GENETIC MUTATIONS

The field of genetics is relatively young. We are still searching for all the genetic connections impacting our ability to remove toxins from our bodies. Some connections have already been found. Bearing in mind that genes are not always expressed (turned on) we are seeing genetic predispositions to heavy metal toxicity.

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THE IMPACT OF GENETIC VARIATION ON METABOLISM OF HEAVY METALS: GENETIC PREDISPOSITION?

The study of genetic variations and their interactions with environmental factors can provide an extra chance to elucidate individuals’ susceptibility to heavy metals. Nowadays, it is well-known that the genetic based factors and in general genetic background are just one part of a bigger complex in defining heavy metal sensitive individuals. In here, other internal and external elements are playing a substantial role. Such inter-individual genetic differences, along with other environmental factors can make a unique phenotype and consequently a distinctive response of individuals to encountered toxins. Therefore, identification of variations in head related genes, as well as their interactions with other environmental factors will provide important data not only about the individual differences and identification of susceptible groups, but also for developing novel preventively or/and therapeutic approaches.

In this review, we briefly discussed various experiments investigating genetic variations in different genes, which are directly (MT, GST, etc.) or indirectly (PON1, MTHFR, etc.) related to heavy metals and their body metabolisms. 

Joneidi, Zeinab et al. “The impact of genetic variation on metabolism of heavy metals: Genetic predisposition?.” Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie vol. 113 (2019): 108642. doi:10.1016/j.biopha.2019.108642

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ASSOCIATION BETWEEN MTHFR C977T/A1298C AND SUSCEPTIBILITY TO AUTISM SPECTRUM DISORDERS: A META-ANALYSIS

The findings of the meta-analysis indicated that MTHFR C677T polymorphism is remarkably associated with ASD in the five genetic models, viz., allelic, dominant, recessive, heterozygote, and homozygote. However, the MTHFR A 1298C polymorphism was not found to be significantly related to ASD in the five genetic models. Subgroup analyses revealed significant associations of ASD with the MTHFR (C677T and A1298C) polymorphism.

Li, Yan et al. “Association between MTHFR C677T/A1298C and susceptibility to autism spectrum disorders: a meta-analysis.” BMC pediatrics vol. 20,1 449. 24 Sep. 2020, doi:10.1186/s12887-020-02330-3

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GENETIC DISORDERS ASSOCIATED WITH METAL METABOLISM

Metabolic disorders related to metals are regarded as quintessential single-gene disorders. However, in recent years, advances in next-generation sequencing and other advanced technologies have revealed that the classical "one gene–one enzyme" paradigm is not always the culprit. It has been reported that defects in multiple genes may lead to the same phenotypic presentation. Furthermore, mutations in different domains of the same protein might produce a difference in the phenotypes. Thus, it very difficult to pin-point a specific mutation and proceed with therapeutic strategies as different mutations respond differently during therapy. This process is not homogeneous across diseases and specific mutations.
In addition, next-generation sequencing has also shown that affected individuals with hybrid phenotypes might have mutations in more than two different genes that are responsible for causing more than two phenotypes in the same individual, which leads to a complex phenotype. Such complex genetic disorders are very difficult to diagnose and become increasingly difficult to manage with a therapeutic plan. Newly discovered disease-causing genes and disorders associated with metal metabolism have provided us with insight into the basics of the micronutrients that are required for the proper maintenance of the human body. Advances in the fields of molecular diagnostics and precision medicine have allowed us to understand more about the metabolism, regulation, and functions of these micronutrients, which will ultimately lead to new therapeutic strategies. However, we still have a lot to learn.

Umair, Muhammad, and Majid Alfadhel. “Genetic Disorders Associated with Metal Metabolism.” Cells vol. 8,12 1598. 9 Dec. 2019, doi:10.3390/cells8121598

MTHFR DEFICIENCY IN BIOLOGICAL SIBLINGS DIAGNOSED WITH AUTISM AND ATTENTION-DEFICIT HYPERACTIVITY DISORDER (ADHD): A REPORT OF TWO CASES

Much research has been dedicated to learning about one of the most important enzymes involved in folate metabolism and pathways involving catecholamine neurotransmitters. The MTHFR C677T mutation is the most common MTHFR mutation. In fact, the MTHFR 677CT mutation is found to be among the genes associated with the increased risk for autism in individuals and is further found in mothers of kids with autism. This, by no means, is a direct correlation of MTHFR C677T to the diagnosis of ASD since ASD and its variability is due to multiple cofactors between genes and multiple environmental factors.
Decreased MTHFR activity, which results in decreased folate metabolism, can be seen in multiple psychiatric illnesses such as schizophrenia, bipolar disorder, depression, ASD, and ADHD. As discussed, research indicates the positive effects of l-methylfolate as adjunctive therapy for certain mental health illnesses. Nevertheless, more research using behavioral scales studying the acute and chronic changes in mood and behaviors with and without the supplement in patients with behavioral health needs would be beneficial and be able to add to the medical knowledge within behavioral health. Studies have yet to show concrete evidence that folate supplements can be helpful in treating mental health illness, but they have demonstrated the importance of being able to detect the MTHFR deficiency in patients with and without mental health illnesses in order to develop a strategic treatment plan to help treat the individual with specific supplements such as folate, L-methylfolate, folic acid, and/or cobalamin.
Khan, Samira, and Abeera Naeem. “MTHFR Deficiency in Biological Siblings Diagnosed With Autism and Attention-Deficit Hyperactivity Disorder (ADHD): A Report of Two Cases.” Cureus vol. 15,3 e36294. 17 Mar. 2023, doi:10.7759/cureus.36294

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ROLE OF MTHFR 677C>T AND 1298A>C GENE POLYMORPHISMS ON RENAL TOXICITY CAUSED BY LEAD EXPOSURE IN WASTEWATER TREATMENT PLANT WORKERS
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The WWTP workers carrying MTHFR 677TT as well as MTHFR 1298CC are more vulnerable to elevation of the Pb excretion in their urine, and elevation in the homocysteine levels than the workers carrying MTHFR 677CC/CT or MTHFR 1298AA/AC, respectively. These elevations in Pb and homocysteine, as well as MDA, could lead to elevation in the urea and creatinine among them. Therefore, the polymorphisms of these two genes could be used as predictor gene susceptibility to kidney impairments among those sludge exposed workers.

Saad-Hussein, Amal et al. “Role of MTHFR 677C>T and 1298A>C gene polymorphisms on renal toxicity caused by lead exposure in wastewater treatment plant workers.” Environmental science and pollution research international vol. 30,35 (2023): 84758-84764. doi:10.1007/s11356-023-28309-y