity syndrome (juvenile parkinsonism). The initial symptoms may be very subtle, such as a mild asymmetric tremor, which occurs in approximately one half of individuals with Wilson disease. Late manifestations include dystonia, spasticity, grand mal seizures, rigidity, and flexion contractures.

About one third of patients present with psychiatric abnormalities, such as reduced performance in school or at work, depression, labile mood, impulsiveness, disinhibition, sexual exhibitionism, self-injurious behavior, and frank psychosis. The reported percentage of patients with psychiatric symptoms as the initial clinical feature is 10%-20%.[2,3]

Skeletal involvement, such as osteoporosis, osteomalacia, chondrocalcinosis, osteoarthritis, and joint hypermobility, is commonly seen in cases of Wilson disease, with more than one half of patients exhibiting osteopenia on conventional radiographs. Coombs-negative hemolytic anemia is a recognized complication of the disease, but it is rare (10%-15% of cases). Patients may present like those with Fanconi syndrome or urolithiasis.

Skin pigmentation and a bluish discoloration at the base of the fingernails (azure lunulae) are recognized in patients with Wilson disease. Cardiac manifestations, such as rhythm abnormalities and increased autonomic tone, have also been described. Some female patients have repeated spontaneous abortions, and most become amenorrheic before diagnosis.[2,3]

Neurologic Wilson disease is usually diagnosed on the basis of clinical findings and laboratory abnormalities. No additional tests are required if KF rings are present and serum ceruloplasmin levels are low. There are a few well-documented cases, however, of neurologic Wilson disease without KF rings. Clinical neurologic examination is more sensitive than any other method for the detection of neurologic abnormalities.[1,5]

The diagnosis is more complex in patients presenting with liver diseases. The serum ceruloplasmin level may be in the low to normal range in as many as 45% of patients with hepatic Wilson disease; however, falsely low levels may also be found in a patient with autoimmune hepatitis or other protein deficiency states, including nephrotic syndrome, malabsorption, protein-losing enteropathy, and malnutrition. Ceruloplasmin is an acute-phase reactant and may be increased in response to inflammation, pregnancy, estrogen use, or infection; therefore, in patients with liver disease, a normal ceruloplasmin level cannot exclude Wilson disease, nor is a low level sufficient to diagnose Wilson disease.

Urinary copper excretion is increased in patients with Wilson disease; however, its usefulness in clinical practice is limited. The estimation of urinary copper excretion may be misleading as a result of incorrect collection of the 24-hour urinary volume or possible copper contamination. In presymptomatic patients, urinary copper excretion may be normal, but increases after a D-penicillamine challenge.[1,4]

Histologic abnormalities on liver biopsy are generally nonspecific and not helpful for the diagnosis of Wilson disease; however, the exclusion of other etiologies may be necessary and require a liver biopsy, which may show classic features of autoimmune hepatitis. The detection of focal copper stores by rhodanine stain is a pathognomonic sign of Wilson disease but is present in only about 10% of patients. The hepatic copper content is increased in 82% of patients with Wilson disease and when exceeding 250 µg/g dry weight provides the strongest evidence for the disease.

CT of the brain may show well-defined, slit-like, low-attenuation foci involving the basal ganglia (particularly, the putamen) as well as regions of low attenuation in the basal ganglia, thalamus, or dentate nucleus. MRI of the brain seems to be more sensitive than CT for detecting early lesions of Wilson disease. Appearance on MRI include atrophy and signal change in the gray matter (typically symmetric) and white matter (often asymmetric).

The most common area in which abnormal signal on MRI is seen is the putamen, followed by the caudate, thalamus, midbrain, cerebral white matter, pons, and cerebellum. Typically, the abnormal signal is hyperintense on T2-weighted images. Occasionally, abnormal hypointense signal on T2-weighted images is seen. These MRI abnormalities sometimes lead to the "face of the giant panda" sign, reflecting hyperintensity in the midbrain tegmentum with relative sparing of the red nuclei ("eyes"), part of the pars reticulata of the substantia nigra ("ears"), and the hypointensity of the superior colliculus ("mouth"). Positron PET reveals a significantly reduced regional cerebral metabolic rate of glucose consumption.[3,4,6]


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