Preventing hyperhomocysteinemia using vitamin B6 supplementation in Givosiran-treated acute intermittent porphyria: Highlights from a case report and brief literature review

• Published in: Molecular genetics and metabolism reports Vol. 39; p. 101076
• Main Authors: Redonnet-Vernhet, Isabelle, Mercié, Patrick, Lebreton, Louis, Blouin, Jean-Marc, Bronnimann, Didier, Mesli, Samir, Guibet, Claire, Ribeiro, Emmanuel, Gensous, Noémie, Duffau, Pierre, Gouya, Laurent, Richard, Emmanuel
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.06.2024; Elsevier
• Subjects: Acute hepatic porphyria; Acute intermittent porphyria; Case Report; CBS deficiency; Givosiran; Hyperhomocysteinemia; Vitamin B6; ALAS1; HHcyt; AHP; CBS deficiency; Givosiran; Hcyt; PBG; CBS; Acute intermittent porphyria; ALA; Hyperhomocysteinemia; Acute hepatic porphyria; Vitamin B6; CHD
• ISSN: 2214-4269; 2214-4269
• DOI: 10.1016/j.ymgmr.2024.101076

Acute hepatic porphyrias are inherited metabolic disorders of heme biosynthesis characterized by the accumulation of toxic intermediate metabolites responsible for disabling acute neurovisceral attacks. Givosiran is a newly approved siRNA-based treatment of acute hepatic porphyria targeting the first and rate-limiting δ-aminolevulinic acid synthase 1 (ALAS1) enzyme of heme biosynthetic pathway. We described a 72-year old patient who presented with severe inaugural neurological form of acute intermittent porphyria evolving for several years which made her eligible for givosiran administration. On initiation of treatment, the patient developed a major hyperhomocysteinemia (>400 μmol/L) which necessitated to discontinue the siRNA-based therapy. A thorough metabolic analysis in the patient suggests that hyperhomocysteinemia could be attributed to a functional deficiency of cystathionine β-synthase (CBS) enzyme induced by givosiran. Long-term treatment with vitamin B6, a cofactor of CBS, allowed to normalize homocysteinemia while givosiran treatment was maintained. We review the recently published cases of hyperhomocysteinemia in acute hepatic porphyria and its exacerbation under givosiran therapy. We also discuss the benefits of vitamin B6 supplementation in the light of hypothetic pathophysiological mechanisms responsible for hyperhomocysteinemia in these patients. Our results confirmed the importance of monitoring homocysteine metabolism and vitamin status in patients with acute intermittent porphyria in order to improve management by appropriate vitamin supplementation during givosiran treatment. •Givosiran is a newly approved siRNA-based therapy for severe acute hepatic porphyria•Hyperhomocysteinemia is frequently observed in acute hepatic porphyria and increased after givosiran administration•Givosiran alters homocysteine metabolism, probably by inducing a functional deficit of CBS enzyme.•Supplementation with vitamin B6, a cofactor of CBS, allows to normalize homocysteine levels while maintaining treatment with givosiran. Supplementation with vitamin B6 allows to normalize homocysteine levels while maintaining treatment with givosiran.