Copper

Neutron activation analysis-electrothermal atomic absorption spectroscopy (ETA-AAS) and inductively coupled plasma atomic emission spectrometry (ICP-AES) have been used for the determination of 46 elements in urine, 35 in blood and 26 in serum of unexposed Italian subjects living in the same region (Lombardy). The results allowed the proposal of reference values for various elements determined in more than 350 healthy subjects, these being Ag, Al, As, Be, Bi, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, Sb, Se, Tl, V, Zn, in urine; Ag, As, Bi, Cd, Cr, Co, Cu, Hg, Pb, Se, Tl, Zn in blood; and Ag, Al, Be, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, Se, Tl, V, Zn in serum (or plasma). For all other elements indicative values are suggested. In addition to the mean value and the "reference range", a "range of uncertainty" and an upper limit above which metabolic abnormalities could be expected have also been defined on the basis of simple statistical considerations.

Wilson disease is an autosomal recessive disorder of copper transport. Disease symptoms develop from the toxic build-up of copper primarily in the liver, and subsequently in the brain, kidney, cornea and other tissues. A candidate gene for WD (ATP7B) has recently been identified based upon apparent disease-specific mutations and a striking amino acid homology to the gene (ATP7A) responsible for another human copper transport disorder, X-linked Menkes disease (MNK). The cloning of WD and MNK genes provides the first opportunity to study copper homeostasis in humans. A preliminary analysis of the WD gene is presented which includes: isolation and characterization of the 5'-end of the gene; construction of a genomic restriction map; identification of all 21 exon/intron boundaries; characterization of extensive alternative splicing in brain; prediction of structure/function features of the WD and MNK proteins which are unique to the subset of heavy metal-transporting P-type ATPases; and comparative analysis of the six metal-binding domains. The analysis indicates that WD and MNK proteins belong to a subset of transporting ATPases with several unique features presumably reflecting their specific regulation and function. It appears that the mechanism of alternative splicing serves to regulate the amount of functional WD protein produced in brain, kidney, placenta, and possibly in liver.

We describe a patient with Wilson's disease who presented with neurologic disease, was treated with D-penicillamine, and suffered sudden neurologic deterioration coincident with therapy. Replicate brain magnetic resonance imaging examinations after six weeks and 11 months of penicillamine therapy documented the development of new brain lesions during this period, while liver biopsy specimen data disclosed that excellent hepatic decoppering had occurred. To develop information on the relative rarity or frequency of neurologic worsening with the initiation of penicillamine therapy, we conducted a retrospective survey of 25 additional patients with Wilson's disease who met the criteria of presenting with neurologic disease and having been treated with penicillamine. The replies indicate that, at least from the patient's viewpoint, this syndrome occurs frequently. We suggest that the cause of this distressing syndrome, and ways to mitigate or circumvent it, must be discovered.