title: Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX gene.
abstract: BACKGROUND
  Clinically indistinguishable attacks of acute porphyria occur in acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). There are few evidence-based diagnostic strategies for these disorders.
  
  
  METHODS
  The diagnostic sensitivity of mutation detection was determined by sequencing and gene-dosage analysis to search for mutations in 467 sequentially referred, unrelated patients. The diagnostic accuracy of plasma fluorescence scanning, fecal porphyrin analysis, and porphobilinogen deaminase (PBGD) assay was assessed in mutation-positive patients (AIP, 260 patients; VP, 152 patients; HCP, 31 patients).
  
  
  RESULTS
  Sensitivities (95% CI) for mutation detection were as follows: AIP, 98.1% (95.6%-99.2%); HCP, 96.9% (84.3%-99.5%); VP, 100% (95.7%-100%). We identified 5 large deletions in the HMBS gene (hydroxymethylbilane synthase) and one in the CPOX gene (coproporphyrinogen oxidase). The plasma fluorescence scan was positive more often in VP (99% of patients) than in AIP (68%) or HCP (29%). The wavelength of the fluorescence emission peak and the fecal coproporphyrin isomer ratio had high diagnostic specificity and sensitivity for differentiating between AIP, HCP, and VP. DNA analysis followed by PBGD assay in mutation-negative patients had greater diagnostic accuracy for AIP than either test alone.
  
  
  CONCLUSIONS
  When PBG excretion is increased, 2 investigations (plasma fluorescence scanning, the coproporphyrin isomer ratio) are sufficient, with rare exceptions, to identify the type of acute porphyria. When the results of PBG, 5-aminolevulinate, and porphyrin analyses are within reference intervals and clinical suspicion that a past illness was caused by an acute porphyria remains high, mutation analysis of the HMBS gene followed by PBGD assay is an effective strategy for diagnosis or exclusion of AIP.
authors.affiliation: Department of Medical Biochemistry and Immunology, University Hospital of Wales and School of Medicine, Cardiff University, Cardiff, UK. whatley@cardiff.ac.uk
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Whatley
authors.forename: Nicola G
authors.initials: NG
authors.lastname: Mason
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Woolf
authors.forename: Robert G
authors.initials: RG
authors.lastname: Newcombe
authors.forename: George H
authors.initials: GH
authors.lastname: Elder
authors.forename: Michael N
authors.initials: MN
authors.lastname: Badminton
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002648:Child; D003304:Coproporphyrinogen Oxidase / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers; D003937:Diagnosis, Differential; D005799:Genes, Dominant; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D011164:Porphyrias / Q000175:diagnosis* / Q000235:genetics; D050768:Protoporphyrinogen Oxidase / Q000235:genetics*; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D017931:DNA Primers; D003304:Coproporphyrinogen Oxidase; D050768:Protoporphyrinogen Oxidase; D011163:Hydroxymethylbilane Synthase