Acute Intermittent porphyria (AIP) is a human disease resulting from a dominantly inherited partial deficiency of the heme biosynthetic enzyme, porphobilinogen deaminase (PBGD)1–3. The frequency of the trait for AIP is 1/10,000 in most populations, but may be markedly higher (1/500) in psychiatric patients1,4. The clinical expression of the disease is characterized by acute, life-threatening attacks of ‘porphyric neuropathy’ that include abdominal pain, motor and sensory neurological deficits and psychiatric symptoms1. Attacks are frequently precipitated by drugs, alcohol and low caloric intake. Identical symptoms occur in other hepatic porphyrias. To study the pathogenesis of the neurologic symptoms of AIP we have generated Pbgd-deficient mice by gene targeting. These mice exhibit the typical biochemical characteristics of human AIP, notably, decreased hepatic Pbgd activity, increased δ-aminolevulinic acid synthase activity and massively increased urinary excretion of the heme precursor, δ-aminolevulinic acid after treatment with drugs such as phenobarbital. Behavioural tests reveal decreased motor function and-histo-pathological findings include axonal neuropathy and neurologic muscle atrophy.
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Kappas, A., Sassa, S., Galbraith, R.A. & Nordmann, Y. The porphyrias. In The Metabolic Basis of Inherited Disease (eds Scriver, C. et al) 1305–1365 (New York, McGraw-Hill, 1989).
Elder, G.H. Molecular genetics of disorders of haem biosynthesis. J. Clin. Pathol. 46, 977–981 (1993).
Bonkovsky, H.L. Advances in understanding and treating ‘the little imitator’, acute porphyria. Gastroenterology. 105, 590–594 (1993).
Tishler, P.V. et al. High prevalence of acute intermittent porphyria in a psychiatric patient population. Am. J. Psychiat. 142, 1430–1436 (1985).
Ledermann, B. & Bürki, K. Establishment of a germ-line competent 0576176 embryonic stem cell line. Exp. Cell Res. 197, 254–258 (1991).
Grandchamp, B. et al. Tissue-specific expression of porphobilinogen deaminase. Two isoenzymes from a single gene. Eur. J. Biochem. 162, 105–110 (1987).
Beaumont, C., Porcher, C., Picat, C., Nordmann, Y. & Grandchamp, B. The mouse porphobilinogen deaminase gene. Structural organization, sequence and transcriptional analysis. J. Biol. Chem. 264, 14829–14834 (1989).
Johnson, P. & Friedmann, T. Limited bidirectional activity of two housekeeping gene promoters: human HPRT and PGK. Gene 88, 207–213 (1990).
Eales, L. & Dowdle, E.B. The acute porphyric attack I. The electrolyte disorder of the acute porphyric attack and the possible role of delta-aminolevulinic acid. S. Afr. J. Lab. Clin. Med. 17, 89–97 (1971).
Andersson, C. & Lithner, F. Hypertension and renal disease in patients with acute intermittent porphyria. J. Int. Med. 236, 169–175 (1994).
Cavanagh, J.B. & Mellick, R.S. On the nature of the peripheral nerve lesions associated with acute intermittent porphyria. J. Neurol. Neurosurg. Psychiat. 28, 320–327 (1965).
Hruska, R.E., Kennedy, S. & Silbergeld, E.K. Quantitative aspects of normal locomotion in rats. Life Sci. 25, 171–180 (1979).
Medinaceli, L., Freed, W.J. & Wyatt, R.J. An index of the functional condition of rat sciatic nerve based on measurements made from walking tracks. Expl. Neurol. 77, 634–643 (1982).
Albers, J.W., Robertson, W.C. & Daube, J.R. Electrodiagnostic findings in acute porphyric neuropathy. Muscle Nerve. 1, 292–296 (1978).
Bonkowsky, H.L. & Schady, W., Manifestations of Acute Porphyria in Seminar Liver Dis. 2, 108–124 (1982).
Müller, W.E. & Snyder, S.H. δ-Aminolevulinic acid: influences on synaptic GABA receptor binding may explain CNS symptoms of porphyria. Ann. Neurol. 2, 340–342 (1977).
Brennan, M.J.W. & Cantrill, R.C. δ-Aminolaevulinic acid is a potent agonist for GABA autoreceptor. Nature 280, 514–515 (1979).
Litman, D.A. & Correia, M.A. L-Tryptophan: a common denominator of biochemical and neurological events of acute hepatic porphyria. Science 222, 1031–1033 (1983).
Nordmann, Y., de Verneuil, H., Deybach, J.-C., Delfau, M.-H., & Grandchamp, B. Molecular genetics of porphyrias. Ann. Med. 22, 387–391 (1990).
Louie, G.V. et al. Structure of porphobilinogen deaminase reveals a flexible multidomain polymerase with a single catalytic site. Nature 359, 33–39 (1992).
Brownlie, P.D. et al. The three-dimensional structures of mutants of porphobilinogen deaminase: Toward an understanding of the structural basis of acute intermittent porphyria. Protein Sci. 3, 1644–1650 (1994).
Chen, C.-H., Astrin, K.H., Lee, G., Anderson, K.E. & Desnick, R.J. Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene. J. Clin. Invest. 94, 1927–1937 (1994).
Meyer, U.A., Strand, L.J., Doss, M., Rees, A.C. & Marver, H.S. Intermittent acute porphyria: demostration of a genetic defect in porphobilinogen metabolism. N. Engl. J. Med. 286, 1277–1282 (1972).
Poland, A. & Glover, E. 2,3,7,8-Tetrachlorodibenzo-p-dioxin: a potent inducer of aminolevulinic acid synthetase.Science 179, 476–477 (1972).
Tomokuni, K., Ichiba, M., Hirai, Y. & Hasegawa, T. Optimized liquid-chromatographic method for fluorometric determination of urinary 8-aminolevulinic acid in workers exposed to lead. Clin. Chem. 33, 1665–1667 (1987).
Bielchowsky, M., Silber-lmprägnation der Neurofibrillen. J. Psychol. Neurol. 3, 169–188 (1904).
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