Mutation as the source of the abnormal gene for plasma cholinesterase Sir, Recently, you published an article by Evans and Magill (1974) suggesting that a mutation hypothesis (one of the alleles for the E1 locus of cholinesterase had mutated) was the most likely hypothesis for explaining the genotype of two deceased parents among whose children there were three phenotypes; usual, silent, and intermediate in the family which they reported. The enzyme from two of the usual phenotypes had activity expected for the EuE' genotype but from one had activity which was twice as high as that from the other two usual phenotypes in the sibship. They discussed three other hypotheses which were considered correctly by the authors to be most unlikely: (1) a child in the sibship did not come from the same two parents, (2) the atypical and silent genes were non-allelic, or (3) there was a supressor gene.There is one explanation for their family data which was not suggested and which in my opinion is far the most likely one. That is that the parents had the genotypes E'E' and E'E' and that the offspring, whose enzyme activity was high and the phenotype was usual, had a genotype EuE' and that there was as much enzyme activity determined by his one Eu allele as is produced on the average in homozygotes for the Eu allele, or he had also the allele at the E2 locus (C5 +) which produces higher activity of either the usual or atypical forms of the enzyme (Harris et al, 1962).We have measured the levels of cholinesterase activity in 26 obligate heterozygotes (EuE'). These individuals had the usual phenotype and were parents or children of eight persons who were homozygous (E'E') for the 'silent' allele and parents or children of 10 persons who were the E'E' genotype. Five of the latter cases were described in Simpson and Kalow (1964). Although the mean activity for the 26 heterozygotes was 137 units (units were in ,umol of acetylcholine hydrolysed by lml of serum at 370 C during 1 h) and the mean for a population of 268 individuals who were probably homozygous for the usual gene and C5 -was 208 units (Simpson, 1971), the variances were large (the standard deviation for the heterozygotes was + 38 and for homozygotes was + 66 units) and consequently there were a few EuE' heterozygotes whose activity was as high or higher than the mean for homozygotes. It is also known that the activity of the enzyme is influenced by age with a sharp decrease up to about the age of 20 years and then a gradual decrease (Scott et al, 1970). In our series of 26 EuEI heterozygotes, the highest activity was 233 units in a woman who was 26 years of age and C5 -; an activity considerably above the mean for the EuEuC5 -genotype.The above data show that there is considerable overlap in the distributions between activity for cholinesterase in sera from the EuEu and EuE' genotypes and that C5 and age also need to be considered. Scott et al (1970) have discussed the problems of discriminating between these two genotypes in detail. It was with great interest that we r...