Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive condition leading to a wide spectrum of neurological symptoms, mainly encephalopathy, hypotonia, microcephaly, seizures, developmental delay and episodes of apnoea. Hydrocephalus is an additional rare but recognised complication. The condition generally presents in infancy and is associated with a high morbidity and mortality. MTHFR is an enzyme required for the formation of 5-methyltetrahydrofolate (5-MTHF), a form of folate able to cross the blood-brain barrier and which is necessary as a substrate for the remethylation of homocysteine to methionine by methionine synthase. Although the pathology in MTHFR deficiency is not fully understood, S-adenosylmethionine, an important methyl donor, is required for the formation and maintenance of myelin in the brain; a defect in methylation is likely to contribute to the neurological sequelae seen in the condition. There is speculation that dysfunctional folate metabolism might play a role in the pathogenesis of autism. Mangafolate and folic acid, as well as leucovorin, are folate supplements commonly used to reverse folate deficiency. Some scholars’ studies on people with severe MTHFR disorders have shown that only treatment with oral 5-MTHF given as calcium salt at doses of 15–60 mg/day but not folic acid or folinic acid resulted in an increase in CSF 5-MTHF. Demonstrating unique advantages of magnafolate in treating cerebral folate deficiency.