PMC5765040_01
Copper accumulations predicted by the FN model (a-b) and performance of two treatments (c-d). a Maximum and minimum level of copper accumulations for different daily intakes. Red/green/blue lines refer to daily copper intakes of 2.0/2.2/2.4 mg. Maximum/minimum accumulations are represented with dotted/solid lines. The minimum accumulations for 2.0 mg/day and 2.2 mg/day copper intakes are constant and have the same profile. The black line at 1850 mg represents the diagnostic threshold. b Minimum copper accumulations for different levels of ATP7b enzyme activity. The cyan/red/green/blue lines correspond to 7%/23.1%/39.3%/55.5% of wild-type activity. The black line at 1850 mg represents the diagnostic threshold. c-d Profiles of the accumulation of copper during treatments to either block its absorption or induce its excretion (also known as cuprupria induction), with initial copper concentrations of 1850 mg in C and 7400 mg in D. The black line represents a normal copper level in a healthy individual
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Fig6
Wilson disease with various degrees of loss of ATP7b enzyme activity (Fig. 6b). Wilson disease investigating the loss of ATP7b activity in mutants having both a pathogenic or a neutral phenotype where any mutant with a loss in enzyme activity less than 30% maintained normal copper transport capability and thus was considered neutral in its phenotypic effect. We investigated a relatively severe case of a 44% loss in ATP7b activity and determined that the hepatic copper accumulation exceeds the diagnostic limit of 1850 mg at the age of 28 (Fig. 6b). The model successfully predicted cases, where as much as 93% of the activity of the adenosine triphosphatase 7 was lost, leading to sufficiently high hepatic copper accumulation to allow definitive diagnosis within the first year of life (blue line in Fig. 6b). The model was used to predict the copper depletion profiles from two different initial levels of copper accumulation: (a) the lower diagnostic limit for hepatic copper accumulation adopted in liver biopsies (1850 mg) (Fig. 6c) and (b) four times this lower limit as the upper bound (7400 mg) (Fig. 6d) to account for diagnosis at a much later stage.