Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026
Novel MTHFR variants manifesting with hereditary spastic paraplegia and recurrent pulmonary embolism: a case report and literature review of adult-onset severe MTHFR deficiency.
СтатьяКлинический случайОбзорНазвание и аннотация: Перевод в очереди
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Li Yi-Xiao, Wang Ming-Qiu, Wang Rui-Yun, Hao Yan-Lei
Аннотация
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.
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.