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Reference Guide
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Adenosylhomocysteinase (AHCY), a crucial enzyme in human metabolism, is responsible for the breakdown of S-adenosylhomocysteine (SAH) into adenosine and homocysteine. 

This reaction is vital as it prevents the inhibition of methyltransferase activities, which are essential for the methylation of DNA, RNA, and proteins. AHCY's activity ensures the proper function of these molecular processes, crucial for cellular regulation and expression.

Deficiency in AHCY leads to hypermethioninemia, a condition marked by elevated methionine levels in the blood, impacting various body systems including the central nervous system, liver, and muscles. 

This can lead to developmental delays, muscular hypotonia, liver dysfunction, and in severe cases, neurological deterioration.

AHCY is expressed across various tissues, with significant levels in the kidney and thyroid, indicating its broad role in human physiology. The enzyme's importance extends to epigenetic regulation, as it is actively recruited to chromatin during critical cellular processes like replication and transcription to meet increased methylation demands.

Understanding AHCY: What is AHCY?  [1., 3., 5., 6.]

Adenosylhomocysteinase (AHCY) is a highly conserved enzyme essential for breaking down S-adenosylhomocysteine (SAH) into adenosine and homocysteine, a key reaction in preventing the inhibition of methyltransferase activities essential for DNA, RNA, and protein methylation. 

Deficiencies in AHCY can lead to hypermethioninemia. 

This enzyme is expressed ubiquitously with significant levels in the kidney and thyroid among other tissues. 

The AHCY enzyme is intricately linked with metabolic processes, epigenetic regulation, and is the sole enzyme in mammals to perform this function.  AHCY's pivotal role is underscored by its recruitment to chromatin during key cellular processes such as replication and transcription, aligning with increased methylation demands.

The AHCY Enzyme and Hypermethioninemia  [2.]

S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare metabolic disorder that specifically affects the transmethylation pathway by impairing the conversion of S-adenosylhomocysteine (SAH) to homocysteine and adenosine. 

In AHCY deficiency, the enzymatic block leads to the accumulation of SAH, a potent inhibitor of most SAM-dependent methyltransferases, resulting in a widespread disruption of essential methylation reactions. 

Consequently, this disruption can cause elevated levels of methionine in the blood, a condition known as hypermethioninemia.

Clinically, AHCY deficiency can vary in presentation, affecting multiple systems including the central nervous system, liver, and muscles.  Patients may exhibit developmental delays, muscular hypotonia, liver dysfunction, and in severe cases, neurological deterioration. 

The metabolic hallmark of AHCY deficiency includes elevated plasma methionine, increased SAH, normal or low total homocysteine (tHcy), and normal to decreased levels of SAM depending on the severity and specifics of the enzyme dysfunction.

Management of AHCY deficiency typically involves dietary control to manage methionine levels and supportive therapies to mitigate symptoms.  However, due to the complexity and rarity of the disorder, treatment is highly individualized, often requiring a multidisciplinary approach and ongoing monitoring.

Variations in the AHCY gene, including different transcript variants, contribute to its complexity and diverse functional impacts, including influencing methylation processes essential for various biological functions. 

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.

SNPs Associated with Alterations in AHCY Function  [3.]

Several SNPs in the AHCY gene have been associated with hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency, an autosomal recessive metabolic disorder. 

Notable mutations include:

W112X (c.335G>A) 

This nonsense mutation changes a tryptophan (Trp) codon to a stop codon at position 112, leading to a truncated AHCY protein.

Y143C (c.428A>G) 

This missense mutation substitutes a tyrosine (Tyr) with a cysteine (Cys) at codon 143, potentially affecting enzyme stability or function.

R49C (c.145C>T) 

Another missense mutation that changes an arginine (Arg) to a cysteine (Cys) at codon 49, which was found to reduce AHCY enzyme activity in red blood cells.

D86G (c.257A>G) 

This substitution of aspartate (Asp) with glycine (Gly) at codon 86 is implicated in reduced enzyme function.

T57I (c.170C>T) and V217M (c.649G>A) 

Both these missense mutations were identified in a female infant, changing threonine (Thr) to isoleucine (Ile) and valine (Val) to methionine (Met) respectively, in compound heterozygous form.

These mutations generally result in reduced enzyme function or stability, contributing to elevated methionine levels due to impaired methylation cycle regulation.

Laboratory Testing for AHCY

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.

Biomarkers Related to AHCY

Homocysteine, Methionine, and SAM (S-adenosylmethionine)

Homocysteine, methionine, and SAM are key biomarkers in methylation pathways closely linked to AHCY activity. 

Homocysteine, a byproduct of methylation, can accumulate if AHCY function is impaired, leading to potential cardiovascular risks. 

Methionine is an amino acid that, with the help of AHCY, is regenerated from homocysteine in a methylation cycle. 

SAM, the principal methyl donor in numerous methylation reactions, is synthesized from methionine and ATP. 

Order Genetic Testing

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See References

[1.] AHCY adenosylhomocysteinase [Homo sapiens (human)] - Gene - NCBI. 

[2.] Barić I, Staufner C, Augoustides-Savvopoulou P, Chien YH, Dobbelaere D, Grünert SC, Opladen T, Petković Ramadža D, Rakić B, Wedell A, Blom HJ. Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders. J Inherit Metab Dis. 2017 Jan;40(1):5-20. doi: 10.1007/s10545-016-9972-7. Epub 2016 Sep 26. PMID: 27671891; PMCID: PMC5203850. 

[3.] Entry - *180960 - S-ADENOSYLHOMOCYSTEINE HYDROLASE; AHCY - OMIM. Accessed May 6, 2024. 

[4.] Feng Q, Keshtgarpour M, Pelleymounter LL, Moon I, Kalari KR, Eckloff BW, Wieben ED, Weinshilboum RM. Human S-adenosylhomocysteine hydrolase: common gene sequence variation and functional genomic characterization. J Neurochem. 2009 Sep;110(6):1806-17. doi: 10.1111/j.1471-4159.2009.06276.x. Epub 2009 Jul 8. PMID: 19619139; PMCID: PMC2838417.

[5.] GeneCards: The Human Gene Database. Published May 6, 2024. 

[6.] Vizán P, Di Croce L, Aranda S. Functional and Pathological Roles of AHCY. Front Cell Dev Biol. 2021 Mar 31;9:654344. doi: 10.3389/fcell.2021.654344. PMID: 33869213; PMCID: PMC8044520.

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