Peters, Mills 255
NEUROLOGICAL RARITY
Porphyria for the
neurologist: the
bare essentials
T J Peters and K R Mills
T
he porphyrias are a heterogeneous
group of disorders in which one or
more of seven enzymes of haem
biosynthesis show reduced activities
due to inherited genetic abnormalities (table
and fig) or secondary enzyme inhibition. Of
particular concern to the neurologist are the
four genetic neuropsychiatric porphyrias,
in order of decreasing prevalence: acute
intermittent porphyria, variegate porphyria,
hereditary coproporphyria, and the extremely
rare Doss porphyria. The overall prevalence
of symptomatic acute porphyria is about 1 in
50,000. Relevant causes of secondary porphyria
include chronic lead poisoning, hereditary
tyrosinaemia, hexachlorbenzene poisoning,
and liver disease including alcoholism and iron
overload.
The hallmark of active or symptomatic
porphyria is increased excretion of
porphobilinogen (PBG) and amino-laevulinic
acid (ALA). As only 10% of individuals who
inherit the genetic defect develop the overt
Practical Neurology 2006; 6: 255-258
clinical features with raised excretion profiles,
a normal excretion of these metabolites does
not exclude inheritance of the defect but does
exclude porphyria as a cause of the present
symptoms. In between attacks the excretion of
ALA and PBG may be normal although they are T J Peters (retired)
usually raised, particularly if the attacks have Head of Department of Clinical
been severe or recent. Biochemistry, King’s College
Qualitative screening tests, still offered by Hospital, London, UK
some laboratories, are notoriously unreliable
with high false positive and false negative K R Mills
rates approaching 50%—tossing a coin is Professor of Clinical
as reliable a diagnostic test! The recently Neurophysiology
introduced semiquantitative assay for PBG is Department of Clinical
Neurophysiology, King’s College
more reliable but for a definitive assessment
Hospital, London, UK
accurate measurement of both PBG and ALA
on a morning urine sample is necessary. Some Correspondence to:
laboratories only assay PBG. This may be Professor K R Mills
misleading: PBG is unstable and degraded in Department of Clinical
stored urine samples, especially if exposed to Neurophysiology, King’s College
light; some drugs mimic PBG in the assay; and Hospital, Denmark Hill,
secondary causes of porphyria (for example, Camberwell, London SE5 9RS, UK;
lead poisoning) and Doss porphyria may be prof.krmills@mac.com
256 Practical Neurology

Figure
The pathway for the biosynthesis of
heme. Ac, acetic -CH2C00-; ALAD, ALA Practical Neurology 2006; 6: 14-27
dehydratase; ALAS, ALA synthase; COX,
coproporphyrignogen oxidase; FECH,
ferrochelatase; HMBS, HMB synthase;
PPOX, protoporphyrinogen oxidase;
Pr, propionic −CH2CH2C00−; UROD,
uroporphyrinogen decarboxylase; UROS,
uroporphyrinogen III synthase; Vi, vinyle
−CH:CH2. (Reprinted from Biochemistry
Illustrated, 5th Edition. Campbell et al,
© 2005 with permission from Elsevier.)

missed. ALA more closely mimics the clinical
severity of the porphyria as it is believed to be
the putative toxin involved.
CLINICAL FEATURES AND
DIAGNOSIS
There are a myriad of clinical features with
central nervous system, peripheral nerve, and
autonomic nerve involvement. The acute attack
is typically ushered in with abdominal pain and
psychiatric symptoms (anxiety, restlessness, and
confusion). A rapidly evolving, predominantly
motor axonal neuropathy then develops with
ascending weakness beginning in the legs
and areflexia. Autonomic features may be
prominent with tachycardia, constipation or
diarrhoea, vomiting, and gastroparesis. The
principal differential diagnoses at this stage are
Guillain-Barré syndrome, acute motor axonal
neuropathy, and poliomyelitis.1 Respiratory
and cranial nerve involvement can occur. If
unrecognised, seizures, hyponatraemia, and
coma may ensue. Severe weakness at this stage
may be confused with critical illness myopathy
or neuropathy. Cerebrospinal fluid examination
(characteristically normal), nerve conduction
studies, and EMG may be required.
Clues to the condition include: unexplained
 Peters, Mills 257

TABLE The genetic porphyrias

Pathway Enzyme Disease Clinical features Diagnostic tests

Succinyl CoA +glycine ALA synthase Not reported — —

Aminolevulinic acid ALA dehydratase Doss porphyria (AR)* Abdominal pain Raised urinary ALA &
(ALA) coproporphyrinogen III

Porphobilinogen Hydroxymethylbilant Acute intermittent Neuropsychiatric Raised urinary ALA, PBG, and
(PBG) synthase porphyria (AD)* features and abdominal porphyrin
pain
Hydroxymethylbilane Uroporphyrinogen III Congenital erythropoietic Severe skin lesions, Normal urinary ALA & PBG
(HMB) synthase porphyria (AR) haemolytic anaemia Raised urinary and faecal porphyrins
Raised erythrocyte protoporphyrins
Uroporphyrinogen III Uroporphyrinogen Porphyria cutanea tarda† Marked skin lesions Normal urinary ALA & PBG
decarboxylase Raised urinary and faecal porphyrins

Coproporphyrinogen Coproporphyrinogen Hereditary coproporphyria Neuropsychiatric Raised urinary ALA & PBG
III oxidase (AD)* features, abdominal Raised urinary and faecal
pain + skin lesions coproporphyrinogen III
Protoporphyrinogen Protoporphyrinogen Variegate porphyria (AD)* Neuropsychiatric Raised urinary ALA & PBG
IX oxidase features, abdominal Characteristic plasma fluorescence
pain + skin lesions Raised faecal porphyrins
Protoporphyrin IX Ferrochelatase Erythropoietic Acute photosensivity, Raised erythrocyte and faecal
protoporphyria (AD)‡ mild anaemia protoporphyrins

HAEM
*Indicates an acute neuropsychiatric porphyria.
†�����������������������������������������������������������������������������������������������������������������������������
15% of patients with porphyria cutanea tarda are hereditary; the majority are due to liver damage in susceptible individuals.
‡Co-inheritana ferro − chelatase expressio − n allele and severe ferrochelatase defect required for clinical expression.

abdominal or back pain, a positive family
history of porphyria, atypical features of
more common neurological disorders, recent
ingestion of porphyinogenic drugs (see http://
www.drugs-porphyria.com) including illicit drug
intake (cannabinoids, amphetamines, cocaine,
barbiturates, etc), dark urine especially when
left standing, unexplained hyponatraemia, and
premenstrual female. Above all, clinical suspicion
and a low threshold for performing the relevant
investigations are key elements in making the
diagnosis. Skin lesions occur in both variegate
porphyria and in hereditary coproporphyria
and thus the presence of vesicular skin
lesions on sun exposed surfaces should not
exclude consideration of the neuropsychiatric
porphyrias.2 Porphyria cutanea tarda is solely
associated with skin lesions and these patients
show consistently normal excretion of PBG and
ALA.
Although described as the neuropsychiatric
porphyrias, psychiatric complications have
been exaggerated in the past; the evidence that
George III suffered from acute porphyria is not
confirmed by re-evaluation of the historical
data. Early surveys of psychiatric hospitals may
have revealed a tenfold higher prevalence of
porphyria in this patient group, but more recent
studies do not confirm this finding. Nonetheless,
undiagnosed porphyria occasionally emerges
in patients attending epilepsy and psychiatric
clinics. Recent studies have indicated that
anxiety states are common in patients with
porphyria3 and appropriate therapy may prove
helpful. Convulsions occur in about 20% of
patients during acute attacks of porphyria.
258 Practical Neurology
A recent report highlights the importance of
considering porphyria in chronic epilepsy,
particularly if there are atypical features and
a poor response to therapy.4 Porphyria should
also feature in the differential diagnosis of
unexplained neuropathy and myopathy.
If the clinical suspicion is strong and the
neurological signs are pressing, a therapeutic
trial of haem arginate (Normosang) should be
started while awaiting the laboratory results.5
As sending samples to one of the UK Supra-
Regional Assay Service laboratories may be
required, this can lead to unacceptable delays
if treatment is contingent on the results. It
is also worth stressing that inheriting the
PRACTICE POINT
• Although neurologists are well aware of the porphyric syndromes, advances prevention. Current practice is to advise the
in diagnostic techniques, the new treatments available, and the patients and their medical attendants of proven
medico-legal implications of a delayed diagnosis demand that the threshold safe drugs rather than provide lists of safe,
for considering the diagnosis should be lowered.
genetic defect for one of the porphyrias does
not protect the patient from appendicitis,
pancreatitis, ovarian cysts, or from Guillain-
Barré syndrome. arginate is readily available such measures are
TREATMENT
The specific treatment for acute attacks
is intravenous haem arginate. This acts
physiologically by inhibiting ALA synthase, the
rate limiting and controlling enzyme in the
haem biosynthetic pathway. Symptoms and
abnormal urinary metabolites resolve within
2–3 days of the four daily infusions. Correction
of any electrolyte disturbance, maintenance of
a high carbohydrate intake, exclusion of any
underlying precipitants of the acute attack
including infection, and general supportive
measures normally prevail. However attacks
may recur, especially in women. Prophylactic
weekly haem arginate may be necessary and for
those with regular menstrual attacks a trial of
gonadotrophin releasing hormone analogues
is worthwhile. The liver is the source of the
excess porphyrin metabolites and so hepatic
transplantation is an option in patients in
whom relentless recurrent attacks occur. The
use of haem oxygenase inhibitors to potentiate
haem arginate remains experimental at this
time. Secondary porphyrias—for example,
chronic lead poisoning—require treatment of
the underlying cause.
COUNSELLING
Having established the diagnosis of an acute
porphyria, detailed analysis of urine and stool
samples will distinguish between the types.
Genetic analysis reveals an ever increasing list
of molecular variants and such analysis is a
valuable confirmatory exercise, and essential for
family studies to identify individuals at risk from
potential attacks. Avoidance of porphyinogenic
drugs is an important contribution to attack
unsafe, and doubtful drugs. A problem arises
when the patient requires treatment with unsafe
drugs for serious underlying disease including
malignancy. In the past patients were denied
curative surgery and chemotherapy because
of the risk of an acute attack. Now that haem
unnecessary.6
ACKNOWLEDGEMENT
We are grateful to the Stone Foundation for
financial support.
REFERENCES
1. Albers JW, Fink JK. Porphyric neuropathy. Muscle
Nerve 2004;30:410–22.
2. Peters & Sarkany (2005).
3. Millward LM, Kelly P, King A, et al. Anxiety and
depression in the acute porphyrias. J Inherit Metab
Dis 2005;28:1–9.
4. Winkler AS, Peters TJ, Elwes RDC. Neuropsychiatric
porphyria in patients with refractory epilepsy:
report of three cases. Journal Neurology Neurosurg
Psychiatry 2005;76:380–3.
5. Thadani H, Deacon A, Peters TJ. Diagnosis and
management of porphyria. BMJ 2000;320:1647–51.
6. Palmieri C, Vigushin DM, Peters TJ. Managing
malignant disease in patients with porphyria. Q J Med
2004;97:115–26.