Hypophosphatasia: Molecular diagnosis of Rathbun's original case

In 1948, Dr. John Campbell Rathbun characterized the disorder "hypophosphat asia" when he reported paradoxically low levels of alkaline phosphatase (AL P) activity in blood and in several tissues from an infant who died with ri ckets and epilepsy, which seemed to reflect "a new developmental anomaly." Hypophosphatasia is now recognized to be an inborn error of metabolism feat uring deficient activity of the tissue-nonspecific isoenzyme of ALP (TNSALP ) caused by deactivating mutations in TNSALP. Here, we show, more than 50 y ears after Rathbun's case report, that analysis of the parental DNA indicat es compound heterozygosity involving two missense mutations (G340A and A881 C) in TNSALP caused the death of Rathbun's patient.