CTH

Cystathionine gamma-lyase (CTH) is a key enzyme in sulfur metabolism, responsible for breaking down cystathionine into cysteine, ammonia, and 2-oxobutyrate in the trans-sulfuration pathway. 

Beyond amino acid metabolism, CTH plays a crucial role in hydrogen sulfide (H₂S) production, influencing cardiovascular health, oxidative stress regulation, neuroprotection, and tumor progression, making it a potential biomarker for various metabolic and pathological conditions.

What is Cystathionine Gamma-Lyase (CTH)?

The Cystathionase Gamma-Lyase, or CTH, gene encodes the CTH protein.

Cystathionine Gamma-Lyase (CTH), or Cystathionase, is a pyridoxal-5'-phosphate (PLP)-dependent enzyme that plays a central role in sulfur metabolism. It catalyzes the breakdown of cystathionine into cysteine, ammonia, and 2-oxobutyrate, a key step in the trans-sulfuration pathway.

Beyond its role in amino acid metabolism, CTH is essential for hydrogen sulfide (H2S) production, which regulates:

• Vascular tone and angiogenesis (cardiovascular health)
• Oxidative stress and inflammation (immune and metabolic regulation)
• Neuroprotection and neurotransmission

CTH dysfunction has been implicated in metabolic, cardiovascular, neurodegenerative, and oncologic diseases, making it a potential biomarker for disease diagnosis and progression.

CTH Mutations and CTH Deficiency

Mutations in the CTH gene can lead to impaired enzyme activity, affecting sulfur metabolism and H2S production. These mutations disrupt PLP binding, reducing enzymatic function and causing metabolic imbalances. 

Diseases associated with CTH deficiency include:

Cystathioninuria & Hypercystathioninemia

Cystathioninuria is a rare autosomal recessive disorder caused by CTH gene mutations, impairing cystathionine breakdown in the trans-sulfuration pathway. This leads to cystathionine accumulation in blood (hypercystathioninemia) and urine (cystathioninuria).

Generally benign and asymptomatic, cystathioninuria may occasionally be associated with mild neurological symptoms (cognitive impairment, tremors, seizures), though these links remain uncertain.

Cardiovascular Disease & Hypertension

CTH-derived H2S is a key vasodilator, regulating blood pressure and endothelial function.

In the cardiovascular system, CTH deficiency can cause:

• Impaired vasodilation → Increased vascular resistance and hypertension
• Smooth muscle hyperproliferation, increasing atherosclerotic risk

Low CTH levels contribute to high blood pressure and a higher risk of artery blockage.

Neurodegenerative Diseases & Cognitive Dysfunction

CTH plays a critical role in brain health by producing H2S, which supports neurotransmission, reduces oxidative stress, and controls inflammation in the nervous system. 

When CTH function is impaired, H2S levels become dysregulated, which may contribute to the development of neurodegenerative diseases such as Alzheimer's and Parkinson's. Without adequate H2S, the brain is more vulnerable to oxidative damage and inflammation, both of which are key drivers of neurodegeneration. 

Additionally, CTH deficiency can lead to a mild increase in homocysteine levels, a known risk factor for cognitive decline. Elevated homocysteine has been linked to neuronal toxicity, which may increase the risk of memory loss and impaired brain function. 

These findings suggest that CTH dysfunction could play a role in accelerating cognitive decline and neurodegenerative disease progression.

Glioblastoma (GBM) and Cancer Progression

In glioblastomas, CTH expression is significantly upregulated, which has been linked to poor survival rates and resistance to therapy. 

CTH contributes to tumor progression by increasing the expression of stemness markers such as SOX2, promoting tumor cell proliferation, and enhancing oxidative stress resistance through hydrogen sulfide (H₂S) production. 

This resistance allows tumor cells to survive and thrive in stressful environments, making them more difficult to target with conventional treatments. 

Peripheral Vascular Disease and Ischemia Recovery

CTH is important in angiogenesis, particularly through NAD-dependent pathways that regulate blood vessel formation and repair. 

In cases of ischemic injury, CTH overexpression has been shown in animal models to enhance endothelial cell proliferation, improving blood flow recovery and supporting tissue healing. Conversely, CTH deficiency impairs neovascularization, leading to poor functional recovery following ischemic events. 

Who Should Get CTH Tested?

CTH testing may provide valuable insights for patients with:

Cardiovascular Risks

Elevated homocysteine is linked to hypertension, atherosclerosis, and vascular inflammation. CTH activity may influence these processes.

Liver diseases: Patients with cirrhosis, hepatitis, or non-alcoholic fatty liver disease (NAFLD) may have altered sulfur metabolism, making CTH a potential marker for liver dysfunction.

Metabolic Disorders

Disruptions in CTH activity can lead to imbalances in sulfur-containing amino acids, potentially contributing to metabolic dysfunctions.

Inflammatory and Oxidative Stress Conditions

As CTH-derived H2S regulates redox balance and inflammatory responses, abnormal levels may be relevant in inflammatory conditions.

Test Procedure and Interpretation

Testing for CTH is often performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for CTH genetic testing are considered to be without mutations that can alter the activity of the CTH proteins.

Clinical Implications of Positive CTH Mutations

The clinical implications of a positive CTH mutation test result will vary by individual, although CTH mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of various symptoms.

Patients or practitioners with questions about the clinical implications of CTH mutations should seek further assessment with a genetic counselor or expert. 

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