Article type: Narrative Review
Article title: Genetics and Phenotypes of Late-Onset Neurodegeneration in Neurodevelopmental Disorders
Journal: Cureus
Year: 2025
Authors: Jamir Pitton Rissardo, Fatemeh Rashidi, Masoumeh Rashidi, Meryem Bahar, Kimia Kheirandishdoolabi, Ana Leticia Fornari Caprara, Farbood Khademhamzeh, Sogand Ranjbar, Omesh Prathiraja, and Maleesha Jayasinghe
E-mail: jamirrissardo@gmail.com
ABSTRACT
Late-onset neurodegenerative diseases may originate from subtle vulnerabilities established during early development, yet the specific mechanisms linking early-life factors to later pathology remain poorly understood. Emerging evidence suggests that prenatal and postnatal influences, including genetic predispositions, maternal health, and environmental exposures, shape neural circuits in ways that may predispose individuals to neurodegeneration. Subclinical abnormalities in synaptic pruning, neurogenesis, and immune regulation are increasingly recognized as latent risk factors, but their precise contribution to disease onset has not been clearly defined. Advances in biomarker discovery, particularly in proteomic, genetic, and imaging domains, offer promising opportunities to detect such vulnerabilities before clinical symptoms arise. Despite these insights, the field lacks longitudinal and mechanistic studies that connect early developmental disruptions to specific neurodegenerative outcomes. Addressing this gap will require integrative research that combines experimental models with life-course studies to clarify causal pathways. By identifying concrete mechanistic links, future work may inform more targeted preventive strategies, rather than broadly proposing reductions in global disease burden.
Keywords: early developmental phenotype; genetic predisposition; mitochondrial dysfunction; neurodegeneration; neurodevelopmental disorders.
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Citation
Pitton Rissardo J, Rashidi F, Rashidi M, Bahar M, Kheirandishdoolabi K, Fornari Caprara AL, Khademhamzeh F, Ranjbar S, Prathiraja O, Jayasinghe M. Genetics and Phenotypes of Late-Onset Neurodegeneration in Neurodevelopmental Disorders. Cureus 2025;17: e93530. doi:10.7759/cureus.93530
Figure 1. Late-onset neurodegeneration in neurodevelopmental disorders.
Table 1. Early-onset Parkinson's disease in subjects with PPP2R5D mutation.