Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and challenging complication of platinum and taxane agents and can have a significant impact on patients' quality of life (QoL).
Objective: This study aims to detect the frequency and severity of CIPN in patients receiving Platinum and Taxane compounds and their effect on QoL.
Methods: This prospective study enrolled 47 patients receiving neurotoxic chemotherapy (taxanes and platinum-based agents) at Assiut University Hospital's Clinical Oncology Department between March 2023 and July 2024, with a median 6-month follow-up. CIPN was detected, graded, and assessed clinically by using the NCI-CTCAE v5.0 criteria and electrophysiologically through nerve conduction studies conducted in collaboration with the Neurology Department. Health-related quality of life (HRQoL) was evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).
Results: In this study, altered sensory symptoms occurred in 80-86.7% of patients across all regimens. Neuropathy grading revealed grade II in 44% of patients, grade I in 29%, and grade III in 25%. Platinum-based regimens were
significantly associated with grade II neuropathy (p<0.001), while platinum+taxane combinations showed the highest rate of grade III neuropathy (p=0.05). Nerve conduction studies demonstrated significant post-chemotherapy reductions in sensory nerve action potential (SNAP) and motor conduction velocities (MCV) (p<0.001). Higher CIPN grades correlated significantly with worse global health status (commonly with patients received platinum + taxane combinations), reduced physical function, and increased symptom burden on both QLQ-C30 and NCI-CTCAE V5 scales (p<0.014).
Conclusion: CIPN is a frequent and devastating complication in patients receiving taxane and platinum-based chemotherapy, with significant clinical, neurophysiological, and QoL implications. Future research should focus on strategies to prevent and mitigate this debilitating side effect.
Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum.
We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects.
Through worldwide collaboration, we identified 211 patients, 97 of them previously unpublished, with recessive EPG5 variants. The phenotypic spectrum ranged from antenatally lethal presentations to milder isolated neurodevelopmental disorders. A novel Epg5 knock-in mouse model of a recurrent EPG5 missense variant featured motor impairments and defective autophagy in brain areas particularly relevant for the neurological disorders in milder presentations. Novel age-dependent neurodegenerative manifestations in our cohort included adolescent-onset parkinsonism and dystonia with cognitive decline, and myoclonus. Radiological features suggested an emerging continuum with brain iron accumulation disorders. Patient fibroblasts showed defects in PINK1-Parkin-dependent mitophagic clearance and α-synuclein overexpression, indicating a cellular basis for the observed neurodegenerative phenotypes. In Caenorhabditis elegans, EPG5 knockdown caused motor impairments, defective mitophagic clearance, and changes in mitochondrial respiration comparable to observations in C. elegans knockdown of parkinsonism-related genes.
Our findings illustrate a lifetime neurological disease continuum associated with pathogenic EPG5 variants, linking neurodevelopmental and neurodegenerative disorders through the common denominator of defective autophagy.
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