Investigating the family
All the porphyrias, except type I 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) but clinical penetrance is low (about 12.7% within families excluding the proband; 0.5-1% 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: www.hgmd.org . All porphyrias show extensive allelic heterogeneity. In most countries mutations are restricted to one or a few families; notable exceptions are the p.Arg59Trp mutation in VP in South Africa, the p.Trp198Ter mutation in AIP in Sweden and the p.Trp283Ter in Switzerland, all having spread through founder effects to produce high prevalence of disease.
|Disorder||Inheritance||OMIM||Gene||Chromosome||Gene size (kb)||Exons||Expression|
Ubiquitous and erythroid-specific mRNAs
Ubiquitous and erythroid-specific isoenzymes
Ubiquitous and erythroid-specific mRNAs
|PCT||AD (20% of patients)||176100||UROD||1p34.1||3||10||Ubiquitous|
XLEPP, X-linked erythropoietic protoporphyria; 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; XL, X-linked.
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 (using cord blood with the exclusion of maternal cell contamination) 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 counselling and sample collection, there may be benefits from organising, family screening in collaboration with a clinical genetics service.
Details of sample requirements should be obtained from a specialist porphyria laboratory before initiating family studies. For genetic analysis, EDTA-anticoagulated blood (5 - 10 mL) is preferred to pre-extracted DNA.
- Genetic analysis to identify the causative mutation in the appropriate gene (AIP:HMBS; VP: PPOX; HCP: CPOX) is the method of choice. 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 genetic testing. 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 coproporphyrinogen 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 non erythroid-specific form of AIP (about 3-5% of families).
- Metabolite analysis may be useful for initial screening of adults and may be 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.
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.
Genetic testing is the method of choice in pre-symptomatic family members. In the small number of patients where a mutation has not been identified, the index case is not available or local conditions prevent genetic testing, the strategies included in the table below can be used, taking into account the drawbacks mentioned in the table.
|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||CPOX gene: as above|
- Whatley SD, Mason NG, Woolf JR, Newcombe RG, Elder GH, Badminton MN. Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX gene. Clin Chem. 2009 Jul;55(7):1406-14.
- Lenglet H, Schmitt C, Grange T, Manceau H, Karboul N, Bouchet-Crivat F, Robreau AM, Nicolas G, Lamoril J, Simonin S, Mirmiran A, Karim Z, Casalino E, Deybach JC, Puy H, Peoc'h K, Gouya L. From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria. Hum Mol Genet. 2018 Apr 1;27(7):1164-1173
- Yasuda M, Chen B, Desnick RJ. Recent advances on porphyria genetics: Inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes. Mol Genet Metab. 2018 Nov 30. pii: S1096-7192(18)30645-0.