• compound heterozygous;
  • double enzyme deficiency;
  • dual porphyrias;
  • enzyme deficiency;
  • haeme biosynthesis;
  • heterozygous;
  • porphyria


  1. Top of page
  2. Abstract
  3. The porphyrias
  4. Dual porphyrias
  5. Acknowledgements
  6. References

Abstract:  The porphyrias are clinically and genetically heterogeneous metabolic diseases, which predominantly result from a hereditary dysfunction in the pathway of haeme biosynthesis. Currently, at least eight different forms of porphyrias can be differentiated, all of them characterized by a specific enzyme deficiency that is either inherited in an autosomal-dominant fashion, autosomal recessively or, in the case of porphyria cutanea tarda, might also be acquired. All genes encoding these enzymes have been cloned and several mutations underlying the different types of porphyrias have been reported. Traditionally, the diagnosis of porphyria is made on the basis of clinical symptoms, characteristic biochemical findings and enzyme assays. In some porphyria patients and families, however, these diagnostic tools can reveal simultaneous findings compatible with two different forms of porphyria, a phenomenon referred to as dual porphyria. Here, we give an overview on what is currently known about these peculiar variants of porphyria and suggest that, whenever feasible, molecular genetic analysis should complement the analytical techniques used to characterize patients and families in which a double enzymatic deficiency within the haeme biosynthetic pathway is assumed.


acute intermittent porphyria


δ-aminolevulinic acid


δ-aminolevulinic acid dehydratase


congenital erythropoietic porphyria


Chester porphyria


coproporphyrinogen oxidase


European Porphyria Initiative


erythropoietic protoporphyria


hereditary coproporphyria


hepatoerythropoietic porphyria






porphobilinogen deaminase


porphyria cutanea tarda


protoporphyrinogen oxidase


uroporphyrinogen decarboxylase


uroporphyrinogen III synthase


variegate porphyria

The porphyrias

  1. Top of page
  2. Abstract
  3. The porphyrias
  4. Dual porphyrias
  5. Acknowledgements
  6. References

Aetiology and mode of inheritance

The porphyrias are metabolic disorders of haeme biosynthesis resulting from an either inherited or acquired catalytic deficiency of the second to eighth enzyme involved in the porphyrin–haeme biosynthetic pathway (Fig. 1). Dominantly or recessively inherited mutations in any of the genes encoding these enzymes lead to a disturbance of haeme synthesis with a pathological accumulation and measurable excretion of porphyrins and/or porphyrin precursors (1,2).


Figure 1.  The pathway of haeme biosynthesis. Catalytic deficiency of the second to eighth enzyme involved in the cascade can cause a specific type of porphyria.

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All porphyrias are monogenetic diseases that are caused by heterogeneous mutations in specific genes, except for porphyria cutanea tarda (PCT) in which an acquired form (PCT type I) has to be differentiated from a hereditary variant (PCT type II) (Table 1) (3).

Table 1.   Classification of the porphyrias in acute and non-acute forms and characteristic genetic aspects of each variant (OMIM, Online Mendelian Inheritance in Man;
 Gene locusGene name (symbol)Mode of inheritance
Acute porphyrias
 Acute intermittent porphyria11q23.3Porphobilinogen deaminase (PBGD)Autosomal dominant
 Variegate porphyria1q22–23Protoporphyrinogen oxidase (PPOX)Autosomal dominant
 Hereditary coproporphyria3q12Coproporphyrinogen oxidase (CPOX)Autosomal dominant
 ALAD deficiency porphyria9q34δ-Aminolevulinic acid dehydratase (ALAD)Autosomal recessive
Non-acute porphyrias
 Porphyria cutanea tarda1p34Uroporphyrinogen decarboxylase (UROD)Autosomal dominant (up to 25% of cases); otherwise acquired
 Erythropoietic protoporphyria18q21.3Ferrochelatase (FECH)Autosomal dominant
 Congenital erythropoietic porphyria10q25.3–q26.3Uroporphyrinogen III synthase (UROS)Autosomal recessive
 Hepatoerythropoietic porphyria1p34Uroporphyrinogen decarboxylase (UROD)Autosomal recessive


There are three possibilities to classify the different types of porphyrias. Traditionally, these disorders have been and still are classified into erythropoietic and hepatic forms, according to the major site of expression of the specific enzymatic deficiency. From a dermatologist's perspective, the porphyrias can also be classified into cutaneous and non-cutaneous forms (Table 2). However, from a general practitioner's point of view, it seems most suitable to classify the porphyrias into acute and non-acute forms, thereby primarily considering if the patient does or does not experience potentially life-threatening acute neurological attacks (Table 1) (1,2). Throughout this review, we will adhere to the latter classification.

Table 2.   Classification of the porphyrias from a dermatologist's perspective into cutaneous and non-cutaneous forms
Cutaneous porphyriasNon-cutaneous porphyrias
Porphyria cutanea tardaAcute intermittent porphyria
Variegate porphyriaδ-aminolevulinic acid dehydratase deficiency porphyria
Erythropoietic protoporphyria 
Hereditary coproporphyria 
Congenital erythropoietic porphyria 
Hepatoerythropoietic porphyria 

Acute porphyrias

The acute porphyrias are comprised of acute intermittent porphyria (AIP) (4), variegate porphyria (VP) (5), hereditary coproporphyria (HCP) (6) and δ-aminolevulinic acid dehydratase (ALAD) deficiency porphyria, which is also known as plumboporphyria or Doss porphyria (7) (Table 1). Whereas AIP is the most frequent type of porphyria worldwide, in some countries other acute forms might be predominant, as is the case for VP in South Africa and in Chile (8,9).

All patients suffering from an acute porphyria can manifest a broad spectrum of often unspecific clinical symptoms, independent of the specific type of acute porphyria present in an individual patient. These symptoms include long-lasting colicky abdominal pain, nausea and vomiting, diarrhoea, tachycardia, hypertension, seizures, muscle weakness, paraplegia and tetraplegia as well as a variety of other neurological signs. Hence, establishing an accurate diagnosis in these disorders demands all diagnostic abilities of the attending physician particularly because the porphyrias are rare diseases, which are rarely considered as differential diagnosis (10).

Acute porphyric attacks can be precipitated by a variety of factors, including porphyrinogenic drugs, alcohol, hormonal changes, recurrent or chronic infection and reduced caloric intake due to fasting or diets (11).

Besides the aforementioned neurological findings, individuals suffering from VP or HCP can also present with cutaneous symptoms on the sun-exposed areas of the skin, including increased photosensitivity, abnormal skin vulnerability, blistering, erosions, scars and postinflammatory hyperpigmentation. Thus, VP and HCP are also referred to as neurocutaneous porphyrias. Of note, the skin findings in VP and HCP are identical to those encountered in PCT, a non-acute type of porphyria. By contrast, however, AIP and ALAD deficiency porphyria do not present with cutaneous symptoms (1,2).

In an effort to set forth standards in diagnosis and management of the acute porphyrias and to provide information and guidelines for patients as well as physicians, a European consortium of porphyria specialists from different European expert centres has founded the European Porphyria Initiative (EPI) in the year 2005. On the EPI web page (, which is constantly updated, important information is available, particularly if physicians are seeking to contact the nearest porphyria centre in their country to discuss specific problems encountered in the management of their patients. Furthermore, a comprehensive overview is given on safe and potentially unsafe drugs that can be administered or should be avoided in patients suffering from an acute porphyria. Motivated by the European expert group, several North American porphyria specialists have recently likewise gathered together and, as a result of their meeting, published recommendations for diagnosis and treatment of the acute porphyrias (12).

Non-acute porphyrias

The non-acute porphyrias consist of PCT, the most frequent type of porphyria worldwide, erythropoietic protoporphyria (EPP), congenital erythropoietic porphyria (CEP) and hepatoerythropoietic porphyria (HEP), the recessively inherited variant of PCT (Table 1). These types of porphyria are of specific interest for dermatologists because they can all present with cutaneous symptoms on sun-exposed body surfaces, including, e.g. photosensitivity, increased skin fragility, vesicles and blisters, erosions and excoriation, burning and stinging, oedema, pruritus, hypertrichosis, scarring, hyperpigmentation and, in the case of CEP and HEP, mild to severe mutilation. PCT occupies an exceptional position among the different types of porphyrias because it is the only type of porphyria in which an acquired form (PCT type I or sporadic PCT) has to be distinguished from a hereditary variant (PCT type II or inherited PCT) (1,2,13).

Laboratory diagnosis

If one of the porphyrias is presumed, diagnostic procedures traditionally comprise a combination of thorough anamnesis (particularly a complete family history), clinical examination and biochemical determination of porphyrins and porphyrin precursors in urine, faeces and blood (14).

In specialized laboratories, these diagnostic procedures can be extended to the measurement of specific enzymatic activities in erythrocytes, lymphocytes or fibroblasts of affected patients (15).

Most recently, however, modern and rapid laboratory techniques such as DNA isolation from peripheral blood followed by polymerase chain reaction (PCR) and automated DNA sequencing have not only been helpful for clinicians in obtaining the most precise confirmation of a putative diagnosis but also enabled molecular biologists and geneticists to learn more about genes and their function as well as to provide affected individuals and their family members with genetic counselling (3).

But even when using all the aforementioned diagnostic tools, the results might still be confusing and sometimes reveal overlapping findings within index patients and their families (16,17). This is particularly true for the so-called dual porphyrias.

Dual porphyrias

  1. Top of page
  2. Abstract
  3. The porphyrias
  4. Dual porphyrias
  5. Acknowledgements
  6. References

Definition and frequency

In the dual porphyrias, laboratory tests indicate the simultaneous deficiency of two enzymes along the haeme biosynthetic pathway either in one individual or within one family. To date, approximately 15 patients and families with this constellation have been reported (18–33), indicating that these porphyria variants are very rare, although some authors already raised the question 20 years ago whether this peculiar form of porphyria is underdiagnosed (34).

The majority of these dual porphyrias comprise the combined deficiency of uroporphyrinogen decarboxylase (UROD) with either porphobilinogen deaminase (PBGD), coproporphyrinogen oxidase (CPOX) or protoporphyrinogen oxidase (PPOX), respectively (18–26,29,31,32), and this is not surprising because PCT is the most frequent type of porphyria in the world. In three families, the simultaneous deficiency of CPOX and either PBGD (27), uroporphyrinogen III synthase (UROS) (28) or ALAD (33) was detected. In one patient with CEP, the UROS defect was accompanied by a deficiency of UROD (30).

The different types of dual porphyrias reported to date are summarized in Table 3.

Table 3.   Chronological order of the different variants of dual porphyrias reported to date
AuthorsEnzyme deficiencies reportedGenetic confirmationReference
Watson et al.Uroporphyrinogen decarboxylase and protoporphyrinogen oxidaseNo(18,19)
Levine et al.Uroporphyrinogen decarboxylase and protoporphyrinogen oxidaseNo(20)
Day et al.Uroporphyrinogen decarboxylase and protoporphyrinogen oxidaseNo(21)
McColl et al.Porphobilinogen deaminase and protoporphyrinogen oxidaseNo(22)
DossPorphobilinogen deaminase and uroporphyrinogen decarboxylaseNo(23)
DossPorphobilinogen deaminase and uroporphyrinogen decarboxylaseNo(24)
DossPorphobilinogen deaminase and uroporphyrinogen decarboxylaseNo(25)
Sturrock et al.Uroporphyrinogen decarboxylase and protoporphyrinogen oxidaseNo(26)
Nordmann et al.Coproporphyrinogen oxidase and uroporphyrinogen III synthaseNo(27)
Gregor et al.Coproporphyrinogen oxidase and porphobilinogen deaminaseNo(28)
Sieg et al.Uroporphyrinogen decarboxylase and protoporphyrinogen oxidaseNo(29)
Freesemann et al.Uroporphyrinogen III synthase and uroporphyrinogen decarboxylaseNo(30)
Doss et al.Coproporphyrinogen oxidase and uroporphyrinogen decarboxylaseNo(31)
Harraway et al.Uroporphyrinogen decarboxylase and porphobilinogen deaminaseyes(32)
Akagi et al.Coproporphyrinogen oxidase and δ-aminolevulinic acid dehydrataseYes(33)

Two types of porphyria within one family

In 1975, Watson et al. for the first time reported on two siblings exhibiting different forms of enzymatic deficiencies affecting haeme biosynthesis. In this family, a 54-year-old woman (designated individual P430) revealed acute neurological attacks and a stool porphyrin excretion pattern indicating VP, whereas her 59-year-old brother (designated individual P431) had never experienced acute attacks and revealed isocoproporphyrin (ISO-COPRO) in the faeces, indicative of PCT. Additionally, several family members showed a biochemical urine and stool porphyrin profile compatible with latent VP. Of note, however, in none of the other family members, ISO-COPRO could be detected in the faeces, raising the question whether, in this family, VP was segregating as an autosomal-dominant trait, whereas individual P431, who exhibited ISO-COPRO in the faeces, was suffering from acquired PCT (18). This problem was then resolved in a later publication from this group in which they reported on the finding of ISO-COPRO in the faeces of a niece of individuals P430 and P431. Based on these data, the authors concluded that both VP and PCT were segregating as independent traits within this family and that the type of PCT present was rather the inherited variant than the acquired form (19).

While in this family the characteristic presence or absence of ISO-COPRO in the faeces of several relatives studied by Watson et al. eventually allowed for an answer to the question which variants of porphyria were present, the authors would have certainly appreciated the possibility of molecular genetic analysis to unequivocally confirm their diagnoses. Unfortunately though, at that time, the genes coding for the different types of porphyrias were not known and, likewise, PCR amplification of specific DNA sections was not available yet.

In the years following the publication from Watson and colleagues, Levine et al. and Day et al. also reported on the coexistence of two distinct types of porphyrias within one family (20,21).

Chester porphyria

The probably most well-known report on a family with dual porphyria is the one about the so-called Chester porphyria.

In 1985, a new variant of porphyria with autosomal-dominant inheritance was reported from a large kindred residing in Chester, UK, designated Chester porphyria (CP). Affected family members revealed acute porphyric attacks and the biochemical characteristics of both VP and AIP, with some patients revealing overlapping values of porphyrins and porphyrin precursors in the urine and faeces. Additional enzymatic studies showed reduced activity of PBGD and PPOX in individuals with overt disease (22). In 1992, the results of a genome-wide linkage analysis performed in the CP family indicated that a novel gene residing on chromosome 11q23.1 might be involved in the pathogenesis of this novel subtype of dual porphyria (35). Interestingly, this locus did not contain any of the thus far known genes coding for enzymes catalysing major steps in haeme biosynthesis.

In an effort to elucidate the molecular basis of this presumably novel type of porphyria, we obtained DNA samples of 10 individuals from the original CP family, five of whom had been classified as affected and the other five as unaffected, in accordance with previous extensive biochemical and enzymatic studies (22,36). Subsequently, several candidate genes within the candidate interval on 11q23.1 were cloned and screened for mutations. However, these initial efforts were not successful.

Although the original linkage report from Norton et al. excluded the PBGD and PPOX gene as candidates (35), we nevertheless decided to sequence these two genes because the biochemical and enzymatic data published by McColl et al. indicated deficiencies of the encoded enzymes (22). Sequencing analysis of the coding regions of the PPOX gene and its promoter region revealed no mutations. In exon 9 of the PBGD gene, however, we detected a nonsense mutation, designated R149X, that was carried by all affected individuals studied (Fig. 2) (37).


Figure 2.  Results of mutation analysis in the Chester porphyria family. The sequence deviation consists of a heterozygous C-to-T transition, indicated by an arrow in the lower panel. This nucleotide change results in a nonsense mutation in exon 9 of the PBGD gene, designated R149X.

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Interestingly, our study revealed that only four of the five individuals from the CP family classified as suffering from overt disease and sent to us for molecular analysis were indeed carriers of the disease-causing mutation R149X. This suggested that the original classification into affected and non-affected individuals in the publications from McColl et al., Norton et al. and Qadiri et al. might have already been somewhat imprecise (22,35,36). Furthermore, this could also explain why the linkage data from Norton et al. erroneously indicated a novel chromosomal locus for CP and why the PBGD gene locus on 11q23.3 was initially excluded on the basis of several recombination events observed in certain members of the CP family (35), assuming that some of the family members revealing the crucial recombination events were perhaps wrongly classified prior to linkage.

Our data show that the individuals from the CP family do not suffer from a novel type of porphyria, but rather from a variant of AIP. It still remains elusive why some individuals revealed the characteristic porphyrin excretion patterns of VP and reduced enzymatic activities of PPOX, likewise indicative of VP.

Interestingly, however, different groups have previously pointed out that biochemical analyses and even the measurement of enzymatic activities in different cells are somewhat imprecise, as a certain overlap between the values measured in patients with overt porphyria, clinically unaffected mutation carriers (the so-called ‘silent’ carriers) and normal control individuals can be found. Thus, the results of biochemical and enzymatic studies in the porphyrias are not always conclusive, sometimes making an accurate diagnosis of the respective type of porphyria difficult if not impossible (16,17).

In support of this notion, several authors found that a coexistent decrease in PBGD activity can be frequently detected in patients suffering from VP who usually exhibit a catalytic deficiency of PPOX solely (38–40). Still, in none of these individuals, the existence of a dual porphyria could be confirmed on the genetic level. Even in a VP family which revealed a concomitant decrease in PBGD activity being as high as 50% of the normal range, no underlying mutation in the PBGD gene was detected and, furthermore, this catalytic deficiency apparently had no clinical consequences (40). Taking these reports into consideration, it might be possible that the accompanying decrease in PPOX activity observed in some members of the CP family is most likely attributable to a phenomenon secondary to the disease-causing genetic defect in the PBGD gene and, thus, has no immediate consequences on the clinical course of the disease.

The results of our studies in the CP family clearly indicate that CP is neither a dual porphyria nor a separate type of porphyria, but rather a variant of AIP. Furthermore, our data also largely exclude the possibility that a hitherto unknown gene is involved in the pathogenesis of the porphyrias.

Confirmation of dual porphyrias by molecular genetic analysis

Until 2006, the diagnosis of dual porphyria in all patients and families reported up to this time was always established on the basis of biochemical measurement of porphyrins and/or porphyrin precursors in urine and faeces and enzymatic assays (18–31). However, in none of these individuals, the diagnosis was confirmed on the molecular genetic level by demonstrating the simultaneous occurrence of two disease-causing mutations in different genes. This might be due to three reasons mainly. First, the fact that PCR-based DNA analysis is a relatively new technique (41) and, thus, the first mutation reports on the porphyrias date from the late 1980s only (42). Second, cDNA and genomic sequences of genes encoding human enzymes involved in haeme biosynthesis were not available until the late 1980s and early 1990s, the first one published being the cDNA sequence of UROD (43). Third, the frequency of type I PCT is approximately three to four times higher than that of type II PCT (1,2) and, therefore, a deficiency of UROD, when encountered in a patient or a family with dual porphyria, might rather be acquired than inherited.

Taking this into consideration, it is understandable that, until recently, there has been no report about a patient with mutations in two genes encoding enzymes of haeme biosynthesis.

In January 2006, two groups independently reported on the first porphyria patients in whom DNA analysis unequivocally confirmed the presence of mutations in two different genes encoding enzymes that catalyse major steps in haeme biosynthesis (32,33).

Harraway et al. reported on a young female patient who developed skin symptoms on the sun-exposed areas of the body and revealed an increased urinary porphobilinogen (PBG) excretion. The initial diagnosis of VP, however, could not be confirmed and biochemical analysis of her urine, faeces and plasma rather indicated a combined deficiency of PBGD and UROD. Subsequent automated sequencing of the PBGD and UROD gene revealed mutations in both genes, confirming the diagnosis of dual porphyria on the molecular genetic level (32).

Akagi et al. studied a male individual who revealed acute porphyric attacks accompanied by an increased urinary excretion of δ-aminolevulinic acid (ALA), PBG and coproporphyrin. Although these findings were suggestive of HCP, the authors noted an elevation of ALA that was higher than that of PBG and, furthermore, an increase of erythrocyte zinc protoporphyrin, suggesting an additional ALAD deficiency. Subsequent automated sequencing of both the CPOX and ALAD gene led to the detection of disease-causing mutations in each gene. Both genetic defects were confirmed by in vitro expression experiments, thereby for the first time unequivocally establishing the molecular basis in an individual with a dual porphyria consisting of a simultaneous CPOX and ALAD deficiency (33).

We strongly believe that the excellent molecular studies performed by the groups of Harraway and Akagi, respectively, point the way to the basic standards that should be fulfilled in the future before the diagnosis of a dual porphyria can be accepted. In our eyes, it should be mandatory that, from now on, all biochemical and enzymatic studies that suggest the simultaneous deficiency of two enzymes along the haeme biosynthetic pathway should always be complemented and confirmed by molecular genetic analysis of the corresponding genes to identify the disease-causing mutations underlying a particular variant of dual porphyria.


  1. Top of page
  2. Abstract
  3. The porphyrias
  4. Dual porphyrias
  5. Acknowledgements
  6. References

This publication is dedicated to Dr David R. Bickers, MD, one of the major experts in the field of porphyrias who is celebrating his 65th birthday on September 23, 2006. PPG was supported, in part, by a Rotation position from the Medical Faculty of the RWTH Aachen. TW is supported, in part, by START grant number 694041 and a Rotation position from the Medical Faculty of the University Hospital of the RWTH Aachen. JF is board member of the European Porphyria Initiative (EPI) and is, in part, supported by grant number A04155HS, GIS-Institut des Maladies rares: Network on rare diseases to the EPI.


  1. Top of page
  2. Abstract
  3. The porphyrias
  4. Dual porphyrias
  5. Acknowledgements
  6. References
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