The enzymatic links and genetic loci in each of the hereditary porphyrias are shown in Table 1. Nearly all are inherited as autosomal dominant traits. The Chester porphyria family pedigree (Fig. 1) shows autosomal dominant inheritance of acute porphyria with attacks of neurovisceral dysfunction without cutaneous hypersensitivity. This was originally reported as a dual porphyria; however, identification of a heterozygous truncating mutation in the HMBS gene and no mutations in other heme biosynthesis enzymes in affected individuals has confirmed that Chester porphyria is a variant of classic AIP. HMBS is transcribed from two promoters to produce ubiquitous and erythroid specific isoforms. In classic AIP both isoforms are deficient; however, in the rare, nonerythroid variant, only the ubiquitous HMBS variant is defective. The rare CEP shows autosomal recessive inheritance. The mutations producing each of the acute porphyrias are heterogeneous at the molecular level and include complete or partial gene deletions, alterations of splicing or stability of mRNA, and missense mutations. In South Africa, the founder effect ensures a predominance of the Arg59Tryp mutation in proto porphyrinogen oxidase, although over 175 other mutations have been reported worldwide.Homozygotic or compound heterozygotic inheritance has been found in a number of the porphyrias, as has con current inheritance of more than one defect. This may present as two types of porphyria in one family or as two types in one patient. Dual porphyrias most commonly arise from a combined deficiency of uroporphyrinogen decarboxylase with PBGD, coproporphyrinogen oxidase, or protoporphyrinogen oxidase.

Table1. Porphyrias: Clinical Involvement, Enzymatic Etiology, and Chromosomal Location

Fig1. THE CHESTER FAMILY PEDIGREE. The propositus, Peter Dobson, was a salmon fisherman from a close-knit community living on the bank of the River Dee, which runs through the city of Chester, UK. Most of the 330 descendants of his marriage in 1888 still live in the city. Many suffered disabling illnesses and psychiatric upsets, which often went unrecognized as porphyria. The family called their illness Dobson’s complaint. Chester porphyria has recently been confirmed as a variant of acute intermittent porphyria. Squares represent male subjects; circles represent females. Courtesy Giles R. Youngs.

The prevalence of the different forms varies widely. For example, in northern Europe and North America, approximately 1 of 10,000 individuals carries the gene for AIP, although only about 10% of the affected persons will present with clinical features. It has been suggested that spontaneous mutation accounts for 3% of AIP cases. Variegate porphyria occurs in 1 of 400 white South Africans. There is a reduction in gene frequency in variegate porphyria from generation to generation that suggests that the allele associated with it is selectively deleterious. The same is probably true of the other porphyrias.

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