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We included two patients in the Envision study who responded clinically well to this treatment. However, in both patients, therapy had to be discontinued because of severe adverse effects: One patient (A) developed local injection reactions which continued to spread all over her body with increasing number of injections and eventually caused a severe systemic allergic reaction. Patient B was hospitalized because of a fulminant pancreatitis. Searching for possible causes, we also measured the patients plasma homocysteine (Hcy) levels in fluoride-containing collection tubes: by LC\u2013MS\/MS unexpectedly, plasma Hcy levels were 100 and 200 in patient A and between 100 and 400\u00a0\u03bcmol\/l in patient B. Searching for germline mutations in 10 genes that are relevant for homocysteine metabolism only revealed hetero- and homozygous polymorphisms in the MTHFR gene. Alternatively, an acquired inhibition of cystathionine-beta-synthase which is important for homocysteine metabolism could explain the plasma homocysteine increase. This enzyme is heme-dependent: when we gave heme arginate to our patients, Hcy levels rapidly dropped. Hence, we conclude that inhibition of \u2202-ALA-synthase 1 by givosiran causes a drop of free heme in the hepatocyte and therefore the excessive increase of plasma homocysteine. Hyperhomocysteinemia may contribute to the adverse effects seen in givosiran-treated patients which may be due to protein-N-homocysteinylation.<\/jats:p>","DOI":"10.1007\/s00277-021-04547-3","type":"journal-article","created":{"date-parts":[[2021,5,29]],"date-time":"2021-05-29T01:02:24Z","timestamp":1622250144000},"page":"1685-1693","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Severe homocysteinemia in two givosiran-treated porphyria patients: is free heme deficiency the culprit?"],"prefix":"10.1007","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1554-8266","authenticated-orcid":false,"given":"Petro E.","family":"Petrides","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elfriede","family":"Schuhmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Torkler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Molitor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Loehr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Obermeier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria K.","family":"Beykirch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,29]]},"reference":[{"key":"4547_CR1","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.ymgme.2019.04.008","volume":"128","author":"J Phillips","year":"2019","unstructured":"Phillips J (2019) Heme biosynthesis and the porphyrias. 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