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Dysregulation of homocysteine homeostasis in acute intermittent porphyria patients receiving heme arginate or givosiran.
To-Figueras, Jordi; Wijngaard, Robin; García-Villoria, Judit; Aarsand, Aasne K; Aguilera, Paula; Deulofeu, Ramon; Brunet, Mercè; Gómez-Gómez, Àlex; Pozo, Oscar J; Sandberg, Sverre.
Afiliação
  • To-Figueras J; Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
  • Wijngaard R; Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
  • García-Villoria J; Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
  • Aarsand AK; Norwegian Porphyria Centre (NAPOS), Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway.
  • Aguilera P; Norwegian Organization for Quality Improvement of Laboratory Examinations, Haraldsplass Deaconess Hospital, Bergen, Norway.
  • Deulofeu R; Dermatology Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
  • Brunet M; Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
  • Gómez-Gómez À; Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
  • Pozo OJ; Integrative Pharmacology and Systems Neuroscience Group, Institut Municipal Investigació Mèdica (IMIM), Hospital del Mar, Barcelona, Spain.
  • Sandberg S; Integrative Pharmacology and Systems Neuroscience Group, Institut Municipal Investigació Mèdica (IMIM), Hospital del Mar, Barcelona, Spain.
J Inherit Metab Dis ; 44(4): 961-971, 2021 07.
Article em En | MEDLINE | ID: mdl-33861472
Acute intermittent porphyria (AIP) is a rare metabolic disease caused by mutations within the hydroxymethylbilane synthase gene. Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients. In this study, we present long-term data for tHcy and related parameters for an AIP patient cohort (n = 37) in different clinical disease-states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy > 15 µmol/L) during the observation period. HHcy was more frequent in AIP patients with recurrent disease receiving heme arginate, than in nonrecurrent (median tHcy: 21.6 µmol/L; range: 10-129 vs median tHcy: 14.5 µmol/L; range 6-77). Long-term serial analyses showed a high within-person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%-78.8%). HHcy was frequently associated with low blood concentrations of pyridoxal-5'-phosphate and folate, while cobalamin concentration and the allele distribution of the methylene-tetrahydrofolate-reductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small-interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105 µmol/L; range 16-212). Screening of amino acids in plasma by liquid-chromatography showed co-increased levels of methionine (median 71 µmol/L; range 23-616; normal <40), suggestive of acquired deficiency of cystathionine-ß-synthase. The kynunerine/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme-dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a co-increase of tHcy and methionine resembling classic homocystinuria.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Arginina / Pirrolidinas / Acetilgalactosamina / Porfiria Aguda Intermitente / Hiper-Homocisteinemia / Heme Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Arginina / Pirrolidinas / Acetilgalactosamina / Porfiria Aguda Intermitente / Hiper-Homocisteinemia / Heme Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2021 Tipo de documento: Article