Acute intermittent porphyria: a clinical and experimental study of the disease and of related aspects of porphyrin metabolism

Abstract

The first observation that acute porphyria occurred in members of the same family was made by Barker and Estes (1912). Gìnther (1922) noted the hereditary implications of the disease but it was Waldenstree (1937) who firmly established its hereditary nature. Gates (1946) reviewed Waldenstrdm's data and considered that the disease was inherited as an irregular dominant character. In the present series of 50 cases at least 19 have one or more relatives with the active or latent condition. 9 latent porphyries were revealed by investigation of relatives. It was only possible to study 11 families in detail (see Appendix). The family trees were constructed on the basis of whether or not porphobilinogen was definitely found in the urine on at least one occasion. There is only one exception to this rule. Case No. 41 died in 1935 and although the urine was noted to be dark in colour it was not tested for porphobilinogen. The clinical and family histories of this patient make the diagnosis of acute porphyria highly probable. The urines were routinely tested by the methods of Watson and Schwartz (1941) and Vahlquist (1939). Where a doubtful positive was obtained about 0.5 to 1 litre of urine was concentrated and any porphobilinogen present was identified by paper chromatography ( Westall, 1952; Cookson and Riraington, 1954). Concentrates of normal urine, so treated, showed no porphobilinogen. This method. proved very helpful in identifying 3 latent porphyrias who excreted small quantities of porphobilinogen - family 2, son of propositus; family 3, father of propositus; family 9, nephew of propositus. It should be noted, however, that out of 18 previously active cases whose urines were tested in a state of remission, 5 had ceased to excrete porphobilinogen (Cases 15, 31, 37, 46 and 47). Case 10 did not excrete porphobilinogen at the age of S years but did do so at 11 years. Thus the absence of porphobilinogen in the urine of a relative does not rule out the possession of the trait and this is of particular importance in testing the urine of the child relative.The findings in this series confirm those of Waldenstrbm (1937, 1956). In 4 families (Nos. 1, 2, 3 and 8) the condition was found in more than 1 generation, apparently transmitted directly from a parent to one or more of the offspring. In another family (No. 7) where it was not possible to test the parents, 2 half -sibs with unrelated fathers were found to be affected. Thus a single gene would seem necessary for the manifestation of the disease. There was no evidence of increased parental consanguinity. This familial distribution is consistent with the hypothesis that the condition is inherited as a Mendelian dominant character, i.e. the individuals are heterozygous for an abnormal gene. In 2 instances, however, (families 1 and 10), where more than one of a group of sibs were affected, it was not possible to detect porphobilinogen in the urines of either of the parents. It must, therefore, be assumed that there is 13 considerable variation in the degree of the expression of the character and that one can get all grades from the acute case, the latent porphyria, to the apparently normal individual who excretes no porphobilinogen. It is possible that some of the latter group might begin to excrete porphobilinogen, if suitably provoked. In only 2 families (Nos. 1 and 8) is there the association of a parent and a child who have both had the active disease. This is not altogether surprising, because if a gene produces a severe and lethal illness variable in its manifestations, then those with the milder form of the affection are more likely to survive to adult life.The apparent sporadic occurrence of the disease (families 5 and ll) might perhaps be attributed to mutation, that is the sudden change from the normal gene to its abnormal counterpart in the germ tract of one or other of the parents. Although the occurrence of a mutation in these families cannot be excluded, it is probable that in the majority of instances where an affected child has been derived from normal parents, one or other of the parents is in fact heterozygous for the gene.From a study of these families, it has been possible to calculate that approximately 25o of the sibs of a case may be expected to have porphobilinogen in the urine. A high proportion of these are liable to have an acute attack. Furthermore, about 1 in 4 of the children of individuals who excrete porphobilinogen may be expected to become similarly affected. If it is true that affected individuals are heterozygous for an abnormal gene, then 2 out of 4 children of parents, only one of whom is affected, should carry the abnormal gene. Thus half of those carrying the gene may not excrete porphobilinogen.