Givosiran is a novel approach to treat patients with acute intermittent porphyrias (AIP) by silencing of ∂-ALA-synthase 1, the first enzyme of heme biosynthesis in the liver. 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–MS/MS unexpectedly, plasma Hcy levels were 100 and 200 in patient A and between 100 and 400 μmol/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 ∂-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.

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N.O-Chelate complexes of R,S-2-(3-thienyl)glycinate (L) have been obtained: ML2 (M = Ni, Cu), (n-Bu3P)(Cl)M(L) (M = Pd. Pt), (η3-C3H5)Pd(L), C6H4CH,CHNMe2Pd(L), (η6-p-cymene)(Cl)Ru(L), (η5-C5Me5)(Cl)M(L) (M = Rh, Ir) and (η5-C5H5)(OC)2Mo(L). The methyl ester of R,S-2-(3-thienvl)glycine (L') forms the complexes trans-CT2PdL′2, cis- Cl2Pt(L')2, (η-Bu3P)(Cl2)M(L') (M = Pd, Pt) and (η5-C5Me5)(Cl)2M(L') (M = Rh, Ir) in which the ligand L' is coordinated through the amino group. The structures of (η3-C3H5)Pd(L) and of (η5-C5Me5)(Cl2)Ir(L') have been determined by X-ray diffraction. N- Benzoyl-2-(3-thienylglycine methyl ester reacts with Cr(CO)6 to yield a tricarbonyl complex with an η6-coordinated phenyl group. N-Benzoyl-R,S-2-(3-thienyl)glycinate (L") and (η5- C5H5)2TiCl2 give the diastereoisomers [(η5-C5H5)2Ti(R-L")(R-L")2/(η5-C5H5)2Ti(S-L") (S-L")] and (η5-C5H5)2Ti(R-L")(S-L") with Ti-O-bonds.

Biallelic variants in the ACADM gene cause medium-chain acyl-CoA dehydrogenase deficiency (MCADD). This study reports on differences in the occurrence of secondary free carnitine (C0) deficiency and different biochemical phenotypes related to genotype and age in 109 MCADD patients followed-up at a single tertiary care center during 22 years. C0 deficiency occurred earlier and more frequently in c.985A>G homozygotes (genotype A) compared to c.985A>G compound heterozygotes (genotype B) and individuals carrying variants other than c.985A>G and c.199C>T (genotype D) (median age 4.2 vs. 6.6 years; p < 0.001). No patient carrying c.199C>T (genotype C) developed C0 deficiency. A daily dosage of 20-40 mg/kg carnitine was sufficient to maintain normal C0 concentrations. Compared to genotype A as reference group, octanoylcarnitine (C8) was significantly lower in genotypes B and C, whereas C0 was significantly higher by 8.28 μmol/L in genotype C (p < 0.05). In conclusion, C0 deficiency is mainly found in patients with pathogenic genotypes associated with high concentrations of presumably toxic acylcarnitines, while individuals carrying the variant c.199C>T are spared and show consistently mild biochemical phenotypes into adulthood. Low-dose carnitine supplementation maintains normal C0 concentrations. However, future studies need to evaluate clinical benefits on acute and chronic manifestations of MCADD.