TYMP – Mitochondrial Neurogastrointestinal Encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal‐recessive multisystem disorder characterized by severe gastrointestinal dysmotility, cachexia, external ophthalmoplegia, peripheral neuropathy and diffuse leukoencephalopathy. Pathogenic biallelic variants in TYMP (HGNC:3148) encoding thymidine phosphorylase (TP) abolish enzyme activity, leading to systemic accumulation of thymidine and deoxyuridine, secondary mitochondrial DNA depletion, deletions and point mutations (PMID:19523753).

Extensive case reports and a large international cohort (n = 102 patients) have confirmed the gene–disease relationship, with more than 80 distinct pathogenic TYMP variants identified across diverse ethnicities (PMID:21933806). Affected individuals typically present in adolescence or early adulthood, although late‐onset presentations (> 40 y) have been documented. Genetic findings include splice‐site (e.g., c.112G>T (p.Glu38Ter)), missense and frameshift alleles; recurrent alleles show founder effects in specific populations.

Segregation analysis across multiple families demonstrates co‐segregation of biallelic TYMP variants with the MNGIE phenotype, including reports of affected sibships and consanguineous pedigrees.

Functional studies corroborate the loss‐of‐function mechanism: TP enzymatic assays show complete or near‐complete loss of activity; patient fibroblasts exhibit thymidine/deoxyuridine overload and progressive mtDNA defects in culture. Preclinical gene‐therapy and hematopoietic stem‐cell transplantation models restore TP activity and normalize nucleoside levels (PMID:21451581). Computational and multiscale simulations of key missense alleles further delineate structural destabilization and impaired substrate binding (PMID:40111159).

The definitive TYMP–MNGIE association underpins current diagnostic algorithms: measurement of plasma thymidine levels, TP activity assays and targeted sequencing of TYMP. Early molecular diagnosis enables timely consideration of allogeneic HSCT or enzyme‐replacement therapies, which may stabilize or improve clinical outcomes.

Key Take-home: Biallelic TYMP loss‐of‐function variants cause definitive autosomal‐recessive MNGIE; early genetic diagnosis guides potentially curative therapies.

References

• Acta Neurol Neurosurg • 2009 • A novel TYMP mutation in a French Canadian patient with mitochondrial neurogastrointestinal encephalomyopathy. PMID:19523753
• Brain | 2011 | Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. PMID:21933806
• Gene Therapy • 2011 • Hematopoietic gene therapy restores thymidine phosphorylase activity in a cell culture and a murine model of MNGIE. PMID:21451581
• J Phys Chem B • 2025 • Multiscale Simulations and Profiling of Human Thymidine Phosphorylase Mutations: Insights into Structural, Dynamics, and Functional Impacts in MNGIE. PMID:40111159

Evidence Based Scoring (AI generated)