Homocystinuria: heterozygote detection using phytohemagglutinin-stimulated lymphocytes

Deficiency of cystathionine synthase activity results in the clinical syndrome of homocystinuria. Using phytohemagglutinin (PHA)-stimulated lymphocytes as a readily available source of this enzyme, its activity has been compared in 48 control subjects, seven homozygotes affected with homocystinuria, and 17 obligate heterozygotes. PHA-induced enzyme levels were highest in controls (mean +/-SEM, 666.9+/-70.2 pmol cystathionine formed/mg protein per 4 h), intermediate in heterozygotes (114.4+/-27.3), and absent to severely deficient in homozygotes (2.0+/-1.6). Since only three of the 17 values from the obligate heterozygotes overlapped into the control range, this simple method may become clinically useful for heterozygote detection of carriers of the gene for abnormal cystathionine synthase. In addition, this system for induction of cystathionine synthase in lymphocytes has a more general relevance to human biochemical genetics in that it demonstrates that the absence of an enzyme in a normal cell does not preclude using that source for diagnosis of genetic disease if the enzyme can be induced.