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

Sibtain Ahmed; Fizza Akbar; Ralph J. DeBerardinis; Min Ni; Bushra Afroze

doi:10.1515/jpem-2023-0083

Article

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

Sibtain Ahmed , Fizza Akbar , Ralph J. DeBerardinis , Min Ni and Bushra Afroze

Published/Copyright: July 13, 2023

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 36 Issue 8

Abstract

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.

Keywords: adult; homocysteinemia; MTHFR deficiency; neonatal; Pakistan

Corresponding author: Dr. Bushra Afroze, Associate Professor and Clinical Biochemical Geneticist, Department of Paediatrics and Child Health, Aga Khan University Hospital, Stadium Road, Karachi, Pakistan, E-mail: bushra.afroze@aku.edu

Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Not applicable as it was a retrospective chart review.
Ethical approval: The study was approved from the Institutional Ethical Review Committee of the Aga Khan University (ERC # 2022-7569-21788).

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Received: 2023-02-27

Accepted: 2023-06-28

Published Online: 2023-07-13

Published in Print: 2023-08-28

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Articles in the same Issue

https://doi.org/10.1515/jpem-2023-0083

Keywords for this article

adult; homocysteinemia; MTHFR deficiency; neonatal; Pakistan