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.

Alder Hey Children's Hospital Liverpool UK

Biochemistry Laboratory Rennes Hospital Rennes France

Biochemistry Laboratory Robert Debré Hospital APHP Paris France

Clínica Comfamiliar Pereira Colombia

Department of Child and Adolescent Medicine Rennes Hospital Rennes France

Department of Genetics AP HP Pitié Salpêtrière University Hospital Paris France

Department of Internal Medicine Angers University Hospital Angers France

Department of Internal Medicine Radboud University Medical Centre Nijmegen The Netherlands

Department of Paediatrics Landeskrankenhaus Bregenz Bregenz Austria

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine General University Hospital Charles University Prague Czech Republic

Department of Pediatrics Caen Hospital Caen France

Department of Pediatrics Competence Center of Inherited Metabolic Disorders Rennes Hospital Rennes France

Department of Pediatrics Estaing Hospital Clermont Ferrand France

Department of Pediatrics National Taiwan University Hospital College of Medicine National Taiwan University Taipei Taiwan

Department of Pediatrics Reference Center for Inborn Error of Metabolism Necker and Robert Debré Hospital APHP Université Paris Cité Paris France

Department of Pediatrics Reference Center for Inborn Error of Metabolism Toulouse Hospital Toulouse France

Department of Pediatrics Tours Hospital Tours France

Departments of Paediatrics and Clinical Genetics Centre for Inherited Metabolic Diseases Copenhagen University Hospital Copenhagen Denmark

Division of Child Neurology and Metabolic Medicine Center for Child and Adolescent Medicine University Hospital Heidelberg Heidelberg Germany

Division of Metabolism and Children's Research Center University Children's Hospital Zürich Switzerland

H U Ntra Sra de la Candelaria Santa Cruz de Tenerife Spain

Hospital Universitario Virgen del Rocío Sevilla Spain

Inserm UMR_S1163 Institut Imagine Paris France

LYPSIS Université Paris Saclay Châtenay Malabry France

Pediatric Neurology Unit Cliniques Universitaires Saint Luc UCLouvain Brussels Belgium

Section of Genetics and Metabolism Children's National Health System Washington District of Columbia USA

Willink Metabolic Unit Manchester Centre for Genomic Medicine Manchester University Hospitals NHS Foundation Trust Manchester

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