Adrenal insufficiency can be associated with biallelic mutations in porphyria genes

Chris Smith; Ahmed Al-Salihi; Andreas Janecke; Elisabeth Steichen; Siddharth Banka; Adam Jackson; Denise Darby; Liezel Griffin; Sarah Stewart; Solaf Elsayed; Neila Talbi; Laurent Gouya; Li Chan; Louise Metherell

doi:10.1530/endoabs.94.OP5.3

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Endocrine Abstracts (2023) 94 OP5.3 | DOI: 10.1530/endoabs.94.OP5.3

SFEBES2023 Oral Poster Presentations Adrenal and Cardiovascular (4 abstracts)

Adrenal insufficiency can be associated with biallelic mutations in porphyria genes

Chris Smith ¹ , Ahmed Al-Salihi ¹ , Andreas Janecke ² , Elisabeth Steichen ² , Siddharth Banka ³ , Adam Jackson ³ , Denise Darby ⁴ , Liezel Griffin ⁴ , Sarah Stewart ³ , Solaf Elsayed ⁵ , Neila Talbi ⁶ , Laurent Gouya ⁶ , Li Chan ¹ & Louise Metherell ¹

Err

Author affiliations

¹Queen Mary University of London, London, United Kingdom. ²Medical University of Innsbruck, Innsbruck, Austria. ³University of Manchester, Manchester, United Kingdom. ⁴Salford Royal Hospital, Manchester, United Kingdom. ⁵Ain Shams University, Cairo, Egypt. ⁶National Institute of Health and Medical Research, Paris, France

Adrenal insufficiency (AI) is life-threatening and can present alone or in combination with other co-morbidities. Acute porphyria attacks can also be serious, resulting in permanent disability or death and symptoms can be similar to AI. Previous literature describing hormonal perturbations in porphyria suggest an association between the two conditions. We were referred a family with 4 individuals with porphyria and AI, the clinical picture included global developmental delay, convulsions, nystagmus, darkening of the skin, high ACTH and low cortisol. Whole exome sequencing, array Comparative Genomic Hybridization and whole genome sequencing ruled out variants in known AI-causing genes, leaving a homozygous mutation, p.Glu339Lys, in PPOX as a possible cause for both conditions. To investigate the mechanism, we created PPOX-knockdown (KD), human adrenocortical cells (H295R). Proliferation was lower in PPOX-KD cells at 72 hours and mitochondrial respiration was diminished, possibly due to toxicity of porphyrin precursors. GSH/GSSG ratio, a marker of oxidative stress, was lower in KD cells suggesting increased ROS in these cells. CYP11A1 expression was unaltered whereas STAR and CYP17A1 were significantly lower in PPOX-KD cells. Finally, and definitively, knockdown of >60% reduced cortisol output by 2.2-fold (P<0.01) at baseline and 1.9-fold (P<0.0001) in forskolin stimulated cells. A further 6 families with AI and mutations in CPOX (n =3) and HMBS (n =3), genes causing porphyrias, have been identified. Unexpectedly, the heterozygous parents are asymptomatic, manifesting neither porphyria nor AI, suggesting that the level of enzyme function is key for both phenotypes. Reduced PPOX activity may cause AI through a reduction in the level or activity of steroidogenic CYP450 enzymes, toxicity of intermediate porphyrins and/or the increased oxidative stress these may cause. The above cases demonstrate an association between AI and biallelic mutations in porphyria genes, we therefore suggest that adrenal function should be monitored in all individuals with porphyria.