Cystathionine β-synthase deficiency in the E-HOD registry-part I: pyridoxine responsiveness as a determinant of biochemical and clinical phenotype at diagnosis

Viktor Kožich*, Jitka Sokolová, Andrew A.M. Morris, Markéta Pavlíková, Florian Gleich, Stefan Kölker, Jakub Krijt, Carlo Dionisi-Vici, Matthias R. Baumgartner, Henk J. Blom, Martina Huemer*, Luis Aldámiz-Echevarría, Rodrigo Rezende Arantes, Francisco Arrieta, Javier Blasco-Alonso, Martijn Brouwers, Michaela Brunner-Krainz, María Bueno, Rosa Burgos Peláez, Aline CanoMaría Luz Couce, Ellen Crushell, Can Ficicioglu, Patrick Forny, María Concepción García Jiménez, Ana Gaspar, Domingo González-Lamuño Leguina, Kimberly A. Chapman, Yin Hsiu Chien, Mirian C.H. Janssen, Pavel Ješina, Robin Lachmann, Christian Lavigne, Allan M. Lund, Natalia Lüsebrink, Francois Maillot, Ana Maria Martins, Silvia Meavilla Olivas, Karine Mention, Fanny Mochel, Ahmad Monavari, Sónia Moreira, Carolina Araujo Moreno, Diana Muacevic-Katanec, Helen Mundy, Elaine Murphy, Giorgia Olivieri, Stéphanie Paquay, Consuelo Pedrón-Giner, Luís Peña Quintana, E-HOD consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Cystathionine ß-synthase (CBS) deficiency has a wide clinical spectrum, ranging from neurodevelopmental problems, lens dislocation and marfanoid features in early childhood to adult onset disease with predominantly thromboembolic complications. We have analysed clinical and laboratory data at the time of diagnosis in 328 patients with CBS deficiency from the E-HOD (European network and registry for Homocystinurias and methylation Defects) registry. We developed comprehensive criteria to classify patients into four groups of pyridoxine responsivity: non-responders (NR), partial, full and extreme responders (PR, FR and ER, respectively). All groups showed overlapping concentrations of plasma total homocysteine while pyridoxine responsiveness inversely correlated with plasma/serum methionine concentrations. The FR and ER groups had a later age of onset and diagnosis and a longer diagnostic delay than NR and PR patients. Lens dislocation was common in all groups except ER but the age of dislocation increased with increasing responsiveness. Developmental delay was commonest in the NR group while no ER patient had cognitive impairment. Thromboembolism was the commonest presenting feature in ER patients, whereas it was least likely at presentation in the NR group. This probably is due to the differences in ages at presentation: all groups had a similar number of thromboembolic events per 1000 patient-years. Clinical severity of CBS deficiency depends on the degree of pyridoxine responsiveness. Therefore, a standardised pyridoxine-responsiveness test in newly diagnosed patients and a critical review of previous assessments is indispensable to ensure adequate therapy and to prevent or reduce long-term complications.
Original languageEnglish
Pages (from-to)677-692
Number of pages16
JournalJournal of Inherited Metabolic Disease
Volume44
Issue number3
DOIs
Publication statusPublished - 1 May 2021

Keywords

  • developmental delay
  • homocystinuria
  • methionine
  • natural history
  • patient registry
  • thromboembolism

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