Hypoventilation and progressive encephalopathy in a neonate with MTHFR deficiency

BMJ Case Rep. 2022 Jan 4;15(1):e246431. doi: 10.1136/bcr-2021-246431.


Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive inherited inborn error of metabolism, which presents with various severity depending on the level of residual enzyme activity. In neonates, it can present with recurrent hypoventilation episodes, persistent encephalopathy with or without microcephaly. MTHFR deficiency also results in hyperhomocysteinemia, homocystinuria and hypomethionemia. We report a male neonate with severe MTHFR deficiency presenting to us on third week of life with progressive encephalopathy, microcephaly, seizures, central hypoventilation. There was similar history in the previous sibling. The patient's blood lactate, ammonia, tandem mass spectrometry for amino acids and acyl carnitine were normal. He remained encephalopathic with progressive increase in need of respiratory support in spite of supportive treatment and metabolic cocktail consisting of riboflavin, pyridoxine, coenzyme Q and carnitine. This neonate had novel homozygous mutation, which results in MTHFR deficiency. In newborn with hypoventilation or recurrent apnoea with encephalopathy and microcephaly, MTHFR deficiency should be considered as a differential diagnosis. Mutation study helps in confirming diagnosis; however, extended newborn metabolic screening with homocysteine level could help in early diagnosis of these cases.

Keywords: hydrocephalus; neonatal and paediatric intensive care; neonatal health.

Publication types

  • Case Reports

MeSH terms

  • Homocystinuria* / complications
  • Homocystinuria* / diagnosis
  • Homocystinuria* / genetics
  • Humans
  • Hypoventilation
  • Infant, Newborn
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / deficiency
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Muscle Spasticity
  • Psychotic Disorders


  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)

Supplementary concepts

  • Methylenetetrahydrofolate reductase deficiency