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  • Clinical Research Article
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Unveiling clinical and genetic landscapes of MMA and CBS: insights from whole exome sequencing in a tertiary care setting

Pediatric Research (2026)Cite this article

Abstract

Background

MMA and CBS deficiency are rare autosomal recessive metabolic disorders caused by defects in cobalamin metabolism and cystathionine-beta-synthase activity, respectively. Advanced molecular genetic techniques, have become essential for diagnosing these conditions. This study aimed to analyze the genetic variations in three MMA and four CBS deficiency cases using WES and correlate the findings with clinical, biochemical, and treatment outcomes.

Methods

Clinical evaluation, biochemical testing, neuroimaging, and WES were performed. WES data were analyzed using the reference genome GRCh37, and variants were classified according to ACMG guidelines. Treatment outcomes were monitored for three months post-intervention.

Results

In MMA cases, a homozygous pathogenic variant (c.394 C > T, p.Arg132Ter) in MMACHC was identified in all three patients. Biochemical abnormalities included methylmalonic aciduria, elevated homocysteine, and megaloblastic anemia. Hydroxycobalamin therapy improved behavioral, cognitive, and dermatological symptoms, though residual neuropathy persisted in one case. In CBS deficiency, pathogenic variants in CBS (c.992 C > T, p.Ala331Val; c.862 G > A, p.Ala288Thr; c.700 G > A, p.Asp234Asn) were identified. Clinical features included developmental delayed milestones, lens dislocation, and vascular complications. Treatment outcomes varied based on early diagnosis and compliance.

Conclusion

This study highlights the importance of newborn screening program with WES in diagnosing and managing MMA and CBS deficiency, facilitating early intervention, improving clinical outcomes, and supporting precision medicine approaches.

Impact

  • Early newborn screening and diagnosis are critical for effective treatment and improved patient outcomes.

  • Novel clinical and pathogenic variants will expand the current understanding of these disorders.

  • WES enhances the diagnostic precision for MMA and CBS deficiency, facilitating timely intervention and superior clinical management.

  • Accurate and early detection of treatable IEMs through NBS can significantly reduce disease burden and healthcare costs.

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Fig. 1: Schematic representation of the research methodology from the diagnosis to treatment.
Fig. 2: WES identified pathogenic/likely pathogenic MMACHC and CBS variants in MMA and CBS deficiency cases.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We express gratitude to the 3biollion company for generously providing sequencing services for the patients at no cost.

Funding

This study supported by a postdoctoral start-up fund from the Maternal and Children’s Health Research Institute, Shunde Women and Children’s Hospital, Guangdong Medical University, China (2024BSHQD002).

Author information

Authors and Affiliations

  1. Maternal and Children’s Health Research Institute, Shunde Women and Children’s Hospital, Guangdong Medical University, Foshan, 528300, China

    Muhammad Wasim & Guoda Ma

  2. Children Hospital & Institute of Child Health, Faisalabad, 38000, Pakistan

    Iram Javed

  3. Lahore College for Women University, Lahore, 54600, Pakistan

    Afia Iqbal

  4. Department of Biotechnology, University of Health Sciences, Lahore, 54600, Pakistan

    Nadia Mustafa

  5. Pathology and Laboratory Medicine, The Aga Khan University, Karachi, 74800, Pakistan

    Haq Nawaz Khan

  6. University of Child Health Sciences, The Children’s Hospital Lahore, Karachi, 54600, Pakistan

    Tipu Sultan

  7. Institute of Pediatrics, Shunde Women and Children’s Hospital, Guangdong Medical University, Foshan, 528300, China

    Yajun Wang

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Contributions

“The study conception and design were a collaborative effort involving all authors. IJ, HNK, YW, GM, and MW were responsible for supervision, material preparation, data collection, and analysis. The initial data and draft of the manuscript was written by MW, IJ, AI, NM, and TS. HNK, YW, GM, and MW provides genetic analyses and provided feedback on earlier versions / final version of the manuscript. The final manuscript was thoroughly reviewed and approved by all authors, including IJ, HNK, and MW.”

Corresponding authors

Correspondence to Muhammad Wasim or Iram Javed.

Ethics declarations

Competing interests

Nothing to declare. The research was conducted in the absence of any financial and commercial relationship.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the institute “Institutional Ethical Review Committee of Children Hospital & Institute of Child Health, Faisalabad”.

Consent to participate

Informed written consent was obtained for all the studied participants from their parents/guardian/head of special education centers.

Consent for publication

Consent has also been taken from the participants to publish this data for the welfare of humankind.

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Wasim, M., Javed, I., Iqbal, A. et al. Unveiling clinical and genetic landscapes of MMA and CBS: insights from whole exome sequencing in a tertiary care setting. Pediatr Res (2026). https://doi.org/10.1038/s41390-026-04834-7

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  • DOI: https://doi.org/10.1038/s41390-026-04834-7

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