Forodesine Hydrochloride

Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes.

Whole exome sequencing of the probands was performed to identify pathogenic variants. We validated the mitochondrial defect by analyzing mtDNA, mitochondrial dNTP pools, respiratory chain activities, and GUK1 activity. To confirm pathogenicity of GUK1 deficiency, we expressed 2 GUK1 isoforms in patient cells.

We identified biallelic GUK1 pathogenic variants in all 4 probands who presented with ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy and altered T‐lymphocyte profiles. Muscle biopsies from all probands showed mtDNA depletion, deletions, or both, as well as reduced activities of mitochondrial respiratory chain enzymes. GUK1 encodes guanylate kinase, originally identified as a cytosolic enzyme. Long and short isoforms of GUK1 exist. We observed that the long isoform is intramitochondrial and the short is cytosolic. In probands’ fibroblasts, we noted decreased GUK1 activity causing unbalanced mitochondrial dNTP pools and mtDNA depletion in both replicating and quiescent fibroblasts indicating that GUK1 deficiency impairs de novo and salvage nucleotide pathways. Proband fibroblasts treated with deoxyguanosine and/or forodesine, a purine phosphatase inhibitor, ameliorated mtDNA depletion, indicating potential pharmacological therapies.

Primary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T‐lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024;96:1209–1224

Few studies have reported the impact of telescoping flow diverters (FDs) in intracranial aneurysm treatment. Our study compared aneurysms treated using telescoping FDs to those treated with a single FD and identified predictors of telescoping.

This was a single-center retrospective review of a prospectively maintained database of aneurysms treated with FDs between 2011 and 2023. All patients who were treated with FDs for intracranial aneurysms were included in the study.

The study comprised 750 patients with 750 aneurysms treated using 871 FDs. The study cohort was divided into 85 patients requiring telescoping FDs and 655 who did not. Rates of hemorrhage (7.1% vs. 1.8%, P < 0.001), symptomatic stroke (5.9% vs. 2.6, P < 0.001), and asymptomatic stroke (1.2% vs. 0.8%, P < 0.001) were significantly higher in the telescoping cohorts. At final follow-up, the rate of nonocclusion (9.8% vs. 5.1%, P = 0.029) and the rate of complete occlusion (88.5% vs. 81.1%, P = 0.029) were significantly higher in the telescoping cohort. On multivariate analysis, fusiform morphology (odds ratio [OR]: 2.4, 95% confidence interval [CI] 1.0-5.0, P = 0.03), increasing aneurysm height (OR: 1.0, 95% CI 1.0-1.1, P= 0.034), and the use of the Pipeline Embolization Device FD (OR: 2.4, 95% CI 1.3-4.4, P = 0.005) were independent predictors of telescoping.

Aneurysms with fusiform morphology, increasing aneurysm height and those that underwent flow diversion using Pipeline Embolization Device had higher odds for telescoping. Significantly higher rates of angiographic occlusion with the use of telescoping FD add to the literature on its efficacy in treating aneurysms of varying morphology.