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Practical Neurology 2006; 6: 255-258
Porphyria for the neurologist: the bare essentials
T J Peters and K R Mills
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
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 usually raised, particularly if the attacks have been severe or recent. Qualitative screening tests, still offered by some laboratories, are notoriously unreliable with high false positive and false negative rates approaching 50%—tossing a coin is as reliable a diagnostic test! The recently introduced semiquantitative assay for PBG is more reliable but for a definitive assessment accurate measurement of both PBG and ALA on a morning urine sample is necessary. Some laboratories only assay PBG. This may be misleading: PBG is unstable and degraded in stored urine samples, especially if exposed to light; some drugs mimic PBG in the assay; and secondary causes of porphyria (for example, lead poisoning) and Doss porphyria may be
T J Peters (retired)
Head of Department of Clinical Biochemistry, King’s College Hospital, London, UK
K R Mills
Professor of Clinical Neurophysiology Department of Clinical Neurophysiology, King’s College Hospital, London, UK Correspondence to: Professor K R Mills Department of Clinical Neurophysiology, King’s College Hospital, Denmark Hill, Camberwell, London SE5 9RS, UK; email@example.com
256 Practical Neurology
Figure The pathway for the biosynthesis of heme. Ac, acetic -CH2C00-; ALAD, ALA 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.)
Practical Neurology 2006; 6: 14-27
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
Not reported Doss porphyria (AR)*
— Abdominal pain
— Raised urinary ALA & coproporphyrinogen III
Succinyl CoA +glycine ALA synthase Aminolevulinic acid (ALA) Porphobilinogen (PBG) Hydroxymethylbilane (HMB) Uroporphyrinogen III Coproporphyrinogen III Protoporphyrinogen IX Protoporphyrin IX ALA dehydratase
Hydroxymethylbilant Acute intermittent synthase porphyria (AD)*
Neuropsychiatric Raised urinary ALA, PBG, and features and abdominal porphyrin pain Normal urinary ALA & PBG Raised urinary and faecal porphyrins Raised erythrocyte protoporphyrins Normal urinary ALA & PBG Raised urinary and faecal porphyrins Raised urinary ALA & PBG Raised urinary and faecal coproporphyrinogen III Raised urinary ALA & PBG Characteristic plasma fluorescence Raised faecal porphyrins Raised erythrocyte and faecal protoporphyrins
Uroporphyrinogen III Congenital erythropoietic Severe skin lesions, synthase porphyria (AR) haemolytic anaemia Uroporphyrinogen decarboxylase Coproporphyrinogen oxidase Protoporphyrinogen oxidase Ferrochelatase Porphyria cutanea tarda† Marked skin lesions Hereditary coproporphyria Neuropsychiatric (AD)* features, abdominal pain + skin lesions Variegate porphyria (AD)* Neuropsychiatric features, abdominal pain + skin lesions Erythropoietic protoporphyria (AD)‡ Acute photosensivity, mild anaemia
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. 15% ‡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 SupraRegional 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
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.
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 prevention. Current practice is to advise the patients and their medical attendants of proven safe drugs rather than provide lists of safe, 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 arginate is readily available such measures are unnecessary.6
• Although neurologists are well aware of the porphyric syndromes, advances in diagnostic techniques, the new treatments available, and the medico-legal implications of a delayed diagnosis demand that the threshold 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 GuillainBarré syndrome.
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
We are grateful to the Stone Foundation for financial support.
1. 2. 3. Albers JW, Fink JK. Porphyric neuropathy. Muscle Nerve 2004;30:410–22. Peters & Sarkany (2005). Millward LM, Kelly P, King A, et al. Anxiety and depression in the acute porphyrias. J Inherit Metab Dis 2005;28:1–9. 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. Thadani H, Deacon A, Peters TJ. Diagnosis and management of porphyria. BMJ 2000;320:1647–51. Palmieri C, Vigushin DM, Peters TJ. Managing malignant disease in patients with porphyria. Q J Med 2004;97:115–26.
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