SIRT1 mediates brain metabolic and developmental consequences of methionine synthase deficiency in inborn errors of cobalamin metabolism

Inborn errors of vitamin B12 metabolism (IECM) resulting from impaired methionine synthase (MTR) activity cause severe cognitive and neurological deficits that remain unresponsive to conventional B12 supplementation. Using a brain-specific Mtr knockout mouse model, we identify the NAD⁺-dependent deacetylase SIRT1 as a central regulator of the pathological phenotype and evaluate the therapeutic efficacy of its pharmacological activator SRT2104. MS deficiency induces profound metabolic, mitochondrial, and epigenomic alterations in the hippocampus, including promoter hypermethylation of the pyruvate dehydrogenase complex, impaired tricarboxylic acid (TCA) cycle activity, and reduced SIRT1 expression. At the functional level, we observe disrupted Wnt signaling associated with decreased neurogenesis, increased astrocytosis, and cognitive impairment. SRT2104 treatment restores mitochondrial and energy metabolism, normalizes Wnt signaling and neurogenesis markers, and rescues learning and memory performance. These findings identify SIRT1 as a therapeutic target in B12-related neurodevelopmental disorders and support the clinical repurposing of SRT2104 to alleviate persistent neurological symptoms.