103 individuals from 16 families with cystic fibrosis and 87 individuals without family history of cystic fibrosis have been studied using the methods of cell culture. Skin fibroblast cultures derived from 19 affected children, and fibroblast cultures from 11 different organs obtained at autopsy from two affected children, showed cellular metachromasia. The morphological appearance and the intracellular mucopolysaccharide content enabled these cultures to be divided into two distinct classes. Class I had discrete cytoplasmic metachromatic vesicles and a mucopolysaccharide content similar to that observed in normal fibroblasts. In class II the metachromasia was present in both vesicles and granules and was evenly distributed throughout the cytoplasm. The mucopolysaccharide content of these cells was markedly increased.
The cultures derived from the parents, presumed heterozygotes, and other members of each family showed cells with the same type of metachromasia as that demonstrated by the propositus. These data strongly suggest that cystic fibrosis is not a homogeneous entity and, moreover, can be caused by homozygosity of genes at two distinct loci.
The recognition of cytoplasmic abnormalities in skin fibroblasts derived from affected individuals and heterozygous carriers for cystic fibrosis should facilitate genetic and biochemical studies on the heterogeneity of this inborn error of metabolism.