TRMT5 – Congestive Splenomegaly

This summary reviews the association between TRMT5 and congestive splenomegaly, with evidence drawn from recent case reports and experimental analyses. The reported clinical cases describe two siblings presenting with features of non‑cirrhotic portal hypertension and hepatopulmonary syndrome, a phenotype that in this context aligns with congestive splenomegaly (PMID:35460901).

Genetic investigations indicate an autosomal recessive inheritance pattern with clear segregation in the affected siblings. In these cases, the identification of pathogenic TRMT5 variants supports a gene‐disease link based on limited but consistent clinical observations (PMID:35460901).

Detailed genetic evidence highlights a recurrent variant, with one representative mutation reported as c.665T>C (p.Ile222Thr). This variant was identified in the affected individuals and, along with familial segregation data, contributes to the limited genetic evidence for this gene‑disease association (PMID:35460901).

Experimental studies further support the pathogenicity of TRMT5 disruptions. Functional assessments reveal that altered TRMT5 activity leads to deficient post‑transcriptional modification of mitochondrial tRNAs, impairing mitochondrial translation and function. Such findings, derived from in vitro assays and cybrid cell models, lend moderate support to the role of TRMT5 in disease mechanisms (PMID:33398350).

It is noteworthy that conflicting evidence exists. Separate reports have implicated TRMT5 mutations in a demyelinating neuropathy syndrome with a distinct clinical presentation, thereby suggesting pleiotropic effects of TRMT5 alterations (PMID:35342985). Such divergent phenotypes underscore the complexity of TRMT5 biology and necessitate further investigation to delineate phenotype‑specific pathogenic mechanisms.

Overall, the clinical and experimental evidence supports a limited yet consistent association between TRMT5 and congestive splenomegaly. While the number of probands remains small, the convergence of segregation data and functional studies provides a rationale for considering TRMT5 mutations in the diagnostic evaluation of familial portal hypertension syndromes.

Key Take‑Home: TRMT5 gene mutations, particularly in familial cases of portal hypertension with splenic congestion, represent a potentially actionable diagnostic marker, warranting further clinical validation.

References

• Clinics and research in hepatology and gastroenterology • 2022 • A novel mutation in TRMT5 associated with idiopathic non‑cirrhotic portal hypertension and hepatopulmonary syndrome: Case report of two siblings PMID:35460901
• Nucleic acids research • 2021 • A deafness‑associated tRNA mutation caused pleiotropic effects on the m1G37 modification, processing, stability and aminoacylation of tRNAIle and mitochondrial translation PMID:33398350
• Neuropathology and applied neurobiology • 2022 • A novel TRMT5 mutation causes a complex inherited neuropathy syndrome: The role of nerve pathology in defining a demyelinating neuropathy PMID:35342985

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