Acute intermittent porphyria: Studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias

Constanza Solis, Antonio Martinez-Bermejo, Thomas P. Naidich, Walter E. Kaufmann, Kenneth H. Astrin, David F. Bishop, Robert J. Desnick

    Research output: Contribution to journalArticle

    Abstract

    Background: Acute intermittent porphyria (AIP), due to half-normal hydroxymethylbilane synthase activity, is characterized by acute life-threatening neurologic attacks whose etiology remains unclear. To date, only 3 patients confirmed to have homozygous dominant AIP (HD-AIP) have been described (hydroxymethylbilane synthase genotypes R167Q/R167Q and R167W/R173Q). Objective: To investigate the genetic, biochemical, clinical, and neuroradiologic features of a severely affected infant with HD-AIP. Design: Clinical, imaging, and genotype/phenotype studies were performed. Results: The proband, homoallelic for hydroxymethylbilane synthase mutation R167W, had approximately 1% of normal hydroxymethylbilane synthase activity, elevated porphyrins and porphyrin precursors, severe psychomotor delay, and central and peripheral neurologic manifestations. When expressed in vitro, the R167W mutant enzyme had less than 2% of normal activity but was markedly unstable, consistent with the proband's severe phenotype. Mitochondrial respiratory chain enzymes were normal. Neuroradiologic studies revealed a unique pattern of deep cerebral white matter injury, with relative preservation of the corpus callosum, anterior limb of the internal capsule, cerebral gray matter, and infratentorial structures. Conclusions: This severely affected patient with HD-AIP expanded the phenotypic spectrum of HD-AIP. His brain magnetic resonance imaging studies suggested selective cerebral oligodendrocyte postnatal involvement in HD-AIP, whereas most structures developed prenatally were intact. These findings indicate that the neurologic manifestations result from porphyrin precursor toxicity rather than heme deficiency and suggest that porphyrin precursor toxicity is primarily responsible for the acute neurologic attacks in heterozygous AIP and other porphyrias.

    Original languageEnglish (US)
    Pages (from-to)1764-1770
    Number of pages7
    JournalArchives of Neurology
    Volume61
    Issue number11
    DOIs
    StatePublished - Nov 2004

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    Hydroxymethylbilane Synthase
    Acute Intermittent Porphyria
    Porphyrins
    Nervous System
    Neurologic Manifestations
    Genotype
    Phenotype
    Internal Capsule
    Porphyrias
    Corpus Callosum
    Oligodendroglia
    Peripheral Nervous System
    Enzymes
    Electron Transport
    Heme
    Molecular Biology
    Extremities
    Central Nervous System
    Magnetic Resonance Imaging
    Mutation

    ASJC Scopus subject areas

    • Neuroscience(all)

    Cite this

    Solis, C., Martinez-Bermejo, A., Naidich, T. P., Kaufmann, W. E., Astrin, K. H., Bishop, D. F., & Desnick, R. J. (2004). Acute intermittent porphyria: Studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. Archives of Neurology, 61(11), 1764-1770. https://doi.org/10.1001/archneur.61.11.1764

    Acute intermittent porphyria : Studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. / Solis, Constanza; Martinez-Bermejo, Antonio; Naidich, Thomas P.; Kaufmann, Walter E.; Astrin, Kenneth H.; Bishop, David F.; Desnick, Robert J.

    In: Archives of Neurology, Vol. 61, No. 11, 11.2004, p. 1764-1770.

    Research output: Contribution to journalArticle

    Solis, Constanza ; Martinez-Bermejo, Antonio ; Naidich, Thomas P. ; Kaufmann, Walter E. ; Astrin, Kenneth H. ; Bishop, David F. ; Desnick, Robert J. / Acute intermittent porphyria : Studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. In: Archives of Neurology. 2004 ; Vol. 61, No. 11. pp. 1764-1770.
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    abstract = "Background: Acute intermittent porphyria (AIP), due to half-normal hydroxymethylbilane synthase activity, is characterized by acute life-threatening neurologic attacks whose etiology remains unclear. To date, only 3 patients confirmed to have homozygous dominant AIP (HD-AIP) have been described (hydroxymethylbilane synthase genotypes R167Q/R167Q and R167W/R173Q). Objective: To investigate the genetic, biochemical, clinical, and neuroradiologic features of a severely affected infant with HD-AIP. Design: Clinical, imaging, and genotype/phenotype studies were performed. Results: The proband, homoallelic for hydroxymethylbilane synthase mutation R167W, had approximately 1{\%} of normal hydroxymethylbilane synthase activity, elevated porphyrins and porphyrin precursors, severe psychomotor delay, and central and peripheral neurologic manifestations. When expressed in vitro, the R167W mutant enzyme had less than 2{\%} of normal activity but was markedly unstable, consistent with the proband's severe phenotype. Mitochondrial respiratory chain enzymes were normal. Neuroradiologic studies revealed a unique pattern of deep cerebral white matter injury, with relative preservation of the corpus callosum, anterior limb of the internal capsule, cerebral gray matter, and infratentorial structures. Conclusions: This severely affected patient with HD-AIP expanded the phenotypic spectrum of HD-AIP. His brain magnetic resonance imaging studies suggested selective cerebral oligodendrocyte postnatal involvement in HD-AIP, whereas most structures developed prenatally were intact. These findings indicate that the neurologic manifestations result from porphyrin precursor toxicity rather than heme deficiency and suggest that porphyrin precursor toxicity is primarily responsible for the acute neurologic attacks in heterozygous AIP and other porphyrias.",
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    T2 - Studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias

    AU - Solis, Constanza

    AU - Martinez-Bermejo, Antonio

    AU - Naidich, Thomas P.

    AU - Kaufmann, Walter E.

    AU - Astrin, Kenneth H.

    AU - Bishop, David F.

    AU - Desnick, Robert J.

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    N2 - Background: Acute intermittent porphyria (AIP), due to half-normal hydroxymethylbilane synthase activity, is characterized by acute life-threatening neurologic attacks whose etiology remains unclear. To date, only 3 patients confirmed to have homozygous dominant AIP (HD-AIP) have been described (hydroxymethylbilane synthase genotypes R167Q/R167Q and R167W/R173Q). Objective: To investigate the genetic, biochemical, clinical, and neuroradiologic features of a severely affected infant with HD-AIP. Design: Clinical, imaging, and genotype/phenotype studies were performed. Results: The proband, homoallelic for hydroxymethylbilane synthase mutation R167W, had approximately 1% of normal hydroxymethylbilane synthase activity, elevated porphyrins and porphyrin precursors, severe psychomotor delay, and central and peripheral neurologic manifestations. When expressed in vitro, the R167W mutant enzyme had less than 2% of normal activity but was markedly unstable, consistent with the proband's severe phenotype. Mitochondrial respiratory chain enzymes were normal. Neuroradiologic studies revealed a unique pattern of deep cerebral white matter injury, with relative preservation of the corpus callosum, anterior limb of the internal capsule, cerebral gray matter, and infratentorial structures. Conclusions: This severely affected patient with HD-AIP expanded the phenotypic spectrum of HD-AIP. His brain magnetic resonance imaging studies suggested selective cerebral oligodendrocyte postnatal involvement in HD-AIP, whereas most structures developed prenatally were intact. These findings indicate that the neurologic manifestations result from porphyrin precursor toxicity rather than heme deficiency and suggest that porphyrin precursor toxicity is primarily responsible for the acute neurologic attacks in heterozygous AIP and other porphyrias.

    AB - Background: Acute intermittent porphyria (AIP), due to half-normal hydroxymethylbilane synthase activity, is characterized by acute life-threatening neurologic attacks whose etiology remains unclear. To date, only 3 patients confirmed to have homozygous dominant AIP (HD-AIP) have been described (hydroxymethylbilane synthase genotypes R167Q/R167Q and R167W/R173Q). Objective: To investigate the genetic, biochemical, clinical, and neuroradiologic features of a severely affected infant with HD-AIP. Design: Clinical, imaging, and genotype/phenotype studies were performed. Results: The proband, homoallelic for hydroxymethylbilane synthase mutation R167W, had approximately 1% of normal hydroxymethylbilane synthase activity, elevated porphyrins and porphyrin precursors, severe psychomotor delay, and central and peripheral neurologic manifestations. When expressed in vitro, the R167W mutant enzyme had less than 2% of normal activity but was markedly unstable, consistent with the proband's severe phenotype. Mitochondrial respiratory chain enzymes were normal. Neuroradiologic studies revealed a unique pattern of deep cerebral white matter injury, with relative preservation of the corpus callosum, anterior limb of the internal capsule, cerebral gray matter, and infratentorial structures. Conclusions: This severely affected patient with HD-AIP expanded the phenotypic spectrum of HD-AIP. His brain magnetic resonance imaging studies suggested selective cerebral oligodendrocyte postnatal involvement in HD-AIP, whereas most structures developed prenatally were intact. These findings indicate that the neurologic manifestations result from porphyrin precursor toxicity rather than heme deficiency and suggest that porphyrin precursor toxicity is primarily responsible for the acute neurologic attacks in heterozygous AIP and other porphyrias.

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