INVESTIGATING THE FAMILY
PORPHYRIA:INHERITANCE AND MOLECULAR GENETICS
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:
www.hgmd.org.
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 |
OMIM
# |
Gene |
Chromosome |
Gene size(kb) |
#
Exons |
Expression |
| 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. |
|
AUTOSOMAL
DOMINANT ACUTE PORPHYRIAS
| |
|
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. |
I. METHODS
| |
|
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. |
II. DIAGNOSIS
OF THE TYPE OF ACUTE PORPHYRIA
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
| Disorder |
Metabolite |
Enzyme |
DNA |
| 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 |
|
III. REFERENCES
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.
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