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896 Part VI: The Erythrocyte Chapter 58: The Porphyrias 897

greatest requirements for heme. The rate of heme synthesis in the liver
is largely regulated by ALAS1 activity. The synthesis of ALAS1, in turn,
is under feedback control by heme, which regulates ALAS1 at the lev-
els of transcription, translation, and transfer into mitochondria. Many
chemicals, hormones, and drugs increase the synthesis of hepatic CYPs,
which increases the demand for heme and lead to induction of ALAS1.
In addition, the ALAS1 gene contains upstream enhancer elements that
are responsive to inducing chemicals and interact with the PXR. There-
fore, ALAS1 and CYPs are subject to direct induction by xenobiotics
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and certain steroids. Chemical exposures that induce hepatic heme
oxygenase and accelerate the destruction of hepatic heme, or inhibit
heme formation, can also induce hepatic ALAS1.
ALAS2 is not inducible in erythroid cells by drugs that induce
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ALAS1 in hepatocytes. The synthesis of ALAS2 is uninfluenced, or
often upregulated, by hemin, at both the transcriptional and the trans-
lational levels. Hemin treatment of marrow cultures increases erythroid
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colony-forming units, whereas hemin treatment of hepatocytes inhib-
its synthesis of ALAS1 and CYPs. An additional distinct difference in
these ALAS isoforms is that SCS-βA associates with ALAS2 but not
with ALAS1, suggesting a tissue-specific difference in mitochondrial
transport of these isoforms.

ERYTHROPOIETIC PORPHYRIAS
There are two major erythropoietic porphyrias in humans. CEP is
caused by mutations of the UROS gene. It is one of the least-common
porphyrias, but is well known as a result of its long history and the
severe photomutilation of exposed areas such as the face and fingers Figure 58–5. A 23-year-old Scottish fisherman with congenital ery-
that is a dramatic feature in many cases (Fig. 58–5). EPP, which is caused thropoietic porphyria and scarring and mutilation of the face, ears, and
digits as a consequence of repeated sun exposure. He was described in
by FECH mutations, is the third most common porphyria, and the most 1898 as having red urine containing excess porphyrins and “hydroa aes-
common in children, but was not well described until 1965. XLP is tivale,” because the symptoms, which began at age 3 years, worsened in
much less common, has the same phenotype as EPP, but normal FECH early summer. A 26-year-old brother was similarly affected. (Reproduced
activity. In 2008, the discovery of gain-of-function mutations in the last with permission from Anderson TM: Hydroa aestivale in two brothers, com-
exon of ALAS2 provided an explanation for the increased level of ery- plicated with the presence of haematoporphyrin in the urine. Br J Dermatol
throcyte protoporphyrin seen in this type of protoporphyria. Charac- 10:1, 1898.)
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teristics in most patients with erythropoietic porphyrias that are distinct
from the hepatic porphyrias include childhood onset, stable symptoms Pathophysiology
and levels of porphyrins over time, and severity largely determined by The uroporphyrinogen III synthase defects in CEP are remarkably het-
genotype rather than factors that affect the heme pathway, primarily in erogeneous at the molecular level, with at least 46 different mutations of
the liver. Substantial increases in erythrocyte zinc protoporphyrin in the UROS gene, and one GATA-1 mutation reported as of this writing.
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ADP and homozygous forms of other hepatic porphyrias, such as HEP The UROS mutations include deletions, insertions, rearrangements,
(the homozygous form of familial PCT), AIP, HCP, and VP, suggest that splicing abnormalities, and both missense and nonsense mutations.
an erythropoietic component may be important in these conditions. 87 The missense mutations are well distributed throughout the
gene. Of the 12 single-base substitutions, four (T228M, G225S, A66V,
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CONGENITAL ERYTHROPOIETIC PORPHYRIA A104V) were hotspot mutations, occurring at CpG dinucleotides. The
identification of a mutation that altered the penultimate nucleotide in
Definition and History exon 4, resulting in an E81D mutation, also produced exon skipping on
CEP is caused by a deficiency of UROS (see Fig. 58–4, step 4), is an approximately 85 percent of the transcripts from that allele. With the
autosomal recessive condition, and is also known as Günther disease. It exception of V82F, all CEP missense mutations occurred in amino acid
results in accumulation and excretion of isomer I porphyrins, especially residues that are conserved in both the mouse and the human enzyme.
uroporphyrin I and coproporphyrin I (see Table 58–1 and Fig. 58–1). Genotype–phenotype correlation in CEP was studied by prokary-
Characteristic manifestations of CEP include chronic, severe photosen- otic expression of mutant UROS cDNAs. Mean activities of the mutant
sitivity and hemolytic anemia evident in early childhood. Atypical pre- enzymes expressed in Escherichia coli ranged from 0 to 36 percent of
sentations include milder disease that resembles PCT, and onset during the activity expressed by the normal cDNA. The majority of the mutant
adult life often in association with a myeloproliferative disorder. Early cDNAs expressed polypeptides with no enzymatic activity. However,
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case descriptions of CEP appeared in 1874 and 1898, and approximately V82F, E81D, A66V, A104V, and V99A showed 36, 30, 15, 8, and 6 per-
3
130 cases were reported up to 1997. However, some of these patients cent enzyme activity, respectively, compared with the normal control.
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may have had HEP, which has very similar clinical features. Perhaps the A66V and V82F were thermodynamically unstable mutants. Homoal-
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most well-known patient was Mathias Petry, who survived until age 34, lelism for C73R, the most common mutation, found in five patients, was
and beginning in 1915, worked with the porphyrin chemist Hans Fisher, associated clinically with the most severe phenotypes, such as hydrops
providing samples for early studies of porphyrin chemistry. 90 fetalis and transfusion dependency from birth.

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