Young Girl With Clumsiness, Dystonia, and Speech Difficulty

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

Disclosures

June 24, 2015

Discussion

The unusual dark, brownish rings around the periphery of the irises of this patient are known as Kayser-Fleischer (KF) rings. This finding, in conjunction with the noted hepatic dysfunction and the hypodense regions in the basal ganglia (ie, caudate nucleus, putamen, and globus pallidus) on MRI of the brain raised suspicion of a diagnosis of Wilson disease.

Figure 1.

MRI of the patient's brain. Image from Kim TJ, Kim IO, Kim WS, et al. MR imaging of the brain in Wilson disease of childhood: findings before and after treatment with clinical correlation. Am J Neuroradiol. 2008;27:1373-1378. ©American Society of Neuroradiology.

The serum copper concentration was elevated, at 187 μg/dL (normal range, 70-150 µg/dL), and the patient was noted to have a low ceruloplasmin level of 12 mg/dL (normal range, 15-60 mg/dL). A 24-hour urine copper value without penicillamine challenge was also markedly elevated, at 1708 µg/24 hours (normal range, 3-35 µg/24 hours). The diagnosis of Wilson disease was established in the patient.

Wilson disease (also known as "hepatolenticular degeneration") is a rare autosomal recessive disorder of copper metabolism, with a prevalence of about 1 in 30,000 people. The normal estimated total body copper content is 50-100 mg, with an average daily intake of 2-5 mg. It is absorbed primarily by enterocytes of the duodenum and proximal small bowel and transported into hepatocytes, where it is used for local metabolic needs and incorporated into ceruloplasmin; excess copper is sequestered and rendered nontoxic through complexes with metallothioneins. Most ingested copper is excreted in bile, and a small fraction is excreted in urine.

Wilson disease is characterized by decreased biliary copper excretion and a defective incorporation of copper into ceruloplasmin. In 1993, the Wilson disease gene ATP7B was identified. This gene, localized to chromosome 13q14, codes for a membrane-bound, P-type copper-transporting ATPase expressed primarily in the liver. ATP7B protein has both a perinuclear location, where it is involved in delivering copper to apoceruloplasmin, and a plasma membrane location, where it is responsible for the efflux of copper from the hepatocyte. As a result of mutations in its function, progressive copper accumulation occurs.

The excess copper is initially bound to metallothionein; however, the binding capacity of metallothionein is eventually exceeded. The excess copper acts as a promoter of free radical formation and causes oxidation of lipids and proteins and hepatocyte dysfunction. Eventually, as liver copper levels increase, copper is released into the circulation and deposited in other organs, such as the brain, kidneys, and cornea.[1,2,3,4]

Wilson disease may present with various clinical conditions. The most common are liver disease and neuropsychiatric disturbances. None of the clinical signs is individually typical or diagnostic of the condition.

One of the most characteristic features of Wilson disease is that no two patients, even within a family, are ever quite alike. Most patients with Wilson disease, however, have some degree of liver disease, regardless of the clinical presentation or presymptomatic status.

The most common age of hepatic manifestation is between 8 and 18 years. Cirrhosis may be present in children younger than 5 years, however, and it may not be detected until advanced chronic liver disease is revealed when patients are in their 50s or 60s, without neurologic symptoms and without KF rings.

Associated liver disease may mimic all forms of common liver conditions, including asymptomatic elevation of aminotransferase levels, acute or chronic hepatitis, fulminant hepatic failure, and cirrhosis. Acute Wilsonian hepatitis is indistinguishable from other forms of acute (viral or toxic) liver diseases. The disease may rapidly deteriorate and resemble fulminant hepatic failure.

Rapid diagnosis may be very difficult. One puzzling feature of fulminant Wilson disease is the greater incidence seen in females (female-to-male ratio, 3-4:1).[1,2,3]

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