MTHFD1 Deficiency in Two Unrelated Children: Highlights on Phenotypic Spectrum and Response to Folic Acid Therapy

Methylene-tetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency is a rare inborn error of immunity (IEI) involving defects in folate metabolism. It can present with combined immunodeficiency and variable phenotypic features, including recurrent bacterial infections, megaloblastic anemia, and failure to thrive.

We describe 2 unrelated Kuwaiti children with MTHFD1 deficiency caused by a homozygous pathogenic variant [c.517C>T (Arg173Cys)].

Both cases presented with unexplained megaloblastic anemia, recurrent sinopulmonary infections, failure to thrive, and developmental delay. The first patient, a 10-year-old girl, was diagnosed with combined immunodeficiency and autoimmune thyroiditis. Treatment with folic acid resulted in significant clinical improvement. The second patient, a 3-year-old girl, presented with sepsis secondary to progressive lobar pneumonia and bone marrow failure. Despite intensive treatment, including broad-spectrum antibiotics, antifungals, IVIG, and dexamethasone for suspected hemophagocytic lymphohistiocytosis, she developed severe complications and passed away on day 18 of PICU admission.

As there is no specific clinical or laboratory phenotype for most IEIs, we emphasize the importance of molecular diagnosis through urgent genetic testing in patients with suspected MTHFD1 deficiency. Precision therapy with prompt folate or folinic acid supplementation can significantly improve outcomes, as evidenced by the survival of one patient with minimal intervention.