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Objective <p>Variants in the <i>MMACHC</i> gene cause combined methylmalonic acidemia (MMA) and homocystinuria, cobalamin C (cblC) type. This study aimed to determine whether heterozygous <i>MMACHC</i> variant carriers exhibit elevated plasma homocysteine (Hcy) levels and to explore the variant-type–specific biochemical effects.</p> Methods <p>In this prospective study, 301 <i>MMACHC</i> variant carriers and 304 controls were enrolled. Plasma Hcy levels, demographic characteristics, and clinical data were collected. Propensity score matching (PSM, 1:1) was performed to balance age and sex between groups. Generalized linear models were applied to investigate the correlation between <i>MMACHC</i> variant carriage and Hcy levels.</p> Results <p>After PSM, 173 carrier–control pairs were included. Carriers showed significantly higher Hcy levels (median 12.27 µmol/L, range 5.30–85.90) than controls (9.80 µmol/L, 3.10–53.30; <i>P</i> &lt; 0.001). Both Male sex (β = 7.816, 95% CI:5.746–9.887) and <i>MMACHC</i> variant carriage (β = 5.741, 95%CI:3.743–7.740) were independently associated with elevated Hcy. Among carriers, missense variants, especially c.80A &gt; G (p.Q27R), were correlated with higher Hcy levels.</p> Conclusion <p>Heterozygous <i>MMACHC</i> variant carriers had higher plasma Hcy levels than age- and sex-matched controls in this study. Missense variants and male sex tended to be associated with higher Hcy levels. These findings suggest that <i>MMACHC</i> variant carriers can present with biochemical abnormalities and associated with alterations in homocysteine metabolism.</p>

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Analysis of homocysteine levels in carriers with MMACHC gene variants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Yi Ding,
  • Yuxin Deng,
  • Haijuan Zhi,
  • Xia Zhan,
  • Wenjun Ji,
  • Zizhen Gong,
  • Lili Hao,
  • Lianshu Han

摘要

Objective

Variants in the MMACHC gene cause combined methylmalonic acidemia (MMA) and homocystinuria, cobalamin C (cblC) type. This study aimed to determine whether heterozygous MMACHC variant carriers exhibit elevated plasma homocysteine (Hcy) levels and to explore the variant-type–specific biochemical effects.

Methods

In this prospective study, 301 MMACHC variant carriers and 304 controls were enrolled. Plasma Hcy levels, demographic characteristics, and clinical data were collected. Propensity score matching (PSM, 1:1) was performed to balance age and sex between groups. Generalized linear models were applied to investigate the correlation between MMACHC variant carriage and Hcy levels.

Results

After PSM, 173 carrier–control pairs were included. Carriers showed significantly higher Hcy levels (median 12.27 µmol/L, range 5.30–85.90) than controls (9.80 µmol/L, 3.10–53.30; P < 0.001). Both Male sex (β = 7.816, 95% CI:5.746–9.887) and MMACHC variant carriage (β = 5.741, 95%CI:3.743–7.740) were independently associated with elevated Hcy. Among carriers, missense variants, especially c.80A > G (p.Q27R), were correlated with higher Hcy levels.

Conclusion

Heterozygous MMACHC variant carriers had higher plasma Hcy levels than age- and sex-matched controls in this study. Missense variants and male sex tended to be associated with higher Hcy levels. These findings suggest that MMACHC variant carriers can present with biochemical abnormalities and associated with alterations in homocysteine metabolism.