THE PORPHYRIAS
DEFINITION
The porphyrias are a group of disorders of the
heme biosynthesis pathway that present with acute
neurovisceral symptoms, skin lesions or both.
All porphyrias result from partial deficiency
of one of the enzymes of heme biosynthesis and,
apart from the sporadic form of porphyria cutanea
tarda, are inherited in monogenic patterns. Accurate
diagnosis of clinically overt (symptomatic)
porphyria requires identification of the unique
pattern of overproduction of heme precursors that
results from each enzyme deficiency (more
about laboratory diagnosis).
All the autosomal dominant porphyrias show low
clinical penetrance. The majority (an estimated
80% within families) of those who inherit an autosomal
dominant porphyria remain asymptomatic throughout
life but which individuals will fall into this
category cannot be predicted. Here the terms
latent or presymptomatic
are used to describe individuals of any age who
have never had symptoms attributable to porphyria.
The term remission is
used to describe individuals in whom previous
symptoms of porphyria have resolved.
The main types
of human porphyria
Disorder |
Enzyme defect |
Neurovisceral crises |
Skin lesions |
Inheritance |
OMIM# |
Acute
porphyrias |
ALA dehydratase deficiency
porphyria (ADP) |
ALAD |
+ |
- |
AR |
|
Acute intermittent porphyria (AIP) |
PBGD |
+ |
- |
AD |
|
Hereditary coproporphyria (HCP) |
CPO |
+ |
+1,2 |
AD |
|
Variegate porphyria (VP) |
PPOX |
+ |
+1,2 |
AD |
|
Non-acute
porphyrias |
Congenital erythropoietic porphyria
(CEP) |
UROS |
- |
+2 |
AR |
|
Porphyria cutanea tarda (PCT) |
UROD |
- |
+2 |
Complex |
|
Erythropoietic protoporphyria (EPP)
|
FECH |
- |
+3 |
AD |
|
1Skin lesions
and neurovisceral crises may occur alone
or together; 2fragile skin,
blisters; 3acute photosensitivity
without fragile skin, blisters. AD:autosomal
dominant AR: autosomal recessive.
ALA: 5-aminolevulinate; PBGD: porphobilinogen
deaminase (hydroxymethylbilane synthase);
CPO:coproporphyrinogen oxidase;
PPOX protoporphyrinogen oxidase; UROS:
uroporphrinogen III synthase; UROD:
uroporphyrinogen decarboxylase; FECH:
ferrochelatase. |
|
TYPES
OF PORPHYRIA
I. ACUTE PORPHYRIAS
The autosomal dominant acute porphyrias
[acute intermittent porphyria (AIP), variegate
porphyria (VP) and hereditary coproporphyria (HCP)]
are characterised by episodic acute neurovisceral
attacks which may be life threatening. Acute attacks
are very rare before puberty, usually start between
the ages of 15 and 35 years, and are commoner
in females. Most patients have one or a few attacks
followed by full recovery but recurrent acute
attacks, which in women may be related to the
menstrual cycle, develop in less than 10%. Attacks
are often provoked by drugs, alcohol, endocrine
factors, infection or calorie restriction and
respond to treatment with human hemin preparations.
Their prevalence in most European countries is
1-2 per 100,000 inhabitants; most of these have
AIP. The main exception is Sweden where the prevalence
of AIP is high (1 per 1500 people in northern
Sweden) due to a founder effect.
More
about laboratory diagnosis, drugs
and treatment.
Clinical features of an acute neurovisceral attack
of porphyria
Symptom/sign |
Percent.
number of acute attacks (n=143) |
Abdominal pain : |
97 |
Non-abdominal pain : |
25 |
Vomiting : |
85 |
Constipation : |
46 |
Psychological symptoms : |
8 |
Convulsions : |
5 |
Muscle weakness : |
8 |
Sensory loss : |
2 |
Hypertension (diastolic >85
mmltg) : |
64 |
Tachycardia (>80 per min) : |
65 |
Hyponatraemia (<135 nmol/L)
: |
37 |
Data
from Mustajoki and Nordmann (1993);
Hift, unpublished, 1986-95. |
|
Acute intermittent porphyria (AIP)
AIP is the commonest of the acute porphyrias.
Acute neurovisceral attacks are the main presenting
clinical manifestation;skin lesions do not occur.
There are two forms: in most patients both the
erythroid and non-erythroid isoforms of PBG deaminase
are deficient but 3-5% of patients have a clinically
identical variant in which only the non-erythroid
isoform of PBG deaminase is deficient and erythrocyte
PBG deaminase activity is normal.
Diagnostic
criteria
Screening
families for AIP
Variegate porphyria (VP)
About 60% of patients with VP present with skin
lesions alone;20% with an acute neurovisceral
attack without skin lesions and 20% with both
of these together. VP is about one-third as prevalent
as AIP in most European countries;but is more
common in South Africa where it affects about
10,000 individuals of Africaans descent due to
a founder effect.
Diagnostic
criteria
Screening
families for VP
Hereditary coproporphyria (HCP)
HCP is the least common of the autosomal dominant
acute porphyrias. Most patients present with an
attack of acute porphyria which is accompanied
by skin lesions (fragile sun-exposed skin with
erosions/ sub-epidermal bullae) in about 30%.
Skin lesions without symptoms of acute porphyria
are uncommon in HCP; this mode of presentation
is usually provoked by cholestasis from some other
cause.
Diagnostic
criteria
Screening
families for HCP
Aminolevulinate dehydratase deficiency porphyria
(ADP)
ADP is a very rare autosomal recessive disorder.
Only 7 patients have been reported since its description
in 1979. All have had acute neurovisceral attacks,
sometimes starting in infancy, and/or peripheral
neuropathy.
II. NON-ACUTE PORHYRIAS
Porphyria cutanea tarda (PCT)
PCT the commonest porphyria, is a cutaneous porphyria
(fragile skin, bullae, hypertrichosis, pigmentation)
which may be acquired (Type I, 80%) or inherited
(Type II, 20%) as an autosomal dominant trait
with low penetrance. Most patients have underlying
liver cell damage with iron overload and there
are strong associations with alcohol, hepatitis
C and mutations in the haemochromatosis (HFE)
gene. It responds to treatment by iron depletion
or low dose chloroquine.
Congenital erythropoietic porphyria (CEP)
CEP is a rare autosomal recessive condition.
Most patients present soon after birth and have
severe photosensitivity, erythrodontia and hemolytic
anaemia. Bone marrow transplantation is the only
effective treatment.
Erythropoietic protoporphyria (EPP)
EPP is an autosomal dominant disorder with low
penetrance. In most patients, clinical expression
requires co-inheritance of a low expression allele
that is present in about 10% of the general population.
It is the only porphyria that presents with acute
photosensitivity, without skin fragility and bullae,
which starts in early childhood. Hepatic failure,
caused by the accumulation of protoporphyrin in
hepatocytes, occurs in less than 2% of cases.
III. OTHER PORPHYRIAS
Rare clinical variants of the autosomal dominant
porphyrias occur in which mutations of the HMBS
gene (homozygous AIP), CPO gene (harderoporphyria
and homozygous HCP), UROD gene (hepatoerythropoietic
porphyria) or PPOX gene (homozygous VP) have been
identified on both alleles. They usually present
in early childhood and most are clinically more
severe than their heterozygous counterparts.
INFORMATION ON PORPHYRIA
Reviews of porphyria and individual
diseases
1. Anderson KE, Sassa, S, Bishop, DF,
Desnick RJ.
Disorders of heme biosynthesis: X-linked sideroblastic
anemia and the porphyrias.
In Scriver CR, Beaudet AL, Sly WS, Valle D (eds.):
The Metabolic and Molecular Basis of Inherited
Disease, 8th edn. New York: McGraw-Hill,
2001; p2961-3062.
2. Bickers DR, Pathak MA, Lim HW.
The Porphyrias. In: Fitzpatrick's Dermatology
in General Medicine, 5th edn., Freedberg IM
et al, ed. New York: McGraw-Hill, 1999: 1766-1803.
3. Elder GH, Hift RJ, Meissner PN.
The acute porphyrias. Lancet 1997; 349:1613-17.
4. Seminars in Liver Disease 1998;
18, Number 1 (whole issue).
5. Elder GH.
Porphyria cutanea tarda.
Seminars in Liver Disease 1998; 18:67-76.
6. Todd DJ.
Erythropoietic protoporphyria.
Brit J Dermatol 1994; 131:751-66.
7.Schneider-yin X, Meier-Weinand A,
Gouya L, Deybach JC, Minder E.
New insights into the pathogenesis of erythropoietic
protoporphyria and their impact on patient management.
Eur J Pediatr 2000, 159, 719-725 .
8. Fritsch C, et al.
Congenital erythropoietic porphyria.
J Am Acad Dermatol 1997; 36:594-610.
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