The porphyrias are a group of eight disorders of the heme biosynthesis pathway that present with acute neurovisceral symptoms, photosensitising skin lesions or both. Seven porphyrias result from partial deficiency of one of the enzymes of heme biosynthesis. One, X-linked erythropoietic protoporphyria (XLEPP), is a consequence of gain of function mutations in the ALA synthase 2 gene. Apart from the sporadic form of porphyria cutanea tarda, all 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
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 more common 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 related to the menstrual cycle, infection or calorie restriction and respond to treatment with human hemin preparations. Recurrent attacks can be managed by regular hemin infusions, or where available givosiran, a newly licensed RNA interference therapy.
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.
Clinical features of an acute neurovisceral attack of porphyria
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.
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 Dutch (Afrikaner) descent due to a founder effect.
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% of patients. Skin lesions without symptoms of acute porphyria are uncommon in HCP; this mode of presentation is usually provoked by cholestasis from some other cause.
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.
Porphyria cutanea tarda (PCT)
PCT, the commonest porphyria, is a cutaneous porphyria (fragile skin, bullae, hypertrichosis, changes in 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 very 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 recessive disorder in which most patients inherit a low expression FECH allele that is present in about 10% of the general population in-trans to a pathogenic null FECH variant. It is one of two porphyrias that present 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.
X-linked erythropoietic protoporphyria (XLEPP)
XLEPP is an X-linked disorder that is clinically indistinguishable from EPP, and patients are also susceptible to liver failure caused by hepatic protoporphyrin accumulation. The condition affects all males and most females who inherited a gain of function deletion in the ALAS2 gene.
Rare clinical variants of the autosomal dominant porphyrias occur in which mutations of the HMBS gene (homozygous AIP), CPOX 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.
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. Bissell DM, Anderson KE, Bonkovsky HL.
N Engl J Med 2017;377:862-72.
3. Karim Z, Lyoumi S, Nicolas G, Deybach JC, Gouya L, Puy H.
Porphyrias: A 2015 update.
Clin Res Hepatol Gastroenterol. 2015;39:412-25.
4. Stein PE, Badminton MN, Rees DC.
Update review of the acute porphyrias.
Br J Haematol. 2017;176:527-538.
5. Singal AK.
Porphyria cutanea tarda: Recent Update.
Mol Genet Metab 2019;128:271-81.
6. Holme SA, Anstey AV, Finlay AY, Elder GH, Badminton MN.
Mol Orphanet J Rare Dis. 2009;4:19.
7. Elder G, Harper P, Badminton M, Sandberg S, Deybach JC.
The incidence of inherited porphyrias in Europe.
Mol J Inherit Metab Dis 2013;36:849-57.
8. Erwin AL, Desnick RJ.
Congenital erythropoietic porphyria. Recent Advances.
Mol Genet Metab 2019;128:288-97.
9. Balwani M, Sardh E, Ventura P et al.
Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.
N Engl J Med. 2020;382:2289-2301.
10. Badminton, MN, Elder GH, Whatley SD.
Clinical and molecular epidemiology of the porphyrias.
In: Ferreira GC. (ed). Handbook of Porphyrin Science. Vol 29; Porphyrias and sideroblastic anaemias. Singapore: World Scientific Publishing, 2013; p120-150.