title: Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias.
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.
  
  
  METHODS
  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.
authors.affiliation: Services of Biochemistry and Neuropediatrics, University Hospital La Paz, Madrid, Spain.
authors.forename: Constanza
authors.initials: C
authors.lastname: Solis
authors.forename: Antonio
authors.initials: A
authors.lastname: Martinez-Bermejo
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Naidich
authors.forename: Walter E
authors.initials: WE
authors.lastname: Kaufmann
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Astrin
authors.forename: David F
authors.initials: DF
authors.lastname: Bishop
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000208:Acute Disease; D001921:Brain / Q000473:pathology*; D005838:Genotype; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics* / Q000494:pharmacology; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009836:Oligodendroglia / Q000473:pathology; D010375:Pedigree; D010507:Periodicity; D010641:Phenotype; D011164:Porphyrias / Q000235:genetics* / Q000503:physiopathology*; D011166:Porphyrins / Q000009:adverse effects / Q000378:metabolism
chemical_list: D011166:Porphyrins; D011163:Hydroxymethylbilane Synthase