Background: Acute intermittent porphyria (AIP), due to halfnormal hydroxymethy lbilane synthase activity, is characterized by acute life threatening neurologi c attacks whose etiology remains unclear. To date, only 3 patients fconirmed 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 infa nt with HD AIP. Design: Clinical, imaging, and genotype/phenotype studies were performed. Results: The proband, homoallelic for hydroxymethylbilane synthase mu tation R167W, had approximately 1%of normal hydroxymethylbilane synthase activi ty, elevated porphyrins and porphyrin precursors, severe psychomotor delay, and central and peripheral neurologic manifestations. When expressed in vitro, the R 167W mutant enzyme had less than 2%of normal activity but was markedly unstable , consistent with the probands severe phenotype. Mitochondrial respiratory cha in enzymes were normal. Neuroradiologic studies revealed a unique pattern of dee p cerebral white matter injury, with relative preservation of the corpus callosu m, anterior limb of the internal capsule, cerebral gray matter, and infratentori al structures. Conclusions: This severely affected patient with HD AIP expanded the phenotypic spectrum of HD AIP. His brain magnetic resonance imaging studie s suggested selective cerebral oligodendrocyte postnatal involvement in HD AIP, whereas most structures developed prenatally were intact. These findings indica te that the neurologic manifestations result from porphyrin precursor toxicity r ather than heme deficiency and suggest that porphyrin precursor toxicity is prim arily responsible for the acute neurologic attacks in heterozygous AIP and other porphyrias.
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