Investigating the family




All the porphyrias, except PCT, are inherited in mendelian patterns. Enzyme deficiency (close to half-normal) is present in all who inherit the gene for an autosomal dominant porphyria (AIP, HCP, VP, EPP) but clinical penetrance is low (about 10% within families; about 2% from studies of the general population). Rare homozygous variants of each of these disorders have been described. Enzyme activities in the autosomal recessive porphyrias (ADP, CEP) are usually less than 20% of normal.

Genes for all the porphyrias have been characterized and large numbers of disease-specific mutations identified. Regularly updated lists of mutations are available from the Human Gene Mutation Database: All porphyrias show extensive allelic heterogeneity. In most countries most mutations are restricted to one or a few families; notable exceptions are the R59W mutation in VP in South Africa , the W198X mutation in AIP in Sweden and the W283X in Switzerland, all having spread through founder effects to produce high prevalences of disease.

Porphyria: inheritance and molecular genetics

Disorder Inheritance
Chromosome Gene size(kb)
# Exons
ADP AR 125270 ALAD 9q34 13 13 Ubiquitous and erythroid-specific mRNAs
AIP AD 176000 HMBS 11q24.1-24.2 10 15 Ubiquitous and erythroid-specific isoenzymes
CEP AR 263700 UROS 10q25.2-26.3 34 10 Ubiquitous and erythroid-specific mRNAs
PCT Complex 176090,176100 UROD 1p34 3 10 Ubiquitous
HCP AD 121300 CPO 3q12 14 7 Ubiquitous
VP AD 600923 PPOX 1q21-23 5 13 Ubiquitous
EPP AD 177000 FECH 18q21.3 45 11 Ubiquitous
ADP, ALA dehydratase deficiency porphyria; AIP, acute intermittent porphyria; CEP, congenital erythropoietic porphyria; PCT, porphyria cutanea tarda; HCP, hereditary coproporphyria; VP, variegate porphyria; EPP, erythropoietic protoporphyria. AD, autosomal dominant; AR, autosomal recessive.


    Family screening to identify those with latent disease is essential for management of the autosomal dominant acute porphyrias. Testing is possible at any age from birth (e.g. cord blood) onwards.
    Informed consent from adult family members is essential for all family studies. Because identification during childhood is beneficial, testing children by parental request is ethically acceptable.
    To ensure appropriate counseling and sample collection, there may be benefits from organising, family screening in collaboration with a clinical genetics centre (more about porphyria specialist centres).
    Details of sample requirements should be obtained from the relevant porphyria reference laboratory before initiating family studies. For genomic DNA analysis, EDTA-anticoagulated blood (5 - 10 mL) is preferred to pre-extracted DNA as it allows additional investigations (eg plasma porphyrin, PBG deaminase) to be performed.


    DNA analysis to identify the causative mutation in the appropriate gene (AIP:HMBS; VP: PPOX; HCP: CPO ) is the method of choice (more information). It requires prior identification of the mutation in an unequivocally affected family member.Problems. Mutations cannot be identified in about 5% of families. An unequivocally affected proband may not be available for mutational analysis.
    Enzyme measurements are not as specific or sensitive as DNA analysis. Erythrocyte PBG deaminase assay is still used for detection of latent AIP when DNA analysis is not available or a mutation cannot be detected. Measurement of protoporphyrinogen and coproporphyringen oxidases is complex and requires nucleated cells.Problems. Usefulness of erythrocyte PBG deaminase is limited by overlap between normal and AIP ranges, dependence on erythrocyte age (not reliable before the age of one year or in haematologically abnormal individuals) and failure to identify erythroid-specific form of AIP (about 3-5% of families).
    Metabolite analysis is useful for initial screening of adults and is sufficiently specific to provide an unequivocal diagnosis, provided the appropriate method is used. These are quantitative measurement of urinary PBG for AIP, plasma fluorescence emission spectroscopy (FES) for VP and faecal coproporphyrin isomer ratio measurement for HCP (more information).Problems. Metabolite analysis is normal before puberty and insensitive after that age. Sensitivity of FES for VP is about 60% over the age of 15 while most adults with latent AIP have normal urinary PBG excretion.
    Gene tracking using intragenic polymorphisms may be useful in families where a mutation cannot be identified but requires unequivocal diagnosis by non-DNA methods of at least two affected family members.


AIP - DNA analysis; reserve erythrocyte PBG deaminase measurement (with urinary PBG in adults) and gene tracking for families where a mutation cannot be identified.

VP - Plasma fluorescence emission spectroscopy (FES) if aged 15 years or over; DNA analysis if aged under 15 or FES normal/equivocal.

HCP – Faecal coproporphyrin isomer ratio; DNA analysis if normal/equivocal.

Acute porphyrias: screening relatives to detect latent porphyria

AIP Urinary PBG: normal before puberty; low sensitivity in adults Erythrocyte PBG deaminase: 10-20% overlap with normal range; must be normal haematology; normal in variant AIP (2-5%) HMBS gene: allelic heterogeneity; requires prior identification of causative mutation in family; accurate, sensitivity at least 95%
VP Plasma porphyrin fluorescence emission peak at 624-626 nm: normal before puberty; over age of 15 y, sensitivity 60% and specificity 100%

Faecal porphyrin analysis: normal before puberty; over age of 15 y, sensitivity 36%

Protoporphyrinogen oxidase: complex assay, requires nucleated cells PPOX gene: as above
HCP Faecal coproporphyrin isomer III/I ratio: sensitivity high in adults, not established in children Coproporphyrinogen oxidase: complex assay, requires nucleated cells CPO gene: as above


1. Puy H. Deybach J-C, Lamoril J et al.
Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria.
Amer J Hum Genet 1997; 60:1373-83.

2. Whatley SD, Puy H, Morgan RR et al.
Variegate porphyria in western Europe: identification of PPOX mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation.
Amer J Hum Genet 1999; 65: 984-94

3. Lamoril J, Puy H, Whatley SD et al.
Characterisation of mutations in the CPO gene in British patients demonstrates absence of phenotype-genotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria.
Amer J Hum Genet 2001; 68: 1130-38

4. Deacon AC, Elder GH.
Front line tests for the investigation of suspected porphyria.
J Clin Pathol 2001;54:500-07.

Link to PubMed >>