Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder

The post-transcriptional modification of tRNAs plays a crucial role in tRNA structure and function. Pathogenic variants in tRNA-modification enzymes have been implicated in a wide range of human neurodevelopmental and neurological disorders. However, the molecular basis for many of these disorders remains unknown. Here, we describe a comprehensive cohort of 43 individuals from 31 unrelated families with bi-allelic variants in tRNA methyltransferase 1 (TRMT1). These individuals present with a neurodevelopmental disorder universally characterized by developmental delay and intellectual disability, accompanied by variable behavioral abnormalities, epilepsy, and facial dysmorphism. The identified variants include ultra-rare TRMT1 variants, comprising missense and predicted loss-of-function variants, which segregate with the observed clinical pathology. Our findings reveal that several variants lead to mis-splicing and a consequent loss of TRMT1 protein accumulation. Moreover, cells derived from individuals harboring TRMT1 variants exhibit a deficiency in tRNA modifications catalyzed by TRMT1. Molecular analysis reveals distinct regions of TRMT1 required for tRNA-modification activity and binding. Notably, depletion of Trmt1 protein in zebrafish is sufficient to induce developmental and behavioral phenotypes along with gene-expression changes associated with disrupted cell cycle, immune response, and neurodegenerative disorders. Altogether, these findings demonstrate that loss of TRMT1-catalyzed tRNA modifications leads to intellectual disability and provides insight into the molecular underpinnings of tRNA-modification deficiency caused by pathogenic TRMT1 variants. [Abstract copyright: Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

Saccular mycotic aneurysm of descending thoracic aorta secondary to vertebral hydatid disease: A rare case

Background/Objective: Hydatid disease of the aorta is very rare. Hydatid disease can result in saccular aneurysm of the thoracic and abdominal aorta. Case report: We report a rare case of saccular aneurysm of the distal descending thoracic aorta. The diameter of the aneurysm was 60 mm. It was managed by Thoracic Endovascular Aneurysm Repair. After 41 months, computed tomography angiography revealed a multi-loculated cystic lesion with 86 � 83�80 mm dimensions in the prevertebral area at the T10-T11 level with bony destruction and erosion of the anterior margin of the vertebral bodies. A computed tomography-guided fine-needle aspiration of the paravertebral cystic lesion was performed. Microscopic study of the fine-needle aspiration specimen demonstrated Echinococcosis granulosus diagnostic of hydatid disease. Conclusion: It is concluded that the case was a mycotic aneurysm of the thoracic aorta secondary to vertebral hydatid disease. © The Author(s) 2021

miRNA contents of cerebrospinal fluid extracellular vesicles in glioblastoma patients

INTRODUCTION: Analysis of extracellular vesicles (EVs) derived from plasma or cerebrospinal fluid (CSF) has emerged as a promising biomarker platform for therapeutic monitoring in glioblastoma patients. However, the contents of the various subpopulations of EVs in these clinical specimens remain poorly defined. Here we characterize the relative abundance of miRNA species in EVs derived from the serum and cerebrospinal fluid of glioblastoma patients. METHODS: EVs were isolated from glioblastoma cell lines as well as the plasma and CSF of glioblastoma patients. The microvesicle subpopulation was isolated by pelleting at 10,000×g for 30 min after cellular debris was cleared by a 2,000×g (20 min) spin. The exosome subpopulation was isolated by pelleting the microvesicle supernatant at 120,000×g (120 min). qRT-PCR was performed to examine the distribution of miR-21, miR-103, miR-24, and miR-125. Global miRNA profiling was performed in select glioblastoma CSF samples. RESULTS: In plasma and cell line derived EVs, the relative abundance of miRNAs in exosome and microvesicles were highly variable. In some specimens, the majority of the miRNA species were found in exosomes while in other, they were found in microvesicles. In contrast, CSF exosomes were enriched for miRNAs relative to CSF microvesicles. In CSF, there is an average of one molecule of miRNA per 150-25,000 EVs. CONCLUSION: Most EVs derived from clinical biofluids are devoid of miRNA content. The relative distribution of miRNA species in plasma exosomes or microvesicles is unpredictable. In contrast, CSF exosomes are the major EV compartment that harbor miRNAs