Young Girl With Clumsiness, Dystonia, and Speech Difficulty
Figure 1.
A 17-year-old girl with multiple complaints is brought to the outpatient clinic by her parents. Her parents have noticed that she has developed slowly progressive clumsiness over the past 6 months. She now displays dystonic movement of all of her limbs. Additionally, her speech and ability to walk have been deteriorating over several months. She was also recently noted to have excessive salivation. There is no history of fever, headache, focal weakness, visual changes, bladder dysfunction, convulsions or trauma. She has had no recent travel and there is no history of animal bites or known toxic exposures.
The patient has a past history of jaundice that occurred 1 year ago. The jaundice persisted for 4 months and then resolved spontaneously. A medical workup at that time did not reveal a clear etiology for the jaundice, and no evidence of liver failure, such as hematemesis, diarrhea, pruritus, abdominal distention, or altered mental status, was noted. The patient is otherwise healthy, with no chronic medical conditions, and the family history is unremarkable. She is the third child of a nonconsanguineous marriage. Her birth history is unremarkable and she has met the normal developmental milestones. She denies the use of any medications, alcohol, or recreational drugs.
On physical examination, she appears mildly jaundiced but is otherwise well-appearing and in no distress. Her mucous membranes are moist. The ophthalmic examination shows icteric sclera, normal pupillary reactions to light, normal visual acuity and fields, and normal optic fundi. Dark, brown-colored rings are noted around the periphery of the iris and are visible on naked eye examination; this is confirmed with a slit-lamp examination. A neurologic examination reveals slow mentation, slurred speech, ataxic gait, diffuse muscle rigidity, and a fine resting tremor. The findings are symmetric and her reflexes are brisk bilaterally, with flexor plantar responses. The liver, palpated at 3 finger-breadths below the costal margin, is enlarged, firm, and nontender. The spleen is not palpable and shifting dullness is not present. There is no parotid enlargement, palmar erythema, gynecomastia, or spider nevi. The chest and cardiovascular examinations are unremarkable.
A complete blood cell count (CBC) and erythrocyte sedimentation rate (ESR) are both within normal limits. A hepatic panel reveals a total bilirubin of 3.6 mg/dL (61.56 µmol/L), an alanine aminotransferase (ALT) of 99 U/L, an alkaline phosphatase of 284 U/L, an albumin of 4.4 g/dL (44 g/L), and a prothrombin time of 18 seconds. Markers for hepatitis B and C are negative
A magnetic resonance imaging (MRI) scan of the brain is performed (see Figure 1; image is not of the actual patient, but is representative of the findings).
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 the MRI scan of the brain raised suspicion for a diagnosis of Wilson disease. The serum copper concentration was elevated at 187 μg/dL (29.4 µmoI/L; normal range, 70-150 µg/dL) and the patient was noted to have a low ceruloplasmin level of 12 mg/dL (120 mg/L; normal range, 15-60 mg/dL). A 24-hour urine copper without penicillamine challenge was also markedly elevated at 1708 µg/24 hours (27.3 µmol/24 hours; normal range, 3-35 µg/24 hours). The diagnosis of Wilson disease was established in the patient.
Wilson disease 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 1-2 mg. It is absorbed in the intestines and transported into hepatocytes, where it is incorporated into copper-containing enzymes, including ceruloplasmin. Excess copper may be rendered nontoxic by forming complexes with apo-metallothionein to produce copper-metallothionein, or it may be excreted into bile. Wilson disease is characterized by a decreased biliary copper excretion and a defective incorporation of copper into ceruloplasmin. In 1993, the Wilson disease gene ATP7B was cloned. This gene, localized to chromosome arm 13q, 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, it is released into the circulation and deposited in other organs, such as the liver, brain, kidneys, and corneas.
Wilson disease may present with a variety of 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 2 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 below the age of 5 years, however, and it may not be detected until advanced chronic liver disease is revealed in their fifties or sixties, without neurological symptoms and without KF rings. Associated liver disease may mimic all forms of common liver conditions, including asymptomatic transaminasemia, 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).
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, in 95% of patients with neurologic symptoms of Wilson disease, in 50-60% of patients without neurologic symptoms, and in only 10% of asymptomatic siblings. Although KF rings are a useful diagnostic sign, they are no longer considered pathognomonic of 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.
Neurologic symptoms usually develop in patients who are in their mid-teenage years or twenties. The hallmark of neurologic Wilson disease is a progressive movement disorder characterized by dysarthria, dysphagia, apraxia, drooling of saliva, and a tremor-rigidity syndrome ('juvenile Parkinsonism'). The initial symptoms may be very subtle, such as a mild asymmetric tremor, which occurs in approximately 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 presenting clinical feature is 10-20%.
Skeletal involvement, such as osteoporosis, osteomalacia, chondrocalcinosis, osteoarthritis, and joint hypermobility, is commonly seen in cases of
Wilson disease, with more than 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 with 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 in
Wilson disease. Some female patients have repeated spontaneous abortions, and most become amenorrheic prior to diagnosis.
The diagnosis of neurologic Wilson disease is usually made on the basis of clinical findings and laboratory abnormalities. No additional tests are required if KF rings are present and/or 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.
The diagnosis is more complex in patients presenting with liver diseases. Serum ceruloplasmin may be in the low-to-normal range in up to 45% of patients with hepatic Wilson disease; however, falsely low levels may also be found in a patient with autoimmune hepatitis or with a number of 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 make a diagnosis of 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-h urinary volume or possible copper contamination. In presymptomatic patients, urinary copper excretion may be normal, but increases after a D-penicillamine challenge.
Liver biopsy findings are generally nonspecific and are not helpful for the diagnosis of Wilson disease; however, the exclusion of other etiologies may be necessary and require a liver biopsy. The detection of focal copper stores by the rhodanine stain is a pathognomonic sign of Wilson disease, but it is only present in a minority (about 10%) of patients. The hepatic copper content is increased in 82% of patients with Wilson disease and usually exceeds 250 µg/g dry weight.
Computed tomography (CT) scanning of the brain may show well-defined, slitlike, 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 scanning of the brain appears to be more sensitive than CT scanning for detecting early lesions of Wilson disease. MRI appearances include atrophy and signal change in the grey matter (typically symmetric) and white matter (often asymmetric). The most common area to see abnormal signal on MRI 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 emission tomography (PET) scanning reveals a significantly reduced regional cerebral metabolic rate of glucose consumption.
Once a diagnosis of Wilson disease is made in an index patient, an evaluation of his or her family is mandatory. The likelihood of finding a homozygote among the patient’s siblings is 25%, and it is 0.5% among the patient’s children. Testing of second-degree relatives is only useful if the gene is found in 1 of the immediate members of the relative's family. No single test is able to identify affected siblings or heterozygote carriers of the Wilson disease gene with sufficient certainty. Today, mutation analysis is the only reliable tool for screening the family of an index case with known mutations; otherwise, haplotype analysis can be used. A number of highly polymorphic microsatellite markers that closely flank the gene allow the Wilson disease gene to be traced in a family. For such an analysis, at least 1 first-degree relative and the index patient are required.
According to the recent AASLD practice guidelines on
Wilson disease, initial treatment for symptomatic patients should include a chelating agent (penicillamine or trientine). Treatment of presymptomatic patients and maintenance therapy of successfully treated symptomatic patients can be accomplished with the chelating agents penicillamine or trientine or, alternatively, with zinc. Liver transplantation, which corrects the underlying hepatic defect in
Wilson disease, is reserved for severe or resistant cases. Penicillamine is still the "gold standard" for therapy; the compound reduces copper bound to protein and thereby decreases the affinity of the protein for copper. Reduction of copper facilitates its binding to the drug. The copper mobilized by penicillamine is then excreted in the urine. Most symptomatic patients, whether hepatic, neurologic, or psychiatric, respond within months of starting treatment. Among neurologic patients, a significant number may experience an initial worsening of symptoms before they get better. Trientine is a copper chelator, acting primarily by enhancing urinary copper excretion. Trientine is approved for the treatment of
Wilson disease and is as effective as penicillamine, with far fewer side-effects. Zinc interferes with the intestinal absorption of copper and increases the fecal excretion of copper. The experience with other drugs, such as ammonium tetrathiomolybdate, is very limited, but it appears to be useful for the initial treatment of patients with neurologic symptoms. Antioxidants, mainly vitamin E, may also have a role as adjunctive treatment, but no rigorous studies have been conducted.
Patients should avoid foods with a high copper content, such as liver, broccoli, legumes, chocolate, nuts, mushrooms, and shellfish (particularly lobster). Drinking water from atypical sources (eg, well water) should be tested for copper concentration and replaced with purified water if greater than 0.2 parts per million of copper are found. Also, patients must avoid most alcohol consumption and potentially hepatotoxic drug therapy.
The patient in this case was started on penicillamine 500 mg 3 times daily (500 mg tid), along with dietary restriction of copper-containing foods. She is being followed in the neurology outpatient clinic and has shown considerable improvement in the last 6 months.
Image courtesy of: T.J. Kim, I.O. Kim, W.S. Kim, et al. MR Imaging of the Brain in Wilson Disease of Childhood: Findings Before and After Treatment with Clinical Correlation. American Journal of Neuroradiology. Vol. 27, issue 6, 1373-1378, 2008, © American Society of Neuroradiology.
