A Pilot Study of Biomarkers Predicting Clinical Expression of Acute Porphyrias

Principal Investigator: Karl E Anderson, MD

Co-investigators: Sahil Mittal, Csilla Halberg, GA Shakeel Ansari, Heidi Spratt

The 3 acute porphyrias are autosomal dominant genetic disorders that present with identical attacks of neurological symptoms. Penetrance is low, and only 10-20% of heterozygotes develop symptoms, usually consisting of intermittent neurovisceral attacks that may be life threatening. Although some exacerbating factors are known and can be avoided to prevent attacks, the marked variation in disease penetrance remains poorly understood.

The recently developed Porphyrias Consortium (PC) provides an opportunity to study samples collected from patients with various degrees of disease expression from 6 centers, and to look for biomarkers of disease severity using ITS Key Resources at UTMB. We will use the methodology available in ITS resources, including the Core Laboratory, Translational Technologies and Biomedical Informatics.

Plasma and urine samples from at least 60 patients with well-documented acute porphyrias from the Longitudinal Study (LS) of the PC will be studied. Patients will be staged according to their history of disease manifestations into 2 groups of 30 each. Group 1 will comprise patients with history of 1-3 attacks but none for at least one year and Group 2 will be patients with repeated attacks that are ongoing or severe disease resistant to standard interventions including hemin.

Approaches to identifying biomarkers will include comparisons of the following between the 2 groups. 1) Patterns of comprehensive clinical test results collected as part of the LS. 2) Panels of proteins and inflammatory markers measured by the Millipore bioplex bead-based ELISA assay, including human metabolic and inflammatory panels in the ITS Core Laboratory. 3) Metabolomic/metabonomic analyses using methods available in the Translational Technologies Key Resource, such as nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry, and the application of statistical and multivariate methods for information extraction and data interpretation.

Analytic identification will include steroid metabolites and lipid profiles, some of which were previously noted to be associated with more active porphyria. 4) An exploration of differences in profiles of >27 free amino acids measured at physiological concentrations. This pilot study will address the variability in clinical expression (i.e. variable penetrance) of 3 human porphyrias that can present with the life-threatening neurological symptoms, and will likely lead to new methods of treatment and prevention and to generate new hypotheses regarding the pathogenesis of tissue damage in these inherited diseases.