The metabolic error in primary hyperoxaluria.

Knowledge of the incidence of a disease in successive generations of a family has value beyond the basis it provides for prediction of the health of future generations. Should the incidence suggest inheritance according to simple Mendelian rules, the disease probably has its origin in abnormality of a single genetic particle, though this has never been directly demonstrated. Garrod (1908) linked the occurrence of metabolic errors with the inheritance of Mendelian characteristics. Abnormalities inherited according to Mendelian laws were shown to result from inactivity of a single enzyme, first in moulds (Beadle and Tatum, 1941) and later in human disease (e.g. deficiency of erythrocyte diaphorase in one type of methaemoglobinaemia (Gibson, 1948)). Alteration of only one amino acid in a protein is sufficient to cause disease, as in the haemoglobino-pathy of sickle-cell anaemia (Ingram, 1957). In the many common diseases with a familial tendency that are, at least partially, genetically determined (e.g. essential hypertension, diabetes mellitus, schizophrenia), simple Mendelian rules do not apply, and summation of the actions of several genes has been evoked. In seeking the mechanisms through which inherited flaws are manifest, it seems simpler to study conditions with clear-cut Mendelian inheritance despite their rarity. The evidence that 'primary hyperoxaluria' is inherited as a Mendelian recessive characteristic will be discussed, and taken as the foundation for a search for an enzymatic fault. All patients with apparently similar metabolic abnormalities will not necessarily have the same metabolic defect, nor will all alterations in one enzyme protein be identical or have the same effect on function. Thus, in the glycogenoses, excess of liver glycogen may be associated with any one of four different enzyme deficiencies (Cori, 1957), and at least five different single amino acid abnormalities of haemoglobin are known. At present only those cases of inherited disease that occur within one family can be considered identical in origin.) is a rare and serious disease, which usually presents before the age of 10 years and often causes death from renal failure before the age of 20. It is characterized by excessive deposition of calcium oxalate in the kidneys, recurrent calcium oxalate stones in the urinary tract, excessive urinary excre-tion of oxalate not caused by excessive ingestion of oxalate, and the finding at necropsy of calcium oxalate crystals throughout the body. None of these abnormalities alone is pathognomonic of the disease, since each occurs in conditions other than primary hyperoxaluria, as …