VARIEGATE PORPHYRIA
(VP)
WHAT IS VARIEGATE PORPHYRIA (VP)?
 Variegate
porphyria is one of seven different
types of porphyria.
The enzyme
protoporphyrinogen
oxidase (PPOX) is defective
in people with VP, as a result of
a mutation
in the gene
for this enzyme. (Look this up by
clicking on the diagram on the right).
The consequence is that people with
VP may have difficulty converting
protoporphyrinogen
to protoporphyrin,
which may result in an accumulation
of porphyrins,
particularly coproporphyrin
and protoporphyrin.
Variegate porphyria
is found throughout the world, but
is particularly common in South
Africa. There is an interesting
history attached to VP in South
Africa. Here it is due to a founder
mutation introduced to the
Cape of Good Hope in 1688. At this
time, there was a small Dutch settlement
at the Cape, the southernmost part
of the African continent. It had
been established 36 years earlier,
in 1652, by the Dutch East India
Company in order to supply fresh
meat, fruit and vegetables to ships
sailing around the Cape during the
long journey between Europe and
the East Indies. By 1688, a number
of Dutch settlers had left the Company
and were farming on their own account
in the expanding settlement. There
was a preponderance of men in the
settlement, and at the request of
the local authorities, the Dutch
East India Company agreed to bring
a group of Dutch orphan women to
the Cape met die oog op huwelik
("with an eye to marriage"),
which they did. One of these orphans,
a young woman named Adriaantje Adriaanse
van Rotterdam, married a local farmer
named Gerrit Jansz van Deventer.
We are not sure whether it was Gerrit
or Adriaantje who carried the mutation
which results in VP into South Africa,
but together they founded a dynasty
which expanded very rapidly and
carried VP with it. Currently we
estimate that there are approximately
30-40 000 people in South Africa
with variegate porphyria! It was
however another 300 years before
we able to show that all the affected
people in this family, all descended
from this single settler couple,
do indeed carry a single mutation,
the R59W
mutation, which is responsible for
the disease. Our colleagues in Rotterdam
have confirmed that the R59W mutation
is indeed derived originally from
Holland, by showing close similarities
between the
DNA of Dutch and South African
families with VP. Hence VP in South
Africa is highly associated with
the
Afrikaner population, though
the link may not always be obvious
in present-day South African patients
since the disease has spread into
English-speaking South African families
and into the South African population
of mixed racial origins as a result
of intermarriage.
The R59W mutation
is not the only mutation accounting
for VP. Even in South Africa, there
are a handful of families carrying
other mutations—we have identified
nine others—who are not related
to the large family described above.
In the world as a whole, over 100
different mutations have been identified,
all resulting in VP, since they
all affect the gene for protoporphyrinogen
oxidase. None of these families
are however related (if they were,
they would share the same mutation).
INHERITANCE OF VP
VP is inherited
as an autosomal
dominant condition. In simple
terms, this means that only one
parent need be affected for the
children to run the risk of showing
the disease. In fact, each child
will have a 50% chance of inheriting
that disease. Both boys and girls
stand an equal chance of inheriting
the disease.
Will everyone who
inherits the gene show the disease?
Not at all. Our research
suggests that 40% of people who
inherit the disease show no clinical
evidence of it. There are even some
people who inherit the mutation
who show no biochemical evidence
of porphyria on biochemical testing,
though this is unusual if the sensitive
plasma fluoresence scanning
test is used. Nearly all the remainder
present with mild skin disease alone.
All patients are at risk of the
acute
attack, but are highly unlikely
to develop one provided they take
care, and particularly if they observe
appropriate
drug precautions. Both these
clinical problems are described
in more detail below.
In summary, it is
true to say that only a minority
of patients carrying VP are particularly
troubled by the disease. Most are
entirely healthy people, troubled
perhaps by minor skin symptoms,
but whose lives are subject to minimal
disruption provided they look after
themselves.
SYMPTOMS OF VP
The acute attack
The
acute attack is a specific condition
in which an accumulation of
ALA and
PBG leads to interference
with the function of the nervous
system. This results in the following
symptoms:
- Abdominal pain which is severe,
unrelenting and often felt in
the loins and thighs as well as
the abdomen.
-
Autonomic instability,
leading to vomiting, constipation,
hypertension and
tachycardia.
- Possible
motor nerve damage, resulting
in paralysis.
Characteristically,
the urine may be very dark which
reflects the large amount of PBG
and porphyrins excreted in it during
this phase.
Note that this is
a very specific complex of symptoms.
One cannot ascribe every odd ache,
pain or sense of being unwell to
one's VP. After all, there are many
people who do not have VP who experience
pain in the abdomen or some nausea
from time to time.
Patients with VP
are sometimes told that the disease
may be associated with insanity.
This is not true. It is known
that during a severe acute attack
the patient may become anxious,
difficult or disturbed. This is
only during the period that he is
very ill with the acute attack,
and he returns to complete normality
as the attack passes. There is also
no doubt that the vast majority
of people with VP are entirely sane
and will remain so.
What causes the acute
attack?
In many instances,
the factor which triggers an acute
attack can be identified. These
include:
- Administration of dangerous
(porphyrinogenic)
medication. This is the commonest
factor and is something that must
always be guarded against. It
is described in more detail below.
- Possibly, fasting and stressful
physical circumstances such as
illness or operations.
Read more about acute attacks
in The
acute attack.
Skin disease
 The
commonest symptom of variegate porphyria
is skin disease. This is essentially
the same type of symptom seen in
porphyria cutanea tarda and
hereditary coproporphyria.
Skin disease is seen only in sun-exposed
areas: typically the backs of the
hands, though the forearms, face,
back of the neck and even the lower
legs and feet are sometimes affected
in people who are exposed to a lot
of sunlight. Skin disease presents
as increased skin fragility, with
minor
trauma resulting in erosions
(sores), blisters and scabs.
Read more in Skin
disease in porphyria.
HOW DO THE SYMPTOMS
OF VP COME ABOUT?
The defective enzyme
protoporphyrinogen oxidase is unable
to convert protoporphyrinogen to
protoporphyrin efficiently. Consequently,
protoporphyrin and the preceding
porphyrins, tend to accumulate.
Consequently porphyrin concentrations
rise in the plasma and eventually
accumulate in the skin as well.
Since porphyrins react with sunlight,
a typical photosensitivity results
in sun-exposed areas. You will find
further explanation in
Skin
disease in porphyria.
When VP is extremely
active, there may even be difficulty
in converting the simple precursors
ALA and PBG to the porphyrins. Consequently
levels of ALA and PBG rise, resulting
in an acute attack. It is not known
whether the ALA and PBG themselves
are directly responsible for the
acute attack, or whether it is some
related mechanism which is responsible.
DRUG SAFETY
IN VP
The single most
important factor triggering the
acute attack is exposure to porphyrinogenic
medication. Essentially drugs which
increase the body's requirement
for haem
may bring about an increased production
of porphyrins, a rise in ALA and
PBG, and the acute attack. It is
essential that patients with VP
read the information on drug
safety in porphyria available
from this site (follow the links
on our menu) and ensure that they
follow the suggestions closely.
In brief:
- Wherever possible, avoid
all drugs if you have
VP
- If medication is absolutely
essential, ensure that you take
only those listed as safe
in our lists.
- Never take a medication whose
name does not appear
in our list. This is no guarantee
that it is safe. It merely means
that it has not been tested.
- If your medical condition is
so serious that only medication
listed as doubtful, dangerous
or unlisted must be taken, then
you should do so only after the
most careful assessment by and
under close supervision by your
doctor.
HOW SHOULD THE
ACUTE ATTACK BE HANDLED?
It is essential
that anybody with VP who experiences
severe abdominal pain, should immediately
cease any medication and report
to a doctor. Such people must be
tested for the presence of PBG which
will confirm or exclude an acute
attack. (One should not just assume
that the problem is an acute attack.
This frequently leads to the difficult
situation where other problems are
overlooked because they are incorrectly
called acute attacks.) Treatment
begins with the immediate withdrawal
of any potentially porphyrinogenic
medication. Simple analgesics
such as paracetamol and codeine
are given for the pain. If these
are inadequate to control the pain,
admission to hospital will be necessary.
The pain may then be controlled
by morphine and pethidine, but it
will be necessary to consider other
aspects of treatment including the
administration of a specific compound
called haem
arginate.
Read Acute
Symptoms for more information.
WHO SHOULD TAKE
THESE DRUG PRECAUTIONS?
All patients
known with VP must following these
precautions. The safest advice is
that all their blood relatives,
including brothers, sisters and
children should take these precautions
too, unless they have been adequately
tested by a laboratory skilled in
the diagnosis of porphyria and pronounced
clear of this disease.
CAN ONE SUFFER
REPEATED ATTACKS OF VP?
This is extremely
rare. In our experience, the few
patients with VP who were thought
to be having repeated attacks turned
out to be suffering from some other
problem.
DIAGNOSIS OF VP
It is absolutely
essential that all people thought
to have VP and all their family
members should be thoroughly and
adequately tested. Full instructions
are given in Diagnosing
porphyria: Introduction and
subsequent pages.
Return
to top of page
|
