5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late-onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult-onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11-54). At onset (median age: 20 years; range 9-38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69-266, to 90 μmol/L, range 20-142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C-terminal regulatory domain of the protein were over-represented compared to early-onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%-58%). This series of patients with late-onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.

Adult Inherited Metabolic Diseases Salford Royal NHS Foundation Trust Salford Care Organisation Northern Care Alliance Salford UK

APHP La Pitié Salpêtrière University Hospital Department of Genetics Paris France

APHP La Pitié Salpêtrière University Hospital Reference Center for Adult Neurometabolic diseases Paris France

Biochemistry Laboratory Robert Debré University Hospital APHP Paris France

Centre de référence pour les maladies mitochondriales de l'enfant à l'adulte Centre Hospitalier Universitaire de Bordeaux Bordeaux France

Department of General Practice Faculty of Medicine of Clermont Ferrand Clermont Ferrand France

Department of Internal Medicine Radboud University Medical Center Nijmegen The Netherlands

Department of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research and Center of Neurology University of Tübingen Tübingen Germany

Department of Paediatrics Landeskrankenhaus Bregenz Austria

Department of Pediatrics and Inherited Metabolic Disorders Charles University 1st Faculty of Medicine and General University Hospital Prague Praha 2 Czech Republic

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

Expert Centre for Neurogenetic Diseases and Adult Mitochondrial and Metabolic Diseases Univ Montpellier CHU Montpellier France

German Center for Neurodegenerative Diseases Tübingen Germany

Inserm U 1127 CNRS UMR 7225 Sorbonne Universités UPMC Univ Paris 06 UMR S 1127 Institut du Cerveau et de la Moelle épinière ICM Paris France

INSERM UMR_S 1256 Nutrition Genetics and Environmental Risk Exposure Faculty of Medicine of Nancy Nancy France

Internal Medicine Department Angers University Hospital Angers France

Laboratoire de Biochimie Centre Hospitalier Universitaire de Bordeaux Bordeaux France

lNSERM U1211 Université de Bordeaux Bordeaux France

LYPSIS2 Université Paris Saclay Chatenay Malabry France

MMDN Univ Montpellier EPHE INSERM Montpellier France

Reference Center for Inborn Errors of Metabolism Pediatric unit University Hospital of Nancy Nancy France

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