Current status of prenatal diagnosis and heterozygote detection of cystic fibrosis.

The hallmark for the laboratory diagnosis of cystic fibrosis is an increased sodium and chloride concentration in the exocrine secretory fluid, sweat. This abnormality is an early and invariable consequence of the cystic fibro­ sis gene in homozygous, affected individuals but is not a suitable diagnostic marker for detection of the heterozygote. In the past five years, laboratory investigations of ion transport in cultured skin fibroblasts and evaluations of the effects ofthe Na+,K+-ATPase inhibitor, ouabain, suggested that cellular expression of the electrolyte transport defect in cystic fibrosis might be detectable in vitro. Enhanced resistance of fibroblasts from cystic fibrosis patients to the cytotoxic effects of ouabain and dexamethasone and abnor­ malities in fibroblast sodium transport have been reported as has a differ­ ence in calcium transport in these cells. Confirmation is lacking both with regard to the diagnostic utility of these findings and to the relationship of the phenom ena to the expression of the cystic fibrosis gene. Since 1967 the accumulation of biologically active “factors” has been suggested to occur in body fluids from cystic fibrosis patients. Although the specificity, chemical identity, and relationship of such “factors” to the pathophysiological changes in cystic fibrosis remain to be established, the possibility of their occurrence has led to the postulated existence of a lectin­ like component in serum which might have utility in heterozygote detec­ tion. Confirmatory results have not been reported. Investigations from Nadler’s laboratory have suggested a deficiency in an isozyme of a protease with arginine esterase activity is associated with cystic fibrosis and could result in the accumulation of biologically active peptides. This quantitative abnormality in arginine esterase holds promise for prenatal diagnosis of cystic fibrosis but has not been validated by other laboratories. Not all individuals with cystic fibrosis may demonstrate this deficiency. This enzy­ matic approach is investigative and does not now have general clinical applicability. At present, there still is no generally accepted technique which can be used to establish definitively the prenatal diagnosis of cystic fibrosis or the carrier state in this disease.