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Chapter 38 Heme Biosynthesis and Its Disorders 501

4 3 2
5 1
6 5
1
2 4
3 6
1 5 3
2 7 2
Married 1888
1
3 8 4
1
1 3 8
2 9 2 7
3 10 1 6
4 5
5 4
6 3
1 2
2 1
3 4 5 6
Key
Porphyria biochemistry positive
Porphyria biochemistry negative
Obligatory porphyria
Porphyria positive (history only)
Not tested
Unknown sex
Fig. 38.3 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.)

shows autosomal recessive inheritance. The mutations producing
Measurement of Porphyrins and Precursors
each of the acute porphyrias are heterogeneous at the molecular level
Fluorescence of urine under ultraviolet (UV) light is recommended and include complete or partial gene deletions, alterations of splicing
as the initial screening test for the acute porphyrias, whereas or stability of mRNA, and missense mutations. An exception is
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plasma fluorescent spectroscopy is the best initial test for diagnosis variegate porphyria in South Africa, in which the founder effect
of cutaneous porphyrias. Diverse techniques such as high-pressure ensures a predominance of the Arg59Tryp mutation in protoporphy-
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liquid chromatography, quantitative extraction, and various forms of rinogen oxidase. 49,50 Homozygotic or compound heterozygotic
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fluorometry are used to measure porphyrins and precursors. The inheritance has been found in a number of the porphyrias, as has
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International Federation of Clinical Chemistry and Laboratory Medicine concurrent inheritance of more than one defect. This may present as
presents diagnostic information on its website (www.ifcc.org). two types of porphyria in one family or as two types in one
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patient. 52,53 Dual porphyrias most commonly arise from a combined
deficiency of uroporphyrinogen decarboxylase with PBGD, copro-
porphyrinogen oxidase, or protoporphyrinogen oxidase. 54
shows autosomal dominant inheritance of acute porphyria with The prevalence of the different forms varies widely. For example,
attacks of neurovisceral dysfunction without cutaneous hypersensitiv- in northern Europe and North America, approximately 1 of 10,000
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ity. This was originally reported as a dual porphyria ; however, individuals carries the gene for AIP, although only about 10% of the
identification of a heterozygous truncating mutation in the HMBS affected persons will present with clinical features. It has been sug-
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gene and no mutations in other heme biosynthesis enzymes in gested that spontaneous mutation accounts for 3% of AIP cases.
affected individuals has confirmed that Chester porphyria is a variant Variegate porphyria occurs in 1 of 400 white South Africans. There
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of classic AIP. HMBS is transcribed from two promoters to produce is a reduction in gene frequency in variegate porphyria from genera-
ubiquitous and erythroid specific isoforms. In classic AIP both iso- tion to generation that suggests that the allele associated with it is
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forms are deficient; however, in the rare, nonerythroid variant only selectively deleterious. The same is probably true of the other
the ubiquitous HMBS variant is defective. The rare congenital EPP porphyrias.