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Background <p>5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants in the <i>MTHFR</i> gene. Although clinical heterogeneity is well recognized, the condition rarely presents as spastic paraplegia with onset in adulthood. We report a case associated with two novel <i>MTHFR</i> pathogenic variants manifesting this clinical phenotype.</p> Methods <p>We describe a 45-year-old Chinese man who developed a spastic gait at age 38, followed by lower limb weakness at age 43. Brain magnetic resonance imaging revealed mild leukoencephalopathy. Laboratory tests identified severe hyperhomocysteinemia. Whole-exome sequencing was performed with screening of genes associated with hereditary spastic paraplegia. Furthermore, a comprehensive literature review was conducted, including all adult-onset cases with detailed clinical and genetic information available up to October 2025.</p> Results <p>Genetic analysis identified three <i>MTHFR</i> variants: c.891T &gt; A (p.Tyr297Ter), c.1916&#xa0;C &gt; T (p.Thr639Ile), and c.665&#xa0;C &gt; T (p.Ala222Val). A total of 28 patients from 17 families were identified through the literature review.</p> Conclusion <p>This study expands the spectrum of pathogenic <i>MTHFR</i> variants and highlights the phenotypic heterogeneity of the disorder. MTHFR deficiency represents a rare yet treatable metabolic cause of spastic paraplegia and should be considered in its diagnostic workup.</p>

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Novel MTHFR variants manifesting with hereditary spastic paraplegia and recurrent pulmonary embolism: a case report and literature review of adult-onset severe MTHFR deficiency

  • 期刊论文

  • 发表日期：

    2026年1月20日

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  • Yi-Xiao Li,
  • Ming-Qiu Wang,
  • Rui-Yun Wang,
  • Yan-Lei Hao

摘要

Background

5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants in the MTHFR gene. Although clinical heterogeneity is well recognized, the condition rarely presents as spastic paraplegia with onset in adulthood. We report a case associated with two novel MTHFR pathogenic variants manifesting this clinical phenotype.

Methods

We describe a 45-year-old Chinese man who developed a spastic gait at age 38, followed by lower limb weakness at age 43. Brain magnetic resonance imaging revealed mild leukoencephalopathy. Laboratory tests identified severe hyperhomocysteinemia. Whole-exome sequencing was performed with screening of genes associated with hereditary spastic paraplegia. Furthermore, a comprehensive literature review was conducted, including all adult-onset cases with detailed clinical and genetic information available up to October 2025.

Results

Genetic analysis identified three MTHFR variants: c.891T > A (p.Tyr297Ter), c.1916 C > T (p.Thr639Ile), and c.665 C > T (p.Ala222Val). A total of 28 patients from 17 families were identified through the literature review.

Conclusion

This study expands the spectrum of pathogenic MTHFR variants and highlights the phenotypic heterogeneity of the disorder. MTHFR deficiency represents a rare yet treatable metabolic cause of spastic paraplegia and should be considered in its diagnostic workup.