Expanding the Phenotypic Spectrum of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency in Childhood: A Case Series

Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn error of folate metabolism. A number of phenotypic findings have been identified to date, and we hereby wish to expand its phenotype based on our Irish experience of the condition. We follow three children with MTHFR deficiency in our National Centre for Inherited Metabolic Disorders, giving an estimated point prevalence of approx. 0.08 cases per 100,000 in the Republic of Ireland. Our first case was referred for a metabolic opinion at 19 months of age. She had a history of global developmental delay with hypotonia, microcephaly, nystagmus, rash, and seizures. The second patient presented at 12 years of age with an osteopenic femoral fracture on the background of low body mass index (BMI). The third case presented at ten and a half years of age with acute mood disturbance with challenging behavior and a history of focal seizures and intellectual disability. It has been reported that early treatment may provide clinical benefit; however, we wish to acknowledge the varying responses to treatment despite pleasing metabolic control in our patients. MTHFR deficiency is a challenging diagnosis in childhood, given its low prevalence, complex phenotypes, and varying responses to treatment. Presymptomatic treatment further to early diagnosis through newborn screening may further improve outcomes.