Clinical Chemistry
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Clinical Chemistry 55: 1406-1414, 2009. First published May 21, 2009; 10.1373/clinchem.2008.122564
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(Clinical Chemistry. 2009;55:1406-1414.)
© 2009 American Association for Clinical Chemistry, Inc.

Evidence-Based Medicine and Test Utilization

Diagnostic Strategies for Autosomal Dominant Acute Porphyrias: Retrospective Analysis of 467 Unrelated Patients Referred for Mutational Analysis of the HMBS, CPOX, or PPOX Gene

Sharon D. Whatley1,a, Nicola G. Mason1, Jacqueline R. Woolf1, Robert G. Newcombe2, George H. Elder1 and Michael N. Badminton1

1 Department of Medical Biochemistry and Immunology, University Hospital of Wales and School of Medicine, Cardiff University, Cardiff, UK; 2 Department of Primary Care and Public Health Centre for Health Sciences Research, Cardiff University, Cardiff, UK.

aAddress correspondence to this author at: Department of Medical Biochemistry and Immunology, University Hospital of Wales and School of Medicine, Cardiff University, Cardiff, UK. Fax 4429208383; e-mail whatley{at}cardiff.ac.uk.

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. .






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