Mechanisms of DiseaseHyperzincaemia and hypercalprotectinaemia: a new disorder of zinc metabolism
Introduction
The importance of trace elements for normal physiology is shown by the severe clinical manifestations of defects in their metabolism. The best characterised disorders are Wilson's disease and Menkes disease.1 The only known disorder of zinc metabolism is acrodermatitis enteropathica, a disorder of intestinal zinc uptake.1 Without zinc supplementation these patients have features of zinc deficiency, including a characteristic rash, growth failure, diarrhoea, and impaired immunity.
Two cases of familial hyperzincaemia have been reported previously;2, 3 one was not associated with any clinical features, and the other was associated with pyoderma gangrenosum.4 We previously identified a patient with very high concentrations of zinc in plasma but with clinical features of zinc deficiency. Biochemical analysis showed that the patient had high concentrations of an unidentified zinc binding protein,5 which was subsequently identified as calprotectin (MRP8, S100A8/MRP14, S100A9 complex).6 We are now able to report four more patients. Two of the newly described patients are related (mother and son).
Calprotectin is known mainly for its association with inflammatory conditions,7, 8, 9 its antimicrobial properties,10 and its possible role in regulation of leukocyte adhesion.11 We describe five patients with a defect in calprotectin metabolism and with similar biochemical and clinical features.
Section snippets
Patients
To date, we have identified five cases. The first (patient 1), previously described elsewhere,5, 6 is a boy now 18 years old. Two further cases with similar clinical features have also been identified; one (patient 2) is a girl aged 9 years and the other (patient 3) is a boy aged 14 years. Patient 4 is the mother of patient 3, aged 35 years.12 Patient 5 is a man aged 21 years with a milder phenotype than the other cases. The local ethics committees approved the study for all patients, and all
Results
Table 1 shows the clinical and laboratory data of patients, with the patient described by Hambidge and colleagues4 included for comparison. All patients presented with recurrent infections, hepatosplenomegaly, arthritis, anaemia, and persistently raised concentrations of C-reactive protein. All patients except patients 2 and 3 had inflammatory skin lesions. Patients 1–3 had also had severe growth failure in early infancy—below the 3rd centile for weight and height for age; patients 1 and 5 had
Discussion
Calprotectin (also known as the S100A8/9 or MRP8/14 complex) is a major calcium-binding protein in the cytosol of neutrophils, monocytes,7, 8 and keratinocytes.17, 18, 19 Although serum concentrations are known to be raised in many inflammatory conditions,7, 9 they are generally lower than 10 mg/L, and thus far below the concentrations we recorded in our patients. All disorders in which plasma calprotectin concentrations are raised are associated with an acute phase response, and hence with
GLOSSARY
- calprotectin
- A 36 kDa calcium and zinc binding protein constituting about 60% of total proteins in the cytosol of neutrophil granulocytes. Calprotectin has antimicrobial properties and can induce zinc-reversible apoptosis.
- ef hand protein
- EF hand is a structural motif in proteins consisting of two perpendicularly placed α helices and an interhelical loop which form a calcium binding site. The feature is named after the E and F helices in pavalbumin in which it was first described.
- electrothermal
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