The MTRR gene plays a vital role in keeping your cells healthy by recycling vitamin B12, essential for many bodily functions. It helps convert homocysteine into methionine, supporting critical processes like DNA repair and brain function.

However, mutations in the MTRR gene disrupt this, leading to elevated homocysteine and various health issues. Researchers primarily link the A66G mutation to cardiovascular problems and developmental delays.

This article will explore:

  • Critical symptoms of MTRR mutations.
  • How these mutations disrupt vitamin B12 metabolism.
  • Health risks like neural tube defects and heart issues.
  • A closer look at the A66G mutation and its impact.

What is the MTRR Gene?

The MTRR gene on chromosome 5 produces an enzyme vital for turning homocysteine into methionine. This process supports DNA methylation and protein production. When MTRR mutations happen, they can mess up DNA methylation and lead to different health problems.

What is the Normal Function of the MTRR Gene?

The MTRR gene helps reactivate methionine synthase. This enzyme is needed to convert homocysteine into methionine, an essential amino acid. 

When methionine synthase becomes inactive, MTRR reacts to it, ensuring that essential processes like protein synthesis, detoxification, and DNA methylation can carry on without interruption.

Enzymes and co-factors interacting with MTRR: Methionine synthase, flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), cobalamin, S-adenosylmethionine (SAM), folate. 

MTRR Gene Mutation Symptoms

Mutations in the MTRR gene can interfere with methylation-related processes, causing increased homocysteine levels and a range of clinical symptoms. These mutations are typically inherited in an autosomal recessive manner, and the severity of symptoms can differ from person to person.

Common symptoms:

  • Cardiovascular disorders
  • Neural tube defects
  • Fatigue and cognitive issues

Elevated Homocysteine Levels

Hyperhomocysteinemia occurs when the body cannot efficiently convert homocysteine into methionine, disrupting normal metabolic processes. This can lead to:

  • Cardiovascular disease (heart attack, stroke)
  • Neural tube defects
  • Cognitive decline
  • Osteoporosis
  • Increased risk of blood clots 

High homocysteine levels have also been associated with an increase in inflammatory markers, further raising cardiovascular risks.

Neurological Symptoms

A disrupted methylation cycle impacts cognitive function and can lead to neurological issues. It also causes homocysteine to build up, harming the brain.

According to a study by Chih-Chia Huang, a patient with MTRR mutations had hyperhomocysteinemia, folic acid deficiency, schizophrenia, and seizures. Researchers from Cell Science Systems also found a difference between A66G polymorphism and intellectual disabilities and developmental delays.

Psychological Impact

Mutations in the MTRR gene can contribute to intellectual disabilities and conditions along the autism spectrum. Likewise, mutations in other genes, such as COMT mutation symptoms, can impact cognitive and psychological health. Disrupted methylation affects brain development, causing cognitive delays and social challenges.

Psychological assessments:

  • A report by the News Center indicates that MTRR mutations often cause intellectual disability, affecting cognitive function and emotional regulation.
  • BioMed Central and MDPI also confirmed that these mutations are also linked to autism spectrum disorders, causing social communication challenges and repetitive behaviors. 

Developmental Delays

Mutations in the MTRR gene can slow physical, cognitive, and social progress, often leading to speech delays or motor skill difficulties.

Affected developmental areas: 

  • Speech and language development
  • Cognitive abilities
  • Motor skills
  • Social interaction

Anemia

MTRR mutations disrupt how vitamin B12 and folate are processed. These are vital for making DNA and healthy red blood cells, and issues with red blood cell production can affect health and energy levels.

Types of anemia commonly observed:

  • Megaloblastic anemia (due to vitamin B12 and folate deficiencies)
  • Pernicious anemia (caused by impaired absorption of vitamin B12)
  • Macrocytic anemia (characterized by enlarged red blood cells)​

How Does the MTRR Gene Mutation Affect the Body?

When the MTRR gene mutates, it disrupts essential processes like folate metabolism and protein production, causing higher homocysteine levels and metabolic issues. These mutations can also lead to oxidative stress and DNA damage and worsen neurological and developmental problems.

Health Conditions Related to MTRR Gene Mutations

MTRR gene mutations can harm overall health by increasing homocysteine levels and interfering with crucial body functions. These issues are linked to severe conditions like homocystinuria, neural tube defects, congenital disabilities, and a higher chance of Down syndrome.

Homocystinuria

Homocystinuria is a rare genetic disorder that prevents the body from adequately processing certain amino acids, causing a build-up of homocysteine in the blood and urine. Elevated homocysteine can harm various systems in the body, and gene mutations affecting the enzymes that break down homocysteine usually cause this condition.

Symptoms: 

  • Eye lens dislocation
  • Developmental and learning delays
  • Risk of blood clots, strokes, or embolism

Birth Defects

MTRR mutations interfere with the body’s ability to properly utilize folic acid, critical for early brain and spinal cord development. This leads to neural tube defects and is a factor in developmental delays, affecting cognitive and motor skills in children. 

Congenital disabilities linked to MTRR mutations:

  • Spina bifida (incomplete closure of the spine)
  • Anencephaly (missing parts of the brain and skull)
  • Encephalocele (brain protrusion through the skull)​

Neural Tube Defects

The MTRR gene supports folate metabolism and proper neural tube formation during fetal development. Mutations like the A66G polymorphism disrupt DNA methylation and increase the risk of neural tube defects

Key statistics:

Down Syndrome

Problems with folate metabolism can affect chromosome division, raising the risk of trisomy 21. Since folate is essential for DNA methylation and fetal development, these issues can lead to developmental delays, making mutations in folate metabolism a critical factor in these conditions.

Meta-analyses show that the A66G polymorphism in MTRR, especially with other folate gene mutations, may increase the risk of Down syndrome. This mutation is also more common in mothers of children with Down syndrome.

What is the MTRR A66G Mutation?

Replacing adenine with guanine at position 66 in the A66G mutation reduces the enzyme’s ability to recycle vitamin B12. This disrupts the methylation cycle and the conversion of homocysteine to methionine.

The prevalence of the A66G mutation varies by population, with studies showing a 28.65% prevalence in Hispanics and 54.4% in Caucasians.

Impact of the MTRR A66G Mutation

As mentioned earlier, the MTRR A66G mutation affects the methionine synthase reductase enzyme, vital for vitamin B12 recycling and methylation. This mutation reduces enzyme activity, causing homocysteine build-up and disruptions in high-metabolism tissues

Conditions correlated with this mutation:

  • Neural tube defects 
  • Down syndrome
  • Cardiovascular diseases
  • Cancer risk (e.g., colorectal cancer)
  • Homocystinuria

Vitamin B12 Utilization Problems

The A66G mutation affects how the body uses vitamin B12 by lowering the activity of methionine synthase, an important enzyme that helps recycle vitamin B12. This disruption causes higher homocysteine levels and interferes with the methylation cycle, affecting vital metabolic processes in the body.

Possible Association with Disease

The A66G mutation in the MTRR gene disrupts vitamin B12 recycling, which can raise homocysteine levels and contribute to:

  • Neural tube defects
  • Congenital heart defects 
  • Prostate cancer
  • Cardiovascular diseases

It impairs DNA synthesis and causes metabolic dysfunction by raising homocysteine levels. Individuals with this mutation often exhibit elevated glucose and triglycerides. When combined with MTHFR polymorphisms, it increases prostate cancer risk.

Increased Homocysteine Levels

The A66G mutation reduces the activity of methionine synthase reductase, which is essential for recycling vitamin B12. As a result, homocysteine levels rise because it’s not correctly converted into methionine, leading to homocystinuria

High homocysteine levels increase the risk of cardiovascular diseases and neurodegenerative disorders. Additionally, this mutation disrupts metabolism and DNA synthesis, heightening the chances of congenital disorders and developmental issues.

Detection and Management of MTRR A66G Mutation

The MTRR A66G mutation is diagnosed through genetic testing, typically using methods like PCR-RFLP. This method amplifies DNA to identify specific mutations in the gene.

Management strategies include:

  • Taking methyl donors like B12 and folic acid.
  • Adding methionine supplements for methylation.
  • Monitoring homocysteine levels to lower cardiovascular risks.
  • Increasing folate and B12-rich foods in your diet.

Key Takeaways

  • The MTRR gene is essential for recycling vitamin B12, necessary for DNA methylation.
  • A66G mutations increase homocysteine levels, raising the risk of neural tube defects, cardiovascular disease, and Down syndrome.
  • Common symptoms include cognitive impairment, fatigue, and developmental delays.
  • Management involves genetic testing, vitamin B12 and folic acid supplementation, and regular homocysteine monitoring.

Frequently Asked Questions

Is the MTRR Gene Mutation Hereditary?

Yes, MTRR gene mutations are hereditary. They are inherited in an autosomal recessive pattern, meaning both parents must pass on a copy of the mutated gene for the condition to manifest in the child. 

Who Should Get Tested for an MTRR Gene Mutation?

Genetic testing is recommended for people with a family history of neural tube defects, cardiovascular diseases, or high homocysteine levels. Pregnant women or those planning pregnancy may also need testing for folate metabolism concerns.

Can MTRR Gene Mutations Be Treated?

Yes, MTRR gene mutations can be treated. The treatment involves vitamin B12, folic acid supplements, regular homocysteine monitoring, and dietary adjustments to reduce complications.