ECEESPE2025 Poster Presentations Adrenal and Cardiovascular Endocrinology (169 abstracts)
Adrenal insufficiency associated with mutations in haem biosynthesis genes
Ahmed Al-Salihi 1 , Chris Smith 1 , Cristina Pérez-Ternero 1 , Adam Jackson 2 , Andreas Janecke 3 , Elisabeth Steichen 3 , Denise Darby 2 , Liezel Griffin 4 , Siddharth Banka 2 , Solaf Elsayed 5 , Neila Talbi 6 , Laurent Gouya 6 , Brigitte Delemer 7 , David Taylor 8 , Li Chan 1 & Louise Metherell 1
1Queen Mary, University of London, London, UK; 2University of Manchester, Manchester, UK; 3University Hospital of Innsbruck, Innsbruck, Austria; 4Salford Royal Hospital, Dermatology Centre, Manchester, UK; 5Ain Shams University, Medical Genetics Department, Cairo, Egypt; 6The National Institute of Health and Medical Research (INSERM), Paris, France; 7Centre Hospitalier Universitaire De Reims, Reims, France; 8King’s College Hospital NHS Foundation Trust, London, UK
JOINT3229
Mutations in the 8 haem biosynthetic pathway genes are traditionally known to cause a group of diseases known as porphyria. While Primary Adrenal Insufficiency (PAI), an intrinsic adrenal defect in glucocorticoid synthesis ± mineralocorticoid synthesis, is linked to mutations in more than 25 genes. Over the last few decades, there have been tantalising case reports linking porphyria with defects in steroidogenesis. We identified seven families (11 individuals) with defects in haem biosynthetic enzymes who exhibit flagrant adrenal insufficiency (AI), with or without porphyria. 1) a kindred (n=4) from Egypt with biallelic mutations in protoporphyrinogen oxidase (PPOX) p.(Glu339Lys), who have variegate porphyria along with severe AI. 2) Three kindreds with mutations in coproporphyrinogen oxidase (CPOX), with variable presentations (i) a female with p.(Pro367Ala) mutation, (ii) siblings of Kurdish descent homozygous for p.(Ser28*) mutation, one of which had no clinical manifestations of HCP but has severe AI, and (iii) a patient with HCP from France who presented with AI aged 64. 3) Three adult patients with mutations in Hydroxymethylbilane Synthase (HMBS) who presented with AI during acute hepatic porphyria attacks. We hypothesized that reduced enzyme activity may cause AI through reduction in the level or activity of steroidogenic CYP450 enzymes due to the lack of haem, toxicity of accumulated intermediate porphyrins, and/or the increased oxidative stress these may cause. We investigated the underlying mechanism, employing knockdown and knockout PPOX and CPOX human adrenal cell lines (H295R) plus an animal model of PPOX deficiency to measure steroid perturbations, enzyme activity and levels of oxidative stress. PPOX knockdown significantly reduces cortisol output in our cell model, whereas CPOX knockdown does not, likely due to differences in residual enzymatic activity. CRISPR knockout of these genes was unsuccessful, consistent with the lethal nature of homozygous null mutations in humans and other mammals, highlighting their essential role in survival. In heterozygous PPOX mice, mimicking an acute porphyria attack by administering 5-aminolevulinic acid (ALA) blunted the Synacthen response in both WT and mutant animals.
Conclusion: Although we have not fully delineated the mechanism, our finding of a link between mutations in haem biosynthesis genes and PAI indicates that testing adrenal function in porphyria patients and their families might be warranted. Furthermore, haem biosynthesis genes should be considered for inclusion in genetic testing panels for isolated adrenal insufficiency.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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