TY - JOUR
T1 - Cystathionine β-synthase deficiency in the E-HOD registry-part I
T2 - pyridoxine responsiveness as a determinant of biochemical and clinical phenotype at diagnosis
AU - Kožich, Viktor
AU - Sokolová, Jitka
AU - Morris, Andrew A.M.
AU - Pavlíková, Markéta
AU - Gleich, Florian
AU - Kölker, Stefan
AU - Krijt, Jakub
AU - Dionisi-Vici, Carlo
AU - Baumgartner, Matthias R.
AU - Blom, Henk J.
AU - Huemer, Martina
AU - Aldámiz-Echevarría, Luis
AU - Arantes, Rodrigo Rezende
AU - Arrieta, Francisco
AU - Blasco-Alonso, Javier
AU - Brouwers, Martijn
AU - Brunner-Krainz, Michaela
AU - Bueno, María
AU - Peláez, Rosa Burgos
AU - Cano, Aline
AU - Couce, María Luz
AU - Crushell, Ellen
AU - Ficicioglu, Can
AU - Forny, Patrick
AU - García Jiménez, María Concepción
AU - Gaspar, Ana
AU - González-Lamuño Leguina, Domingo
AU - Chapman, Kimberly A.
AU - Chien, Yin Hsiu
AU - Janssen, Mirian C.H.
AU - Ješina, Pavel
AU - Lachmann, Robin
AU - Lavigne, Christian
AU - Lund, Allan M.
AU - Lüsebrink, Natalia
AU - Maillot, Francois
AU - Martins, Ana Maria
AU - Olivas, Silvia Meavilla
AU - Mention, Karine
AU - Mochel, Fanny
AU - Monavari, Ahmad
AU - Moreira, Sónia
AU - Moreno, Carolina Araujo
AU - Muacevic-Katanec, Diana
AU - Mundy, Helen
AU - Murphy, Elaine
AU - Olivieri, Giorgia
AU - Paquay, Stéphanie
AU - Pedrón-Giner, Consuelo
AU - Quintana, Luís Peña
AU - E-HOD consortium
N1 - Funding Information:
The European network and registry for homocystinurias and methylation defects (EHOD) project has been established with funding from the European Union in the framework of the Health Program (No. 2012_12_02). From the end of the EU-project phase, the E-HOD project has received ongoing support from SOBI, Recordati Rare Disease Foundation, Vitaflo, and Nutricia Metabolics Germany.
Funding Information:
This work was supported by the grant NV19-01-00307 (Agentura Pro Zdravotnick? V?zkum Cesk? Republiky), and institutional programs RVO-VFN 64165 (General University Hospital in Prague) and Progres Q26 (Charles University). The authors would like to thank patients, data managers and nutritionists for providing data for the registry. Several authors of this publication are members of the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN)?Project ID No 739543. The European network and registry for homocystinurias and methylation defects (EHOD) project has been established with funding from the European Union in the framework of the Health Program (No. 2012_12_02). From the end of the EU-project phase, the E-HOD project has received ongoing support from SOBI, Recordati Rare Disease Foundation, Vitaflo, and Nutricia Metabolics Germany.
Funding Information:
Viktor Kožich, Jitka Sokolová and Jakub Krijt declare that Charles University-First Faculty of Medicine received a partial reimbursement for preclinical testing of OT-58 from Orphan Technologies. Andrew A.M. Morris received honoraria for lectures from Recordati & Nutricia and Advisory Board fees from Nutricia; he is an Expert Witness for a relevant medicolegal case. Stefan Kölker received funding from Recordati Rare Diseases for postmarketing authorization studies on Cystadane (betaine anhydrous). Martina Huemer has received honoraria for a lecture from Aeglea and research grant from Nutricia Metabolics. Carlo Dionisi-Vici received a research fund and reimbursement for attending a symposium from Medifood, honoraria from Recordati-Orphan Europe and Nutricia, and consulting fee from Nutricia. Markéta Pavlíková, Florian Gleich, Henk Blom and Matthias M.R. Baumgartner declare that they have no conflict of interest.
Funding Information:
This work was supported by the grant NV19-01-00307 (Agentura Pro Zdravotnický Výzkum Ceské Republiky), and institutional programs RVO-VFN 64165 (General University Hospital in Prague) and Progres Q26 (Charles University). The authors would like to thank patients, data managers and nutritionists for providing data for the registry.
Publisher Copyright:
© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM
PY - 2021/5/1
Y1 - 2021/5/1
N2 - 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.
AB - 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.
KW - developmental delay
KW - homocystinuria
KW - methionine
KW - natural history
KW - patient registry
KW - thromboembolism
U2 - 10.1002/jimd.12338
DO - 10.1002/jimd.12338
M3 - Article
SN - 0141-8955
VL - 44
SP - 677
EP - 692
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 3
ER -