Hypophosphatasia: molecular diagnosis of Rathbun's original case.

Abstract

In 1948, Dr. John Campbell Rathbun characterized the disorder "hypophosphatasia" when he reported paradoxically low levels of alkaline phosphatase (ALP) activity in blood and in several tissues from an infant who died with rickets and epilepsy, which seemed to reflect "a new developmental anomaly." Hypophosphatasia is now recognized to be an inborn error of metabolism featuring deficient activity of the tissue-nonspecific isoenzyme of ALP (TNSALP) caused by deactivating mutations in TNSALP. Here, we show, more than 50 years after Rathbun's case report, that analysis of the parental DNA indicates compound heterozygosity involving two missense mutations (G340A and A881C) in TNSALP caused the death of Rathbun's patient.