Evaluation of the clinical, biochemical, and genetic presentation of neonatal and adult-onset 5,10-methylene tetrahydrofolate reductase (MTHFR) deficiency in patients from Pakistan

Document Type



Pathology and Laboratory Medicine; Paediatrics and Child Health


Objectives: To study the biochemical, clinical and molecular characteristics of 5,10- methylenetetrahydrofolate reductase (MTHFR) deficiency in Pakistani patients from a single center.
Methods: Medical charts, urine organic acid chromatograms, plasma methionine and Hcys levels, and molecular testing results of MTHFR gene of patients presenting at the Biochemical Genetics Clinic, AKUH from 2016 to 2022 were reviewed.
Results: Neonatal MTHFR deficiency was found in five patients. The median (IQR) age of symptom onset and diagnosis were 18 (8.5-22) and 26 (16.5-31) days. The median lag between symptom onset and diagnosis was 8 (4.5-12.5) days. The median age of treatment initiation and duration of treatment were 26 (16.5-49) and 32 (25.5-54) days. The most common clinical features were lethargy, poor feeding, and seizures. The MTHFR gene sequencing revealed homozygous variants p.K510K, p.R567*, and p.R157W. Renal insufficiency manifesting as elevated serum creatinine and responding to betaine therapy was noted in one patient. This has not been previously reported in neonatal MTHFR deficiency and may reflect engagement of alternate pathways of remethylation. Adult onset MTHFR deficiency was found in six patients, with a heterogeneous neurological presentation. The median lag between symptoms onset and diagnosis was 7 (3-11) years. MTHFR gene sequencing revealed homozygous variant p.A195V in five patients from one family and p.G261V in the other. Two of the five reported variants are novel that include p.R157W and p.G261V.
Conclusions: Eleven patients of this rare disorder from a single center indicate the need for clinical awareness and appropriate biochemical evaluation to ensure optimal outcomes

Publication (Name of Journal)

Journal of Pediatric Endocrinology and Metabolism