2 In healthy cells, ROS are generally maintained at manageable levels.
Oxidative DNA base damage from reactive oxygen species (ROS) represents one of the most common endogenous sources of DNA damage and is an inevitable, constant byproduct of normal cellular metabolism. The human body relies upon multiple levels of quality control mechanisms that serve to correct injuries that occur due to both endogenous and exogenous factors.
Regardless of the specific manifestations, peripheral neuropathies add to the burden of patients with DNA repair disorders and an improved understanding of how the underlying disease mechanisms influence the development of neuropathies in these patients would support the development and assessment of effective therapies. In each of these cases, differences exist among patients regarding the age of susceptibility, precise anatomical distribution of the neuropathy, and overall severity. Depending on the specific underlying deficiency, these can present as either demyelinating or axonal peripheral neuropathies. Although the true incidence is likely underreported, a review of current literature shows documentation of sensory, motor, and sensorimotor peripheral neuropathies in patients with DNA repair or genome instability disorders. 1 As these are inherited disorders that impair ubiquitous biological processes, the peripheral neuropathy that occurs tends to be a polyneuropathy rather than a mononeuropathy. Peripheral neuropathy represents one of the many complex clinical manifestations that can be present in patients with DNA repair disorders and, as such, symptoms related to this may be overshadowed by other complications.
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Longitudinal physiological monitoring of these neuropathies with serial electrodiagnostic studies may provide valuable noninvasive outcome data in the context of future natural history studies, and thus the responses of these neuropathies may become sentinel outcome measures for future clinical trials of treatments currently in development such as adeno-associated virus gene replacement therapies. It is also unclear why different DNA repair disorders manifest with different types of neuropathy, and why neuropathy is not universally present in those diseases. Although plausible biological explanations exist for why the peripheral nerves are specifically vulnerable to impairments of DNA repair, specific mechanisms such as oxidative stress remain largely unexplored in this context, and bear further study. Three additional recessive DNA repair disorders are associated with neuropathies, including trichothiodystrophy, Werner syndrome, and ataxia-telangiectasia. Cockayne syndrome has classically been linked to demyelinating polyneuropathies, whereas xeroderma pigmentosum has long been associated with axonal polyneuropathies. Chronic motor, sensory, and sensorimotor polyneuropathies have all been observed in affected individuals, with specific physiologies associated with different categories of DNA repair disorders.
One part of the nervous system that is impaired in certain DNA repair disorders is the peripheral nerve. The consequences of a genetic defect affecting a component of this delicate mechanism are quite harmful, characterized by a cascade of premature aging that injures a variety of organs, including the nervous system. Intensity and precocity of signs are dependent on the gene involved groups A, C, D and G are associated with a more severe disease.Repair of genomic DNA is a fundamental housekeeping process that quietly maintains the health of our genomes.
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