ACADS

ACADS, known as Short-Chain Acyl-CoA Dehydrogenase, stands as a cornerstone in fatty acid metabolism, catalyzing the initial steps in the oxidation of short-chain fatty acids. Its role extends beyond mere energy production, influencing lipid metabolism and maintaining metabolic homeostasis. Against this backdrop, the clinical significance of ACADS spans a spectrum of metabolic disorders, ranging from Short-Chain Acyl-CoA Dehydrogenase (SCAD) deficiency to broader metabolic dysregulations. 

Understanding ACADS  [1., 3.]

The ACADS gene encodes a mitochondrial enzyme, short-chain acyl-CoA dehydrogenase (SCAD), which is a crucial component of the fatty acid beta-oxidation pathway. 

This tetrameric flavoprotein belongs to the acyl-CoA dehydrogenase family and specifically catalyzes the initial step in the breakdown of short-chain fatty acids into acetyl-CoA, facilitating energy production from fats.

This enzymatic process is crucial for maintaining energy balance, especially in organs with high metabolic demands such as the liver.  

Mutations in ACADS can lead to SCAD deficiency, affecting the body's ability to metabolize fats properly, which can result in metabolic disturbances and clinical symptoms related to energy deficiency.

Mutations in ACADS can lead to short-chain acyl-CoA dehydrogenase deficiency, a condition marked by metabolic complications due to impaired fatty acid breakdown. The gene exhibits broad expression across various tissues, including high levels in the duodenum, liver and fat.

Alternative splicing of ACADS results in different isoforms, further indicating the gene's complex regulation and function in cellular energy metabolism. This gene is also associated with essential pathways like mitochondrial fatty acid beta-oxidation and is linked to other fatty acid metabolism disorders.

ACADS Gene in Short-Chain Acyl-Coenzyme A Dehydrogenase Deficiency (SCADD)  [4.]

Short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD) is an autosomal recessive metabolic disorder caused by mutations in the ACADS gene, which affects mitochondrial fatty acid oxidation. 

This deficiency can manifest with a wide range of clinical symptoms from severe metabolic crises in infancy to asymptomatic adults. 

The biochemical hallmark of SCADD is the elevated level of butylcarnitine in newborn screening tests and increased excretion of ethylmalonic acid in urine. Genetic confirmation involves identifying mutations in the ACADS gene, including novel missense mutations such as c.1031A>G found in a Korean neonate, the first documented case in this population. 

Although SCADD's presentation can vary widely, management typically involves preventive measures against metabolic decompensation, especially during illness or fasting.

Genetic Alterations in the ACADS Gene

The gene for the ACADS protein may contain alterations or mutations that cause increase or decrease of function of the ACADS 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 ACADS Function  [4.]

Specific SNPs associated with alterations in ACADS function and the development of SCADD include: 

c.1031A>G (p.E344G)

Located in exon 9, this novel missense mutation substitutes glutamic acid with glycine, affecting protein stability and function.

c.511C>T (R147W)

A common variant found in exon 5, it replaces arginine with tryptophan at position 147 in the mature enzyme, prevalent in European populations.

c.625G>A (G185S)

Another common variant in exon 6, this mutation substitutes glycine with serine at position 185 of the mature enzyme.

G108D 

Identified in Japanese neonates through screening, this mutation significantly reduces enzymatic activity compared to the wild type.

Laboratory Testing for ACADS

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.

ACADS-Related Biomarkers in Metabolic Assessment

In conjunction with ACADS, various other biomarkers play integral roles in assessing metabolic function and diagnosing related disorders. 

Carnitine Palmitoyltransferase I (CPT-I) Genetic Testing  [2.] 

Carnitine palmitoyltransferase I is an enzyme involved in the beta-oxidation of long-chain fatty acids. 

Like ACADM, CPT-I plays a crucial role in fatty acid metabolism and energy production. 

CPT1A deficiency is typically confirmed through molecular genetic testing, identifying biallelic pathogenic variants in the CPT1A gene.  Alternatively, a diagnosis can be made by measuring reduced activity of the CPT 1 enzyme in cultured skin fibroblasts, especially when genetic testing does not provide conclusive results.

During diagnosis, it's common to find enzyme activity ranging from 1%-5% of normal.

Plasma Acylcarnitines

Plasma acylcarnitines serve as metabolic intermediates and biomarkers for assessing mitochondrial function and fatty acid oxidation. 

Abnormal profiles of plasma acylcarnitines, characterized by alterations in specific acylcarnitine species, may signify disruptions in fatty acid metabolism pathways.  

Quantitative analysis of plasma acylcarnitines using mass spectrometry techniques provides valuable diagnostic information for various metabolic disorders, including those related to ACADS deficiency.

Urinary Organic Acids

Urinary organic acids, metabolic byproducts excreted in urine, offer insights into aberrant metabolic pathways and potential enzymatic deficiencies. 

Anomalies in urinary organic acid profiles, such as the presence of dicarboxylic acids or ketone bodies, may indicate deficiencies in fatty acid oxidation enzymes, including ACADS.  

Gas chromatography-mass spectrometry facilitates quantitative analysis of urinary organic acids, aiding in the diagnosis and monitoring of metabolic disorders associated with impaired fatty acid metabolism.

Glucose and Insulin Levels

Glucose and insulin levels provide additional perspectives on carbohydrate metabolism and insulin sensitivity, which intersect with fatty acid oxidation pathways. 

Dysregulation of glucose metabolism, such as insulin resistance or hyperglycemia, can influence fatty acid oxidation and exacerbate metabolic dysfunction.  

Monitoring glucose and insulin levels alongside biomarkers of fatty acid metabolism, including ACADS, enhances the comprehensive assessment of metabolic health and informs therapeutic interventions for metabolic disorders.

Order Genetic Testing

Click here to compare genetic test panels and order genetic testing for health-related SNPs.