. 2022 Jul;45(4):848-861.

doi: 10.1002/jimd.12504. Epub 2022 May 9.

Influence of early identification and therapy on long-term outcomes in early-onset MTHFR deficiency

Mathilde Yverneau¹, Stéphanie Leroux¹, Apolline Imbard^{2

3

4}, Florian Gleich⁵, Alina Arion⁶, Caroline Moreau⁷, Marie-Cécile Nassogne⁸, Marie Szymanowski⁹, Marine Tardieu¹⁰, Guy Touati¹¹, María Bueno¹², Kimberly A Chapman¹³, Yin-Hsiu Chien¹⁴, Martina Huemer^{15

16}, Pavel Ješina¹⁷, Mirian C H Janssen¹⁸, Stefan Kölker⁵, Viktor Kožich¹⁷, Christian Lavigne¹⁹, Allan Meldgaard Lund²⁰, Fanny Mochel²¹, Andrew Morris^{22

23}, Mónica Ruiz Pons²⁴, Gloria Liliana Porras-Hurtado²⁵, Jean-François Benoist^{2

3

4}, Léna Damaj²⁶, Manuel Schiff^{3

27}; E-HOD Consortium

Collaborators, Affiliations

Collaborators

E-HOD Consortium:
Ana Maria Martins, Javier Blasco Alonso, Brigitte Chabrol, Ellen Crushell, Carlo Dionisi-Vici, Stephanie Grünewald, Karine Mention, Helen Mundy, Elaine Murphy, Pilar Quijada Fraile, Carlos José Ruiz, Maria Ángeles Ruiz Gómez, Saikat Santra, Thomas Scherer, Collette Stainforth, Karolina M Stepien, Gere Sunder-Plassmann, Johan L K Van Hove

Affiliations

¹ Department of Child and Adolescent Medicine, Rennes Hospital, Rennes, France.
² Biochemistry Laboratory, Robert Debré Hospital, APHP, Paris, France.
³ Department of Pediatrics, Reference Center for Inborn Error of Metabolism, Necker and Robert-Debré Hospital, APHP, Université Paris Cité, Paris, France.
⁴ LYPSIS, Université Paris-Saclay, Châtenay-Malabry, France.
⁵ Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
⁶ Department of Pediatrics, Caen Hospital, Caen, France.
⁷ Biochemistry Laboratory, Rennes Hospital, Rennes, France.
⁸ Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium.
⁹ Department of Pediatrics, Estaing Hospital, Clermont-Ferrand, France.
¹⁰ Department of Pediatrics, Tours Hospital, Tours, France.
¹¹ Department of Pediatrics, Reference Center for Inborn Error of Metabolism, Toulouse Hospital, Toulouse, France.
¹² Hospital Universitario Virgen del Rocío, Sevilla, Spain.
¹³ Section of Genetics and Metabolism, Children's National Health System, Washington, District of Columbia, USA.
¹⁴ Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹⁵ Division of Metabolism and Children's Research Center, University Children's Hospital, Zürich, Switzerland.
¹⁶ Department of Paediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria.
¹⁷ Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, General University Hospital, Charles University, Prague, Czech Republic.
¹⁸ Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹⁹ Department of Internal Medicine, Angers University Hospital, Angers, France.
²⁰ Departments of Paediatrics and Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
²¹ Department of Genetics, AP-HP, Pitié-Salpêtrière University Hospital, Paris, France.
²² Willink Metabolic Unit, Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester.
²³ Alder Hey Children's Hospital, Liverpool, UK.
²⁴ H.U. Ntra. Sra. de la Candelaria, Santa Cruz de Tenerife, Spain.
²⁵ Clínica Comfamiliar, Pereira, Colombia.
²⁶ Department of Pediatrics, Competence Center of Inherited Metabolic Disorders, Rennes Hospital, Rennes, France.
²⁷ Inserm UMR_S1163, Institut Imagine, Paris, France.

PMID: 35460084
DOI: 10.1002/jimd.12504

Free article

Influence of early identification and therapy on long-term outcomes in early-onset MTHFR deficiency

Mathilde Yverneau et al. J Inherit Metab Dis. 2022 Jul.

Free article

. 2022 Jul;45(4):848-861.

doi: 10.1002/jimd.12504. Epub 2022 May 9.

Authors

Collaborators

E-HOD Consortium:
Ana Maria Martins, Javier Blasco Alonso, Brigitte Chabrol, Ellen Crushell, Carlo Dionisi-Vici, Stephanie Grünewald, Karine Mention, Helen Mundy, Elaine Murphy, Pilar Quijada Fraile, Carlos José Ruiz, Maria Ángeles Ruiz Gómez, Saikat Santra, Thomas Scherer, Collette Stainforth, Karolina M Stepien, Gere Sunder-Plassmann, Johan L K Van Hove

Affiliations

¹ Department of Child and Adolescent Medicine, Rennes Hospital, Rennes, France.
² Biochemistry Laboratory, Robert Debré Hospital, APHP, Paris, France.
³ Department of Pediatrics, Reference Center for Inborn Error of Metabolism, Necker and Robert-Debré Hospital, APHP, Université Paris Cité, Paris, France.
⁴ LYPSIS, Université Paris-Saclay, Châtenay-Malabry, France.
⁵ Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
⁶ Department of Pediatrics, Caen Hospital, Caen, France.
⁷ Biochemistry Laboratory, Rennes Hospital, Rennes, France.
⁸ Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium.
⁹ Department of Pediatrics, Estaing Hospital, Clermont-Ferrand, France.
¹⁰ Department of Pediatrics, Tours Hospital, Tours, France.
¹¹ Department of Pediatrics, Reference Center for Inborn Error of Metabolism, Toulouse Hospital, Toulouse, France.
¹² Hospital Universitario Virgen del Rocío, Sevilla, Spain.
¹³ Section of Genetics and Metabolism, Children's National Health System, Washington, District of Columbia, USA.
¹⁴ Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹⁵ Division of Metabolism and Children's Research Center, University Children's Hospital, Zürich, Switzerland.
¹⁶ Department of Paediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria.
¹⁷ Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, General University Hospital, Charles University, Prague, Czech Republic.
¹⁸ Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹⁹ Department of Internal Medicine, Angers University Hospital, Angers, France.
²⁰ Departments of Paediatrics and Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
²¹ Department of Genetics, AP-HP, Pitié-Salpêtrière University Hospital, Paris, France.
²² Willink Metabolic Unit, Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester.
²³ Alder Hey Children's Hospital, Liverpool, UK.
²⁴ H.U. Ntra. Sra. de la Candelaria, Santa Cruz de Tenerife, Spain.
²⁵ Clínica Comfamiliar, Pereira, Colombia.
²⁶ Department of Pediatrics, Competence Center of Inherited Metabolic Disorders, Rennes Hospital, Rennes, France.
²⁷ Inserm UMR_S1163, Institut Imagine, Paris, France.

PMID: 35460084
DOI: 10.1002/jimd.12504

Abstract

MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p = 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome.

Keywords: EHOD; MTHFR deficiency; homocystinuria; neurodevelopmental outcome; newborn screening; remethylation defects.

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References

REFERENCES

1. Schiff M, Blom H. Treatment of inherited homocystinurias. Neuropediatrics. 2012;43(06):295-304.
1. Matthews RG, Sheppard C, Goulding C. Methylenetetrahydrofolate reductase and methionine synthase: biochemistry and molecular biology. Eur J Pediatr. 1998;157(S2):S54-S59.
1. Huemer M, Baumgartner MR. The clinical presentation of cobalamin-related disorders: from acquired deficiencies to inborn errors of absorption and intracellular pathways. J Inherit Metab Dis. 2019;42(4):686-705.
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Influence of early identification and therapy on long-term outcomes in early-onset MTHFR deficiency

Collaborators

Affiliations

Influence of early identification and therapy on long-term outcomes in early-onset MTHFR deficiency

Authors

Collaborators

Affiliations

Abstract

References

REFERENCES

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Supplementary concepts

LinkOut - more resources

Full Text Sources