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Porphyria for Neurologist

Porphyria for Neurologist

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Published by: Lakshya J Basumatary on Sep 24, 2010
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255Peters, Mills
Porphyria for theneurologist: thebare essentials
T J Peters and K R Mills
T J Peters (retired)
Head of Department of ClinicalBiochemistry, King’s CollegeHospital, London, UK
K R Mills
Professor of ClinicalNeurophysiologyDepartment of ClinicalNeurophysiology, King’s CollegeHospital, London, UK
Correspondence to:
Professor K R MillsDepartment of ClinicalNeurophysiology, King’s CollegeHospital, Denmark Hill,Camberwell, London SE5 9RS, UK;prof.krmills@mac.com
he porphyrias are a heterogeneousgroup of disorders in which one ormore of seven enzymes of haembiosynthesis show reduced activitiesdue to inherited genetic abnormalities (tableand fig) or secondary enzyme inhibition. Of particular concern to the neurologist are thefour genetic neuropsychiatric porphyrias,in order of decreasing prevalence: acuteintermittent porphyria, variegate porphyria,hereditary coproporphyria, and the extremelyrare Doss porphyria. The overall prevalenceof symptomatic acute porphyria is about 1 in50,000. Relevant causes of secondary porphyriainclude chronic lead poisoning, hereditarytyrosinaemia, hexachlorbenzene poisoning,and liver disease including alcoholism and ironoverload.The hallmark of active or symptomaticporphyria is increased excretion of porphobilinogen (PBG) and amino-laevulinicacid (ALA). As only 10% of individuals whoinherit the genetic defect develop the overtclinical features with raised excretion profiles,a normal excretion of these metabolites doesnot exclude inheritance of the defect but
 exclude porphyria as a cause of the presentsymptoms. In between attacks the excretion of ALA and PBG may be normal although they areusually raised, particularly if the attacks havebeen severe or recent.Qualitative screening tests, still offered bysome laboratories, are notoriously unreliablewith high false positive and false negativerates approaching 50%—tossing a coin isas reliable a diagnostic test! The recentlyintroduced semiquantitative assay for PBG ismore reliable but for a definitive assessmentaccurate measurement of both PBG and ALAon a morning urine sample is necessary. Somelaboratories only assay PBG. This may bemisleading: PBG is unstable and degraded instored urine samples, especially if exposed tolight; some drugs mimic PBG in the assay; andsecondary causes of porphyria (for example,lead poisoning) and Doss porphyria may be
Practical Neurology 2006;
6: 255-258
Practical Neurology 2006;
6: 14-27
Practical Neurology
missed. ALA more closely mimics the clinicalseverity of the porphyria as it is believed to bethe putative toxin involved.
There are a myriad of clinical features withcentral nervous system, peripheral nerve, andautonomic nerve involvement. The acute attackis typically ushered in with abdominal pain andpsychiatric symptoms (anxiety, restlessness, andconfusion). A rapidly evolving, predominantlymotor axonal neuropathy then develops withascending weakness beginning in the legsand areflexia. Autonomic features may beprominent with tachycardia, constipation ordiarrhoea, vomiting, and gastroparesis. Theprincipal differential diagnoses at this stage areGuillain-Barré syndrome, acute motor axonalneuropathy, and poliomyelitis.
Respiratoryand cranial nerve involvement can occur. If unrecognised, seizures, hyponatraemia, andcoma may ensue. Severe weakness at this stagemay be confused with critical illness myopathyor neuropathy. Cerebrospinal fluid examination(characteristically normal), nerve conductionstudies, and EMG may be required.Clues to the condition include: unexplained
The pathway for the biosynthesis of heme. Ac, acetic -CH
C00-; ALAD, ALAdehydratase; ALAS, ALA synthase; COX,coproporphyrignogen oxidase; FECH,ferrochelatase; HMBS, HMB synthase;PPOX, protoporphyrinogen oxidase;Pr, propionic
; UROD,uroporphyrinogen decarboxylase; UROS,uroporphyrinogen III synthase; Vi, vinyle
(Reprinted from
Biochemistry Illustrated 
, 5th Edition. Campbell
et al 
,© 2005 with permission from Elsevier.)
257Peters, Mills
abdominal or back pain, a positive familyhistory of porphyria, atypical features of more common neurological disorders, recentingestion of porphyinogenic drugs (see http://www.drugs-porphyria.com) including illicit drugintake (cannabinoids, amphetamines, cocaine,barbiturates, etc), dark urine especially whenleft standing, unexplained hyponatraemia, andpremenstrual female. Above all, clinical suspicionand a low threshold for performing the relevantinvestigations are key elements in making thediagnosis. Skin lesions occur in both variegateporphyria and in hereditary coproporphyriaand thus the presence of vesicular skinlesions on sun exposed surfaces should notexclude consideration of the neuropsychiatricporphyrias.
Porphyria cutanea tarda is solelyassociated with skin lesions and these patientsshow consistently normal excretion of PBG andALA.Although described as the neuropsychiatricporphyrias, psychiatric complications havebeen exaggerated in the past; the evidence thatGeorge III suffered from acute porphyria is notconfirmed by re-evaluation of the historicaldata. Early surveys of psychiatric hospitals mayhave revealed a tenfold higher prevalence of porphyria in this patient group, but more recentstudies do not confirm this finding. Nonetheless,undiagnosed porphyria occasionally emergesin patients attending epilepsy and psychiatricclinics. Recent studies have indicated thatanxiety states are common in patients withporphyria
and appropriate therapy may provehelpful. Convulsions occur in about 20% of patients during acute attacks of porphyria.
TABLE The genetic porphyriasPathwayEnzymeDiseaseClinical featuresDiagnostic tests
Succinyl CoA +glycineALA synthaseNot reportedAminolevulinic acid(ALA)ALA dehydrataseDoss porphyria (AR)*Abdominal painRaised urinary ALA &coproporphyrinogen IIIPorphobilinogen(PBG)HydroxymethylbilantsynthaseAcute intermittentporphyria (AD)*Neuropsychiatricfeatures and abdominalpainRaised urinary ALA, PBG, andporphyrinHydroxymethylbilane(HMB)Uroporphyrinogen IIIsynthaseCongenital erythropoieticporphyria (AR)Severe skin lesions,haemolytic anaemiaNormal urinary ALA & PBGRaised urinary and faecal porphyrinsRaised erythrocyte protoporphyrinsUroporphyrinogen IIIUroporphyrinogendecarboxylasePorphyria cutanea tardaMarked skin lesionsNormal urinary ALA & PBGRaised urinary and faecal porphyrinsCoproporphyrinogenIIICoproporphyrinogenoxidaseHereditary coproporphyria(AD)*Neuropsychiatricfeatures, abdominalpain + skin lesionsRaised urinary ALA & PBGRaised urinary and faecalcoproporphyrinogen IIIProtoporphyrinogenIXProtoporphyrinogenoxidase Variegate porphyria (AD)*Neuropsychiatricfeatures, abdominalpain + skin lesionsRaised urinary ALA & PBGCharacteristic plasma fluorescenceRaised faecal porphyrinsProtoporphyrin IXFerrochelataseErythropoieticprotoporphyria (AD)‡Acute photosensivity,mild anaemiaRaised erythrocyte and faecalprotoporphyrinsHAEM
*Indicates an acute neuropsychiatric porphyria.†15%ofpatientswithporphyriacutaneatardaarehereditary;themajorityareduetoliverdamageinsusceptibleindividuals.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.

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