Journal ofNeurology, Neurosurgery, and Psychiatry 1997;62:319-328 319 REVIEW J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.319 on 1 April 1997. Downloaded from The little imitator-porphyria: a neuropsychiatric disorder Helen L Crimlisk Abstract Porphyria is derived from the Greek word por- Three common subtypes of porphyria phuros meaning purple. Protoporphyrin IX is give rise to neuropsychiatric disorders; the biologically active substance, an important acute intermittent porphyria, variegate feature of which is its metal binding capacity. porphyria, and coproporphyria. The sec- Both chlorophyll and haem are metallopor- ond two also give rise to cutaneous symp- phyrins and are involved in the processes of toms. Neurological or psychiatric energy capture and utilisation in animals and symptoms occur in most acute attacks, plants. The description of the porphyrins by and may mimc many other disorders. Nobel laureate Hans Fischer' in 1930 as: The diagnosis may be missed because it is "The compounds which make grass green not even considered or because of techni- and blood red." cal problems, such as sample collection indicates the central position of these sub- and storage, and interpretation of results. stances in the biological sciences. A negative screening test does not exclude The porphyrias are a heterogeneous group the diagnosis. Porphyria may be overrep- of overproduction diseases, resulting from resented in psychiatric populations, but genetically determined, partial deficiencies in the lack of control groups makes this haem biosynthetic enzymes. Their manifesta- Department of uncertain. The management of patients tions are broad and their relevance in neu- Neuropsychiatry, with porphyria and psychiatric symptoms ropsychiatric disorders may sometimes be Institute ofNeurology, causes considerable Queen Square, problems. Three overlooked.2 Indeed, porphyria was described London, UK cases are described to illustrate some of by Waldenstr6m3 as the "the little imitator," H L Crimnlisk these issues. Advances in molecular biol- by contrast with syphilis, "the big imitator" of Address for correspondence: ogy permit identification of patients and the 20th century. is confus- Dr Helen L Crimlisk, early Terminology Neuropsychiatry Group, latent carriers in the family. Care to avoid ing and they have been categorised in several Department of Clinical relapses and improved treatments have different ways: as acute, non-acute, hepatic, Neurology, Institute of http://jnnp.bmj.com/ Neurology, Queen Square, reduced the mortality. cutaneous, and neurovisceral, among others. London WC1N 3BG. The most useful clinical categorisation is Received 25 June 1996 (3 Neurol Neurosurg Psychiatry 1997;62:319-328) based on symptoms and divides the and in final revised form (table 1), 18 December 1996 disease into cutaneous, neuropsychiatric, and Accepted 8 January 1997 Keywords: porphyria; psychosis; metalloporphyrins mixed disorders. on October 1, 2021 by guest. Protected copyright. Table 1 Biochemistry ofthe porphyrias (neuropsychiatric involvement in bold) Pathway Enzyme Disorder Inheritance Neuropsychiatric Cutaneous Glycine + succinyl-CoA * ALA synthetase 5-aminolaevulinic acid (ALA) * ALA dehydratase Plumboporphyria Autosomal + + + 0 recessive Porphobilinogen (PBG) * PBG deaminase Acute intermittent porphyria Autosomal + ++ 0 dominant Hydroxymethylbilane * Uroporphyrinogen synthetase Congenital erythropoietic Autosomal 0 + + + Uroporphyrinogen m (URO) porphyria recessive * Uroporphyrinogen oxidase Porphyria cutanea tarda Autosomal 0 + + + dominant (20%) or acquired Coproporphyrinogen m (COPRO) * Coproporphyrinogen oxidase Hereditary coproporphyria Autosomal + + + + dominant Protoporphyrinogen IX (PROTO) * Protoporphyrinogen oxidase Variegate porphyria Autosomal + + + + + dominant Protoporphyrin IX * Ferrochelatase Erythropoietic protoporphyria Autosomal 0 + + + haem dominant 320 Crimlisk Most porphyrins are inborn errors of result of the hypothesis of McAlpine and metabolism, but some-for example, por- Hunter'5 that George III's frequent bouts of J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.62.4.319 on 1 April 1997. Downloaded from phyria cutanea tarda-may be acquired. The insanity were due to porphyria, although this neuropsychiatric porphyrias (for example, view is still controversial.'6 17 Porphyria has acute intermittent porphyria) and the mixed also been implicated in van Gogh's illness'8 porphyrias (for example, variegate porphyria and in the obstetric history of Queen Anne.'9 and hereditary coproporphyria) may give rise Waldenstrom in Sweden20 and Dean in to acute, potentially fatal, neurovisceral crises, South Africa'" have commented on the rarity with neuropathy, delirium, psychosis, auto- of manifest porphyria before the introduction nomic instability, and abdominal pain. of porphyrinogenic drugs such as barbiturates Variegate porphyria and hereditary copropor- and sulphonamides. In South Africa, where phyria also cause dermatological features, usu- the 20 original Free Burghers have multiplied ally in the form of a bullous or erythematous 12 500 fold since the 17th century, this auto- rash. Plumboporphyria has only been somal dominant condition did not confer life described in a few cases but resembles acute threatening disadvantages on people with the intermittent porphyria clinically. Other condi- genotype. The widespread use of potentially tions such as hereditary tyrosinaemia and lead porphyrinogenic drugs and greater alcohol poisoning may produce secondary abnormali- consumption may have led to increased clini- ties of porphyrin metabolism with similar clin- cal manifestation of the underlying genetic ical and biochemical features. defect.7 Eighty per cent of patients who have inher- ited haem biosynthetic enzyme deficiencies never develop symptomatic disease and are Epidemiology thought to be "latent porphyrics".4 Relatively The estimated gene frequency of acute inter- little progress has been made in predicting mittent porphyria is 1-2 in 10 00020; however, who will develop clinical features,5 although there is great regional variability. The preva- women seem to be at much greater risk than lence of variegate porphyria among the men. The characterisation of individual molec- Afrikaans population of South Africa, where ular defects in the genes encoding the haem the introduction of the disorder has been biosynthetic enzymes has led to the identifica- traced back to a Dutch immigrant in 1688,'3 is tion of homozygous forms-for example, 1 in 250. The resultant high awareness of var- harderoporphyria, the homozygous form of iegate porphyria may have resulted in an coproporphyria.6 These are often associated underestimate of the importance of acute with more florid clinical features. intermittent porphyria.'6 Other than in South Recent developments in molecular genetics Africa, acute intermittent porphyria seems to make the accurate diagnosis of porphyria pos- be the most common, with ratios of acute sible in the proband as well as allowing genetic intermittent porphyria:variegate porphyria: counselling and screening in family members. hereditary coproporphyria of 100:15:7 in Appropriate advice on avoiding potentially Germany2' and 100:50:26 in Czechoslovakia.22 porphyrinogenic drugs has been shown to In addition to the three autosomal dominant reduce the incidence of attacks.7 The preva- subtypes of porphyria mentioned above, lence of the phenotype may be increasing,7 plumboporphyria, an autosomal recessive con- making detection of apparently latent carriers dition which presents with neuropsychiatric http://jnnp.bmj.com/ more important. Whereas advances have been symptoms, has been described in six cases made in the diagnostic tests available, pitfalls worldwide23 and a localised cluster of cases, in diagnosis are still common8 resulting in the known as "Dobson's complaint" (a combina- false belief that "porphyria has been tion of the enzyme deficits responsible for excluded". Finally, a recent family study9 acute intermittent porphyria and variegate found a higher incidence of generalised anxi- porphyria with a similar clinical picture) has been described in Cheshire, UK.24 An out- ety disorder in "latent" relatives of patients on October 1, 2021 by guest. Protected copyright. with acute intermittent porphyria, raising break of "secondary porphyria" occurred in doubts as to the relation between phenotype Turkey after the exposure of 4000 people to a and genotype in so-called "latent" carriers. fungicide, hexachorobenzene, resulting in a mixed porphyric picture in many people as well as the death of many infants through Historical aspects breast milk transmission.25 Porphyria is less The first description of acute porphyria as a common before adolescence and after the clinical syndrome was in 1889 by Stokvis.'° menopause, and symptomatic cases are four The attack occurred after the administration times more common in women, with a particu- of sulphonal, a drug which had been intro- lar preponderance premenstrually.26 duced as a hypnotic a year earlier. Congenital Waldenstrbm'2 first showed the presence of erythropoietic porphyria was recognised as an excess porphyrin metabolites in asymptomatic inborn error of metabolism by Garrod in relatives of patients with acute intermittent 1923.1" Important work on the description of porphyria and proposed the now accepted the clinical condition originated in areas where hypothesis of autosomal dominance with vari- the incidence of porphyria