Brain Dysfunction in Genetically Determined Accelerated Aging Syndromes

Human progeroid syndromes, caused by single-gene mutations, offer unique insights into the genetic determinants of brain development, ageing, and neurodegeneration. However, the link between these mutations and neurological phenotypes remains poorly understood. This integrative translational review synthesizes clinical, neuroimaging, cognitive, and experimental data across DNA repair disorders, RecQ helicase-associated syndromes, laminopathies, and other rare conditions. We propose a working hypothesis: severe, primary neurodegeneration occurs most consistently when the mutant gene is functionally expressed in post-mitotic neurons, as seen in DNA repair disorders. However, exceptions and complexities exist. Neurological phenotypes can also arise secondarily from glial dysfunction (e.g., Penttinen syndrome), vascular pathology (e.g., strokes in Hutchinson-Gilford progeria), or systemic disease. Furthermore, neuron-specific protective mechanisms, such as miR-9-mediated silencing of progerin, can uncouple systemic ageing from brain ageing. Current animal models often fail to replicate human gene expression patterns and neuropathology, limiting translational utility. This framework integrates clinical observations with biological mechanisms, supporting practical monitoring strategies while emphasising the need for human-relevant models to clarify how genetic mutations lead to brain dysfunction.