ALDH6A1

The ALDH6A1 gene encodes the mitochondrial enzyme methylmalonate semialdehyde dehydrogenase (MMSDH), predominantly expressed in the liver, kidney, and heart, with lower levels in muscle and brain. 

This enzyme, part of the aldehyde dehydrogenase (ALDH) family, is crucial in the catabolism of valine, pyrimidine, leucine, isoleucine, uracil, and thymine, and is unique as the only Co-A dependent aldehyde dehydrogenase. 

MMSDH plays a significant role in detoxifying harmful aldehydes, converting them to less toxic acids, thereby protecting cells and mitochondria from oxidative stress. Specifically, it converts methylmalonate semialdehyde to propionyl-CoA and malonate semialdehyde to acetyl-CoA. 

ALDH6A1 is upregulated during lipogenesis and is involved in the maturation of fibroblasts into adipocytes. It is also linked to age-related cardiac degeneration and is vital for GABA metabolism, influencing various pathologies including cancer. 

Deficiency in MMSDH due to ALDH6A1 mutations leads to the accumulation of specific metabolites, resulting in conditions like methylmalonate semialdehyde dehydrogenase deficiency, often accompanied by psychomotor delay, and a poorer prognosis in certain cancers.

What is ALDH6A1? [1., 3., 4.] 

The ALDH6A1 gene encodes a mitochondrial enzyme known as methylmalonate semialdehyde dehydrogenase (MMSDH). It is found in high levels in the liver, kidney and heart

and at lower levels in muscle and brain. [7.] 

This enzyme belongs to the aldehyde dehydrogenase (ALDH) protein family and is involved in the catabolism of valine and pyrimidine, as well as in the catabolism of leucine and isoleucine, uracil and thymine. [6., 8.]  It is the only known Co-A dependent aldehyde dehydrogenase. [7.]

MMSDH is particularly important in the detoxification processes by converting toxic aldehydes, which cause oxidative stress by damaging cells and mitochondria, into their corresponding acids. [10.] 

MMSDH specifically converts methylmalonate semialdehyde to propionyl-CoA and malonate semialdehyde to acetyl-CoA. [7.] 

ALDH6A1 is upregulated during lipogenesis, specifically in the maturation of fibroblasts into mature adipocytes. [7.] 

It is also known as a cardiac protein, and has been associated with age-related cardiac degeneration in aged rats. [7.] 

ALDH6A1 and other ALDH isoforms are also associated with the metabolism of GABA. [11.] GABA is a neurotransmitter that, when dysregulated, can contribute to various pathologies including cancer. 

Specifically, ALDH6A1 is implicated in the conversion of γ-aminobutyraldehyde to γ-aminobutyric acid (GABA).

The enzyme 4-aminobutyrate aminotransferase and ALDH6A1 are significantly reduced in ccRCC patients, affecting GABA metabolism and correlating with poorer survival. Overexpression of ALDH6A1 has been shown to impair tumor metabolism of ccRCC cells, indicating its role in maintaining normal cellular function, at least in part through its involvement in GABA metabolism. [9.] 

Deficiency in this enzyme leads to the accumulation of specific metabolites such as beta-alanine, 3-hydroxypropionic acid, and isomers of 3-amino and 3-hydroxyisobutyric acids in urine. 

Its dysfunction is associated with disorders like methylmalonate semialdehyde dehydrogenase deficiency and several cancers.  Its deficiency is not well characterized, but is known to be accompanied by psychomotor delay. [7.]  

ALDH6A1 in Health and Disease

ALDH6A1 and Methylmalonate Semialdehyde Dehydrogenase Deficiency [6.] 

Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is a rare autosomal recessive metabolic disorder resulting from mutations in the ALDH6A1 gene. 

The disorder presents with a highly variable clinical phenotype, ranging from severe developmental delays and dysmyelination to transient elevations in metabolites such as lactate, methylmalonic acid, 3-hydroxyisobutyric acid, and 3-aminoisobutyric acid. 

Biochemically, patients exhibit elevated levels of various acids in urine, including 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric, and methylmalonic acids, as well as β-alanine. 

Genetic studies have identified compound heterozygous mutations, such as c.514T>C (p.Tyr172His) and c.1603C>T (p.Arg535Cys), which occur in conserved residues and are predicted to be damaging to the protein's function. 

Reduced MMSDH enzyme activity has been demonstrated in patient fibroblasts, confirming the functional impact of these mutations. 

Diagnosis of MMSDH deficiency is challenging due to the clinical and biochemical variability that is present. 

Research suggests that MMSDH deficiency may be under-recognized, partly due to the normalization of biochemical abnormalities over time, highlighting the need for increased awareness and improved diagnostic strategies for this rare metabolic disorder. [6.] 

ALDH6A1 in Hepatocellular Cancer [10.] 

Aldehyde dehydrogenases (ALDHs) are a family of enzymes crucial for the detoxification of aldehydes, which are byproducts of alcohol metabolism and other cellular processes. 

In hepatocellular carcinoma (HCC), several ALDHs, including ALDH1B1, ALDH1L1, ALDH2, ALDH4A1, ALDH5A1, ALDH6A1, ALDH7A1, ALDH8A1, and ALDH9A1, are significantly downregulated. This downregulation correlates with poorer clinical outcomes, advanced cancer stages, and higher tumor grades.

In HCC, ALDH6A1 expression is notably downregulated, both at the mRNA and protein levels compared to normal liver tissues. 

This downregulation is significantly associated with advanced tumor stages, higher tumor grades, and poorer prognosis, especially in Asian patients. [10.] Lower expression levels of ALDH6A1, alongside other aldehyde dehydrogenase (ALDH) family members, indicate a worse prognosis and are linked to increased malignancy in HCC.

ALDH6A1 in Prostate Cancer [2.] 

ALDH6A1 genes may be upregulated in aggressive and metastatic prostate cancer, making them a potential marker for survival in late metastatic cancer. [2.] 

One study demonstrated that ALDH6A1 was strongly expressed in aggressive prostate cancers and lymph node metastases but showed reduced expression in bone metastases. In the same study, ALDH6A1 expression was significantly associated with lymphatic invasion, indicating its role in cancer metastasis. [2.] 

ALDH6A1 in Clear Cell Renal Cell Carcinoma [5.] 

In clear cell renal cell carcinoma (ccRCC), the enzyme ALDH6A1 (aldehyde dehydrogenase 6 family, member A1) has anti-tumorigenic effects. 

Along with ABAT (gamma-aminobutyric acid transaminase), ALDH6A1 is regulated by the transcription factor HNF4A. Both enzymes are significantly downregulated in ccRCC tissues, and their low expression correlates with poor survival outcomes. 

Functionally, overexpression of ALDH6A1 in ccRCC cell lines significantly decreases cell proliferation and migration and impairs oncologic metabolism by reducing lactate production and the NADPH/NADP+ ratio.

Patients with lower levels of ALDH6A1 tend to have worse prognoses. 

In summary, ALDH6A1 acts as a tumor suppressor in ccRCC by being involved in critical metabolic pathways and is regulated by HNF4A. Its downregulation is associated with increased tumorigenic potential and poor patient outcomes, making it a significant focus for potential therapeutic interventions.

ALDH6A1 in Bladder Cancer [9.] 

Overall, ALDH6A1 appears to function as a tumor suppressor in bladder cancer, where its decreased expression is associated with advanced disease stages, resistance to chemotherapy, and poorer patient prognosis.

ALDH6A1, an important detoxification enzyme, is remarkably downregulated in bladder cancer tissues and cell lines compared to normal tissues. [9.] 

Low expression of ALDH6A1 is positively associated with advanced cancer subtypes and cisplatin resistance, suggesting that reduced levels of this enzyme are indicative of a more aggressive and treatment-resistant form of bladder cancer.

The downregulation of ALDH6A1 in bladder cancer is linked to poorer outcomes in patients. [9.]  This implies that ALDH6A1 could serve as a predictive biomarker for bladder cancer prognosis.

Genetic Alterations in the ALDH6A1 Gene

The gene for the ALDH6A1 protein may contain alterations or mutations that cause increase or decrease of function of the ALDH6A1 protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Specific SNPs Associated with Alterations in ALDH6A1 Function 

The following ALDH6A1 SNPs have been researched to better understand the health consequences associated with these genetic mutations. 

c.514 T > C; p. Tyr172His [6.]

This mutation in the ALDH6A1 gene results in a tyrosine-to-histidine substitution at position 172. This specific SNP is associated with:

Severe Developmental Delays:

• Significant delays in reaching developmental milestones, such as sitting with assistance and an inability to crawl or pull to stand, have been noted.

Neurological Abnormalities:

• Delayed Myelination: Brain MRI showed a diffuse delay in myelination, indicating substantial neurological impact.

• Hypotonia: The patient presented with markedly decreased axial tone.

• Visual Fixation and Tracking Difficulties: These were observed early in development.

Biochemical Abnormalities:

• Elevated Plasma and Urine Methylmalonic Acid (MMA): fluctuating levels of MMA were noted.

• Elevated Plasma Lactate: elevated lactate levels have been noted, indicating a possible mitochondrial dysfunction or metabolic acidosis.

• Elevated Urine 3-Hydroxyisobutyric Acid

Physical Dysmorphisms:

• Square Face Shape: with slight frontal bossing, a tall forehead, and sparse hair temporally have all been observed.

• Ocular Findings: including skin folds over upper eyelids and increased distance between eyes.

• Nose and Mouth Anomalies: short and anteverted, or tilted upward, nose with a broad, flat base, and a tented mouth with a high-arched palate.

• Unusually Wide Big Toes: Noted bilaterally, along with a single palmar crease on the right palm.

c.1603C > T; p. Arg535Cys SNP [6.] 

The c.1603C > T; p. Arg535Cys mutation in the ALDH6A1 gene results in an arginine-to-cysteine substitution at position 535. This specific SNP is associated with:

Severe Developmental Delays:

• Similar to the other mutation, this SNP contributed to the patient’s significant delays in developmental milestones.

Neurological Abnormalities:

• Diffuse Delay in Myelination: Observed in brain MRI, showing slow progression in myelination over time.

• Thin Corpus Callosum: MRI revealed a diffusely thin corpus callosum.

• Dystonia: Inappropriate coordination and dystonic movements were noted.

Biochemical Abnormalities:

• Variable Elevated Plasma Lactate: The patient had periods of elevated lactate levels, independent of clinical status.

• Elevated Urine 3-Aminoisobutyric Acid and β-Alanine: Persistent elevated levels indicating metabolic abnormalities.

• Elevated Urine 3-Hydroxyisobutyric Acid: Detected through GCMS profiles.

Enzyme Activity:

• Reduced MMSDH Enzyme Activity: Fibroblast studies demonstrated reduced activity of MMSDH, indicating that the mutation leads to a loss of function of the enzyme.

Laboratory Testing for ALDH6A1

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home. 

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing. Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

ALDH6A1 Related Biomarkers

Other Aldehyde Dehydrogenase Enzymes

Including genetic testing for other detoxification enzymes, particularly those in the aldehyde dehydrogenase family, can provide further information regarding an individual’s health risks, particularly involving cancer.  

Several other members of the aldehyde dehydrogenase (ALDH) enzyme family have been implicated in various diseases, especially cancer. 

For instance, ALDH1A1, ALDH2 and ALDH3A2 have been studied as potential biomarkers for cancer stem cells, for monitoring cancer progression and determining prognosis, and alcohol-related disorders. 

Evaluating the levels of these enzymes alongside ALDH6A1 may provide insights into the interplay between different ALDH isoforms and their roles in disease pathogenesis.

FAQ: ALDH6A1 (Aldehyde Dehydrogenase 6 Family Member A1)

What is ALDH6A1?

ALDH6A1 (Aldehyde Dehydrogenase 6 Family Member A1) is an enzyme that belongs to the aldehyde dehydrogenase family. It plays a role in the metabolism of certain aldehydes and is involved in various biochemical pathways, including the breakdown of branched-chain amino acids and fatty acids.

What is the Function of ALDH6A1 in the Body?

ALDH6A1 is involved in:

• Detoxification: Converting toxic aldehydes into less harmful acids, thus protecting cells from oxidative stress and damage.

• Metabolism: Participating in the metabolic pathways of branched-chain amino acids and fatty acids, which are important for energy production and cellular function.

What is ALDH6A1 Deficiency?

ALDH6A1 deficiency, also known as Methylmalonate Semialdehyde Dehydrogenase Deficiency, is a rare genetic disorder caused by mutations in the ALDH6A1 gene, leading to reduced or absent enzyme activity.

This deficiency can disrupt normal metabolic processes and result in the accumulation of toxic substances in the body.

What are the Symptoms of ALDH6A1 Deficiency?

Symptoms of ALDH6A1 deficiency can vary but may include:

• Developmental delays

• Intellectual disabilities

• Neurological issues, such as seizures or movement disorders

• Metabolic abnormalities, which may lead to fatigue, weakness, or other systemic symptoms

How is ALDH6A1 Deficiency Diagnosed?

ALDH6A1 deficiency is diagnosed through genetic testing to identify mutations in the ALDH6A1 gene. 

Additional tests, such as enzyme activity assays and metabolic profiling, can help confirm the diagnosis by measuring the levels of specific metabolites in the blood and urine.

What are the Health Implications of ALDH6A1 Deficiency?

ALDH6A1 deficiency can lead to several health issues, including:

• Neurological disorders: Developmental delays, intellectual disabilities, and other neurological symptoms due to the accumulation of toxic metabolites.

• Metabolic disorders: Disruptions in normal metabolic processes that can affect energy production and overall health.

• Systemic symptoms: Generalized fatigue, weakness, and other symptoms related to impaired metabolism.

How is ALDH6A1 Deficiency Managed?

Management of ALDH6A1 deficiency involves:

• Symptom management: Treating specific symptoms, such as neurological issues, with appropriate medications and therapies.

• Nutritional support: Providing a specialized diet that avoids certain amino acids and fatty acids that cannot be properly metabolized.

• Regular monitoring: Regular check-ups with healthcare providers to monitor metabolic function and overall health.

Can Lifestyle Changes Affect ALDH6A1 Deficiency?

While lifestyle changes cannot directly affect the genetic basis of ALDH6A1 deficiency, certain measures can help manage symptoms and improve quality of life:

• Dietary modifications: Following a specialized diet tailored to reduce the intake of specific amino acids and fatty acids.

• Regular exercise: Engaging in appropriate physical activity to support overall health and well-being.

• Avoiding stress and infections: Managing stress and avoiding infections that can exacerbate metabolic symptoms.

Where Can I Find More Information About ALDH6A1 and Related Conditions?

For more information about ALDH6A1 and related conditions, consider consulting:

• Healthcare providers: Medical professionals can provide personalized advice and diagnosis.

• Scientific literature: Research articles and reviews on ALDH6A1 and its role in metabolism and health.

• Reputable health organizations: Websites of organizations such as the National Institutes of Health (NIH), Genetic and Rare Diseases Information Center (GARD), and American Society of Human Genetics (ASHG).

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