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The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Mitochondrial Metabolism

ABSTRACT: The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Mitochondrial Metabolism

PROVIDER: PRJNA971742 | ENA |

REPOSITORIES: ENA

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The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Mitochondrial Metabolism

Project description:The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Mitochondrial Metabolism

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

Project description:Inborn errors of vitamin B12 metabolism (IECM) resulting from impaired methionine synthase (MS, encoded by MTR) activity cause severe cognitive and neurological deficits that are often unresponsive to conventional B12 supplementation. Using a brain-specific Mtr knockout mouse model, we identified the NAD⁺-dependent deacetylase SIRT1 as a central regulator of the pathological phenotype, and evaluated the therapeutic efficacy of its pharmacological activator, SRT2104. MS deficiency led to profound metabolic, mitochondrial, and epigenomic alterations in the hippocampus, including promoter hypermethylation of the pyruvate dehydrogenase complex, impaired TCA cycle activity, and reduced SIRT1 expression. At the functional level, we observed a disruption of Wnt signaling, associated with decreased neurogenesis, increased astrocytosis, and cognitive impairment. Treatment with SRT2104 effectively restored mitochondrial and energy metabolism, normalized Wnt signaling and neurogenesis markers, and rescued learning and memory performance. These findings identify SIRT1 as a potential therapeutic target in B12-related neurodevelopmental disorders and support the clinical repurposing of SRT2104 to alleviate persistent neurological symptoms.

2026-01-06 | PXD071487 | Pride

SIRT1 is a therapeutic target of brain metabolic and developmental consequences of methionine synthase deficiency in inborn errors of cobalamin metabolism

Project description:Inborn errors of vitamin B12 metabolism (IECM) with impaired methionine synthase (MS) activity (encoded by MTR), manifest severe cognitive and neurological symptoms unresponsive to B12 therapy. We explored the effects of Mtr brain-selective deletion at postnatal stage in mouse, identified histone deacetylase SIRT1 as a target of innovative therapy and evaluated the SRT2104 SIRT1 pharmacological activator to reverse alterations. We observed hippocampal significant metabolomic, behavioral, epigenome-wide, and proteomic alterations with promoter hypermethylation of pyruvate dehydrogenase and an abolished expression of SIRT1. MS disrupted the SIRT1/Wnt axis, with decreased neurogenesis and increased astrocytosis associated with altered learning abilities in water maze. Treatment with SRT2104 reversed the alterations of TCA, neurogenesis/astrocytosis and cognition. Our data highlight the prominent role of SIRT1 in brain neurodevelopmental and metabolic alterations of IECM, and the SRT2104 SIRT1 pharmacological activator as a promising drug repurposing candidate to treat B12-IECM resistant neurological manifestations.

2026-04-01 | GSE311053 | GEO

SIRT1 is a therapeutic target of brain metabolic and developmental consequences of methionine synthase deficiency in inborn errors of cobalamin metabolism

Project description:SIRT1 is a therapeutic target of brain metabolic and developmental consequences of methionine synthase deficiency in inborn errors of cobalamin metabolism

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Knowledge base and mini-expert platform for the diagnosis of inborn errors of metabolism.

Project description:PurposeRecognizing individuals with inherited diseases can be difficult because signs and symptoms often overlap those of common medical conditions. Focusing on inborn errors of metabolism (IEMs), we present a method that brings the knowledge of highly specialized experts to professionals involved in early diagnoses. We introduce IEMbase, an online expert-curated IEM knowledge base combined with a prototype diagnosis support (mini-expert) system.MethodsDisease-characterizing profiles of specific biochemical markers and clinical symptoms were extracted from an expert-compiled IEM database. A mini-expert system algorithm was developed using cosine similarity and semantic similarity. The system was evaluated using 190 retrospective cases with established diagnoses, collected from 15 different metabolic centers.ResultsIEMbase provides 530 well-defined IEM profiles and matches a user-provided phenotypic profile to a list of candidate diagnoses/genes. The mini-expert system matched 62% of the retrospective cases to the exact diagnosis and 86% of the cases to a correct diagnosis within the top five candidates. The use of biochemical features in IEM annotations resulted in 41% more exact phenotype matches than clinical features alone.ConclusionIEMbase offers a central IEM knowledge repository for many genetic diagnostic centers and clinical communities seeking support in the diagnosis of IEMs.

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Demonstration of a complementary approach for genetic diagnosis of inborn errors of immunity using proteogenomic analysis

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2023-11-25 | PXD038352 | JPOST Repository

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Scalable generation and functional classification of genetic variants in inborn errors of immunity to accelerate clinical diagnosis and treatment

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2025-06-05 | GSE298853 | GEO

Molecular Assessment of S. aureus strains in patients with inborn errors of immunity by WGS

Project description:Molecular Assessment of S. aureus strains in patients with inborn errors of immunity by WGS

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