DNA diagnosis of fatal fructose intolerance from archival tissue

Hereditary fructose intolerance is a recessively-transmitted disorder of metabolism caused by deficiency of aldolase B in the liver, intestine and kidney, that responds favourably to an exclusion diet. The occurrence of fatal hepatorenal failure in a 16-year-old girl, who had received infusions of fructose and sorbitol during minor surgery, led us to suspect that she had suffered from hereditary fructose intolerance. Molecular analysis of leucocyte DNA obtained from her brother who had had a long-standing aversion to fruit and sugar, showed two previously unknown mutations in the aldolase B gene. An initiation codon mutation, M-1T, was inherited from the father, whereas Y203X, inherited from the mother, is a nonsense mutation that replaces a tyrosine codon by the ochre termination signal. The only source of genomic DNA from the index case was a fixed fragment of necrotic liver that had been obtained by needle aspiration postmortem and was embedded in paraffin wax. Analysis of aldolase B genes in this sample by procedures based on the polymerase chain reaction (PCR) confirmed the presence of both mutations in the proposita, the diagnosis of hereditary fructose intolerance, and the cause of death.