Clinical spectrum and genetic landscape of MTHFR deficiency: a cohort study including novel variants

Methylene tetrahydrofolate reductase (MTHFR) deficiency is a rare inherited metabolic disorder that impairs myelination and brain development, leading to primary clinical manifestations, particularly neurological deficits. The aim of this study was to comprehensively describe the clinical presentation, biochemical profile, and molecular spectrum of patients with MTHFR deficiency. This multicenter, retrospective, descriptive study evaluated the medical records of 19 patients diagnosed with MTHFR deficiency at ten metabolic disease centers. A total of 13 patients had early-onset disease. In the early-onset group, all patients had varying degrees of neurodevelopmental delay. The median diagnostic delay from the first symptom to diagnosis was 3 months in early-onset cases and 118 months in late-onset cases. MTHFR deficiency exhibits a broad clinical spectrum, with acute deterioration possible even in chronically affected patients. MTHFR deficiency should be considered among treatable neurometabolic disorders in patients with otherwise unexplained neurodevelopmental or neuropsychiatric manifestations, particularly when accompanied by additional neurological findings.