Wilson disease clinical presentations

Stremmel W, Meyerrose KW, Niederau C, Hefter H, Kreuzpaintner G, Strohmeyer G. Wilson disease clinical presentation, treatment, and survival. Ann Intern Med 1991 115(9) 720-6. 

Several clinically distinct forms of Wilson s disease have been described. Thus, a relatively mild, late-onset form of the disease, has been described in Jewish patients from Eastern Europe. These patients usually present with the neurologic signs of the disease. In contrast, the more common early-onset (childhood) forms of the disease often present first with liver problems, followed by neurologic manifestations. 

Symptoms in patients with Wilson s disease usually begin in the second or third decade of life, but may be earlier or later. However, mutations that completely destroy gene function may be associated with onset of liver disease as early as 3 years of age. The initial clinical presentation may be hepatic, with presentation similar to acute hepatitis or to chronic active hepatitis neurological (e.g., clumsiness, dysarthria, ataxia, and tremors) renal (renal tubular acidosis with aminoaciduria) or, less commonly, hematological, with hemolysis secondary to acute release of free copper from tissue and subsequent oxidation of erythrocyte membranes. The hepatic, and possibly CNS, damage may also be secondary to copper-induced oxidative damage to mitochondrial membranes. Hepatic levels of Cp messenger ribonucleic acid (mRNA) are reduced in patients with Wilson s disease, probably secondary to inhibition of transcription by increased intracellular levels of apoCp. ... 

Wilson s disease is an autosomal recessive disease of copper metabolism. It has a prevalence of 1 in 30,000 live births in most populations. The disease has a highly variable clinical presentation. It is characterized by impairment of biliary copper excretion, decreased incorporation of copper into ceruloplasmin, and accumulation of copper in the liver and, eventually, in the brain and other tissues. The biochemical findings include low serum ceruloplasmin, high urinary copper excretion, and high hepatic copper content. Some patients have normal serum cerulo-plasmia levels, and heterozygous individuals do not consistently show reduced levels of this protein. 

Most patients with Wilson disease, whatever their clinical presentation, have some degree of liver disease. Chronic liver disease (if undiagnosed and untreated) may precede manifestation of neurological symptoms for more than 10 years. Patients can present with liver disease at any age. The most common age of hepatic manifestation is between 8 and 18 years, but cirrhosis may already be present in children below the age of 5. On the other hand, Wilson disease is diagnosed also in patients presenting with advanced chronic liver disease in their 50s or 60s, without neurological symptoms and without Kayser-Fleischer rings. 

The differential diagnosis includes idiopathic torsion dystonia, parkinsonism, idiopathic torticollis, Huntington s disease, Wilson s disease, and Meige s syndrome (blepharospasm, oromandibular dystonia). A retrospective evaluation of the records of patients with idiopathic cervical dystonias (n = 82) and tardive cervical dystonias (n = 20) has been performed, in a search for clinical features that could help separate these closely related disorders (332). Despite the overall similarity, the presence of a dystonic head tremor was strongly suggestive of the idiopathic form, which was present in 42% and did not occur at all in the tardive group. A family history of dystonia (10%) was also exclusive to the idiopathic group. 

Kidneys Dysfunction of the proximal tubule may occur as a late manifestation of Wilson s disease. Epithelial flattening, a loss of the brush-border membrane, mitochondrial anomalies and fatty cellular changes can be observed. These findings are, in turn, responsible for proteinuria with a predominance of hyperaminoaciduria (L. UzMAN et al., 1948). Enhanced calciuria and phosphat-uria may cause osteomalacia as well as hypoparathyroidism. (329, 344) Glucosuria and uricosuria, if present, are without clinical relevance. Due to decreased bicarbonate resorption, tubular acidosis may occur, with a tendency towards osteomalacia as well as the development of nephrocalcinosis and renal stones (in some 15% of cases). (344, 356, 392) The intensity of the copper deposits in the kidneys correlates closely with the cellular changes and functional disorders. The glomerular function is not compromised, with the result that substances normally excreted in the urine are not retained. 

The classic clinical finding of increased copper deposition in the eye is the Kayser-Fleischer ring, caused by deposition of copper in Descemet membrane at limbus of the cornea. Although found in about 95% of patients with neurological or psychiatric manifestations, it is present in only about half of patients with hepatic forms of Wilson s disease" and is rarely present in children. As mentioned earlier, hemolytic anemia and renal failure commonly accompany acute forms of Wilson s disease hemolytic anemia may be episodic even in chronic forms of Wilson s disease. ... 

Another disease related to a dysfunction in copper metabolism is Wilson s disease. Unlike in Menkes patients, copper in Wilson s patients is readily absorbed through the intestine and into the ceU. Within the cell, however, abnormally low levels of the copper-storage protein cemloplasmin are present. As a result, copper accumulates in the cytosol and is eventually released into the blood stream. The clinical manifestations of Wilson s disease are liver disease and neurological damage. 

Why indeed do the sensory neurones escape functional damage One is left to wonder at the wide variation in the clinical picture if the basic biochemical defect is uniform. For instance some patients present with wild tremor or spontaneous movements, some with dystonia, some with choreiform movements, whilst others are akinetic. Transient lapses of consciousness are occasionally seen as are epileptic seizures and a few patients may suffer severe psychiatric disturbances which, on occasion, precede the onset of other signs of nervous system disease. In fact it is probably true to say that no two patients with neurological Wilson s disease are ever alike. 

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