Chromosome-21 and Paroxysmal Nocturnal Hemoglobinuria.

LTHOUGH great strides have been made in the past decade in both cytogenetics and biochemical genetics, the location of genes on the 44 autosomes has remained unknown. The experiments of nature in which an additional chromosome-21 is present and where a portion of this chromosome has been deleted have provided, for the first time, a clue to the possible location of some autosomal genes. The studies of Alter and his associates”2 were the first of a series of investigations suggesting that a gene regulating the formation of leukocyte alkaline phosphatase was located on this chromosome.37 A flurry of reports has followed suggesting that genetic control of ABO blood group substances,8 galactose-1-phosphate uridyl transferase#{176} but not the D antigen ‘#{176} may also be located on this chromosome. Like Alter et al., we were struck by the fact that paroxysmal nocturnal hemoglobulinuria ( PNH ) is associated with low leukocyte alkaline phosphatase activity.11 It also occurred to use that the clinical course of this disease, with its onset in the second, third, or fourth decade of life, its chronicity, and its involvement of several cell lineages, all are compatible with the hypothesis that this disorder, like chronic grantilocytic leukemia ( CGL), may be due to proliferation of a clone of cells with a deletion of genetic material from chromosome-21. It is particularly interesting, in this regard, that the blood of patients with paroxysmal nocturnal hemoglobinuria appears to consist of a mixture of normal and abnormal erythrocytes.12”3 The highly variable course of the disease might be due to the results of competition-with the ecologic sense-between the normal and abnormal clones of cells. A further intriguing possibility seemed to be that the hitherto unexplained decrease in acetylcholinesterase activity14”5 could be due to the presence of the gene controlling the formation of this enzyme on the deleted chromosomal segment. The latter possibility seemed to be strengthened by the unpublished obseravtion of Samuels’6 that the red cell cholinesterase activity in treated chronic granulocytic leukemia in relapse was also diminished, particularly in the more severely anemic patients studied. Sawitsky et al.17 had previously reported a slightly lowered red cell cholinesterase activity