The role of oxidative stress in congenital syndromes

The role of oxidative stress in congenital syndromes

Children born with various syndromes caused by genetic or acquired factors have been the focus of numerous clinical and scientific studies. It is important to both understand the underlying mechanism and to alleviate the condition if possible.

A recent one Antioxidants The review addresses the role of oxidative stress in genetic disorders such as trisomy 21 (Down syndrome, DS), Marfan syndrome (MFS), and fetal alcohol spectrum disorders (FASD). This information has the potential to support the development of more specific and effective preventive and/or therapeutic strategies in the future.

Learn: The influence of oxidative stress on pediatric syndromes.Image source: SciePro / Shutterstock.com

introduction

Oxidative stress is the condition in which antioxidant activity is unable to buffer the activity of oxidizing species in the body. This is largely due to the overproduction of oxidizing species, including radical oxygen species (ROS); However, it could also be due to low ROS levels.

Oxidizing species

ROS mediate a variety of useful functions, including killing pathogens during inflammatory responses or regulating cardiovascular function and protein activation. However, when ROS are not adequately regulated by cellular antioxidants, they can cause tissue damage and organ dysfunction.

ROS include superoxide (O2-), hydroxyl (OH-) and hydrogen peroxide (H2O2). O2- is the most stable and primary ROS from which the other two are derived. The most harmful ROS is OH- as it can damage DNA, proteins, lipids and carbohydrates.

Superoxide anions are formed in the mitochondria through a misstep in the electron transport chain (ETC), which is responsible for the formation of the energy-rich molecule adenosine triphosphate (ATP).

The production of O2- during this process is more likely when the cell produces excess ATP, leading to a reduction in ETC activity, or there is a stress-induced uncoupling of some parts of the ETC. ROS can also arise from smoking, exposure to ozone or ionizing radiation, ultraviolet radiation and some heavy metals.

The effects of ROS production include DNA breaks and other types of damage that can lead to cancer, accelerated aging, neurodegenerative diseases, autoimmune diseases or cardiovascular diseases. Epigenetic changes that alter DNA repair can also occur.

Antioxidants

Antioxidants belong to enzymatic and non-enzymatic groups. Enzymatic antioxidants include, among others, superoxide dismutase (SOD) in the mitochondria, reducing superoxide ions, catalases, glutathione peroxidase (GTPx), and glutathione transferases (GSTs). GTPx is known for its action in detoxifying lipid peroxides and splitting H2O2 into two water molecules.

Non-enzymatic antioxidants include vitamin E or alfa-tocoferol, carotenoids and vitamin C, which works with vitamin E, resveratrol and other plant polyphenols.

Pediatric syndromes

Several syndromes involve oxidative stress, including DS, MFS, FASD, Gaucher syndrome, ataxia-telegiectasia (AT), Fanconi anemia, autism spectrum disorders (ASD), and primitive immunodeficiencies (PIs).

FASD

FASD refers to a spectrum of cognitive and behavioral disorders in the newborn that are related to maternal alcohol consumption during pregnancy. Fetal alcohol syndrome (FAS) is the leading cause of intellectual disability worldwide and the leading cause of preventable neurodevelopmental disorders. Therefore, alcohol in any dosage is completely prohibited during pregnancy until a safe minimum is established.

The mechanism of damage in FASD is alcohol-induced oxidative stress on the developing hippocampus. This is caused by the inability of the fetus to efficiently metabolize more than half of the maternally ingested alcohol.

The resulting formation of ROS in response to the overexpression of the NOX2 and NOX4 enzymes damages the brain, particularly due to its high content of fatty acids, which represent the ideal substrate for ROS activity.

Antioxidant therapy for women who drink during pregnancy could prevent such harmful effects, several mouse experiments using vitamin E, vitamin C, astaxanthin and omega-3 fatty acids suggest.

AT

AT is a purely genetic syndrome with multiple clinical manifestations in the first 20 years of life. Of these, T-cell tumors and cerebellar ataxia are the most debilitating. The pathology lies in the Ataxia Telangiectasia Mutated (ATM) gene, which is crucial for initiating DNA repair.

As with many other genetic disorders, many of the defects are also secondary to increased ROS activity through mitochondrial dysfunction and the upregulation of other ROS sources. Oxidized low-density lipoprotein (ox-LDL) is a trigger of immune cell-mediated inflammation and vascular changes with increased DNA fragmentation.

D.S

In DS, the additional 21st chromosome is the location of the main enzymatic antioxidant SOD-1, which converts superoxide into H2O2 for further conversion into water by catalase or GTPx. The overexpression of SOD-1 by 50% in these patients, without a corresponding increase in the other two enzymes, could explain the accumulation of H2O2 and the resulting oxidative stress.

The amyloid beta-A4 precursor protein is tripled, resulting in an excess of beta-amyloid (Aβ), which is characteristic of Alzheimer's disease (AD). DS is the main cause of early-onset AD, which is related to oxidative stress as it prevents the normal cellular elimination of abnormal proteins. The accumulation of Aβ aggregates could drive lipid peroxidation.

Several other proteins and transcription factors involved in regulating antioxidant responses have been reported to be affected in DS. The oxidative stress associated with these changes may be responsible for the cognitive and intellectual disabilities associated with DS, as well as the cardiac abnormalities commonly seen in these children.

Antioxidant supplements and exercise may be helpful in reducing or improving the neurological manifestations of DS.

Other pediatric syndromes

Decreased antioxidant activity in the brain has been observed in ASD. Ongoing studies are investigating the extent to which therapy with exogenous antioxidants could help these patients.

Similar results have been reported in many other genetic syndromes, such as the accumulation of toxic metabolites with resulting ROS production in Gaucher disease, and the overproduction of H2O2 and nitric oxide (NO) caused by the aneurysmal dilatation of the aorta in MFS leads to overexpression of the ROS-producing enzymes NOX4 and SOD.

Conclusions

The current review reports that oxidative stress can cause many anatomical and physiological abnormalities in several syndromic diseases in children. While this is the primary cause of FASD, in genetic syndromes it is a secondary cause of the disease condition.

Clinically, this shows that FASD is completely preventable by avoiding oxidative stress during pregnancy. In genetic pediatric syndromes, the accumulation of oxidizing species resulting from dysregulation of multiple signaling pathways could potentially be counteracted by judicious antioxidant supplementation.

In addition to such dietary supplements, the benefits of regular exercise and a healthy diet in reducing oxidative stress should also be highlighted. Further studies are needed to determine how physicians can appropriately recommend these strategies to their patients.​​​​​​​

Reference:

• Micangeli, G., Menghi, M., Profeta, G., et al. (2022). Der Einfluss von oxidativem Stress auf pädiatrische Syndrome. Antioxidantien. doi: 10.3390/antiox11101983. https://www.mdpi.com/2076-3921/11/10/1983

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