Diagnosis and characterization of presymptomatic patients with Wilson's disease and the use of molecular genetics to aid in the diagnosis.

Wilson's disease (WD) is an autosomal recessive disorder of copper accumulation leading to liver and/or brain damage. Although fatal if untreated, the condition can be treated effectively. Autosomal recessive inheritance indicates that siblings of affected patients are at 25% risk of having the disease. If they are diagnosed prior to becoming symptomatic, affected siblings can be kept free of symptoms by prophylactic therapy. In this paper we have examined the utility of copper-related variables, along with other clinical and molecular findings, in identifying those siblings of affected patients who should be further evaluated with a liver biopsy. Data are presented on a series of 13 presymptomatic patients in whom we have made the diagnosis of WD based on liver biopsy findings. Signs of liver disease were present in 12 out of 13 cases. The classic, noninvasive, screening approaches that we evaluated were not adequate to identify all cases of WD in this group of patients. These included positive Kayser-Fleischer (KF) rings, elevated liver serum alanine transferase, elevated urine copper, or elevated plasma nonceruloplasmin copper. We have introduced the use of molecular genetics for screening siblings of affected patients for WD. We show that a probe from the linked retinoblastoma (RB) gene can be very helpful in problem cases. However, at this time, the quantitative determination of liver copper concentration remains as the definitive diagnostic criterion.