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November 2004

Acute Intermittent Porphyria: Studies of the Severe Homozygous Dominant Disease Provides Insights Into the Neurologic Attacks in Acute Porphyrias

Author Affiliations

Author Affiliations: Services of Biochemistry (Dr Solis) and Neuropediatrics (Dr Martinez-Bermejo), University Hospital La Paz, Madrid, Spain; Departments of Radiology (Dr Naidich) and Human Genetics (Drs Solis, Astrin, Bishop, and Desnick), Mount Sinai School of Medicine of New York University, New York, NY; and Departments of Pathology and Neurology, Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, Md (Dr Kaufmann).

Arch Neurol. 2004;61(11):1764-1770. doi:10.1001/archneur.61.11.1764

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.