Acylcarnitine- Medical Genetics

An acylcarnitine profile test is a procedure to test for certain inherited disorders that impact how certain amino acids and fatty acids are metabolized. These metabolic disorders can be life-threatening, with patients failing to thrive and experiencing the following symptoms: seizures, cardiomyopathy, liver failure, gastrointestinal distress, myopathies, and coma.

These illnesses are inborn errors of metabolism and can lead to death in children born with these conditions. Most of the metabolic disorders tested for by acylcarnitine profile tests are inherited.

When the acylcarnitine test is done

The test is performed in certain situations listed below:

• Screening newborns for disorders of fatty acid metabolism or disorders of organic acid metabolism.
• Screening siblings of newborns who have such metabolic disorders.
• Pre-natal screening for metabolic disorders.
• Children and adults with myopathies (muscle symptoms) and where fatty-acid oxidation problems are suspected.
• Post-mortem test.

Disorders the acylcarnitine test can detect

High plasma levels of acylcarnitine compounds are present in cases of obesity and type 2 diabetes. However, the test is not usually done to test for diabetes. The acylcarnitine test is most commonly done to screen for inherited metabolic disorders.

There are several inherited metabolic disorders that can be detected using the acylcarnitine test. Some of these metabolic problems are fatty acid oxidation disorders in which a specific enzyme needed for the proper breakdown of fats is missing in the body.

There are about 24 conditions that the acylcarnitine test can be used to diagnose. The most common fatty acid oxidation disorders that the acylcarnitine test can help diagnose are listed below, along with their prevalence:

• Medium chain acyl CoA dehydrogenase deficiency (MCADD): This is the most common of the metabolic disorders, with a prevalence of 1 in 20,000 births.
• Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency: The prevalence of this condition is 1 in 40,000 to 1 in 120,000 individuals.
• Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency: This occurs in 1 out of 120,000 births.
• Glutaric acidemia type II: This happens in 1 out of 100,000 newborns.

How the acylcarnitine test is done

The test is done by tandem mass spectrometry (MS/MS) and variations thereof. Mass spectrometry is a way that molecules are measured based on their masses. Mass spectrometry, in general, is a commonly used analytical technique to identify components in a sample. Tandem mass spectrometry uses two analyzers in the machine.

In fatty acid oxidation disorders, specific types and amounts of acylcarnitine molecules are present. It is these molecules that spectrometry can detect.

Samples used for the test

Acylcarnitine mass spectrometry is done on different types of samples listed below:

• Blood serum: This is blood without any clotting factors or cells present.
• Blood plasma: Concentrations of free carnitines in plasma are about 36% higher than with dried blood spots, which suggests this may be a better sample to use for diagnosis.
• Dried blood spots: a small sample of blood is collected from the heel of a newborn. The blood is placed on cellulose-based filter paper in 4 circles. This is then sent to the laboratory for further testing.
• Urine: While urine samples are non-invasive, they are not as sensitive as blood samples.
• Bile: Only used post-mortem to help determine a cause of death.

Blood can either be spot dried and sent to the lab or, if collected in liquid form, should be frozen and shipped on dry ice. Samples are usually taken after the patient has fasted for at least 4 hours.

The tandem mass spectrometry procedure

The basic procedure for a plasma sample is as follows:

• The sample is diluted with reagents that help to extract the molecules of interest.
• The mixture is centrifuged, and the supernatant containing the acylcarnitine extracts is removed.
• Tandem mass spectrometry is then completed.
• A positive and negative control, and standards, are included when samples are tested.
• The type of acylcarnitine and the quantity that is detected by the spectrometry will be interpreted by an expert.

Interpretation of the results

The results of the tandem mass spectrometry are interpreted by comparing the values of different acylcarnitine compounds with a set of known reference values.

The reference values are for different ages, so this is also taken into account when analyzing what acylcarnitine compounds are detected. An ABMG-certified biochemical geneticist interprets the results.

It is important to understand that certain medications can cause false results because they can interfere with the test. The following medications are known to be problematic in this regard:

• valproic acid
• pivalic acid
• cefotaxime 

It is, therefore, important that all medications a patient takes are known and recorded before performing an acylcarnitine profile test.

Once test results are interpreted, further genetic testing may be done to look for the gene that is implicated in causing a particular metabolic disorder. After a diagnosis is confirmed, a treatment plan can be made to help manage the condition.

References:

• Dambrova, M., Makrecka-Kuka, M., Kuka, J., Vilskersts, R., Nordberg, D., Attwood, M. M., ... & Schiöth, H. B. (2022). Acylcarnitines: nomenclature, biomarkers, therapeutic potential, drug targets, and clinical trials. Pharmacological Reviews, 74(3), 506-551.
• Diekman, E. F., Jans, J. J., van der Ham, M., Prinsen, B. H., Visser, G., & Verhoeven-Duif, N. M. (2013). Differences between acylcarnitine profiles in plasma and bloodspots. Molecular genetics and metabolism, 110(1-2), 116-121.
• Gucciardi, A., Zaramella, P., Costa, I., Pirillo, P., Nardo, D., Naturale, M., ... & Giordano, G. (2015). Analysis and interpretation of acylcarnitine profiles in dried blood spot and plasma of preterm and full-term newborns. Pediatric research, 77(1), 36-47.
• Mihalik, S. J., Goodpaster, B. H., Kelley, D. E., Chace, D. H., Vockley, J., Toledo, F. G., & DeLany, J. P. (2010). Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity, 18(9), 1695-1700.
• Millington, D. S., & Stevens, R. D. (2011). Acylcarnitines: analysis in plasma and whole blood using tandem mass spectrometry. Metabolic Profiling: Methods and Protocols, 55-72.
• Song, Y., Lyu, C., Li, M., Rahman, M. L., Chen, Z., Zhu, Y., ... & Zhang, C. (2021). Plasma acylcarnitines during pregnancy and neonatal anthropometry: a longitudinal study in a multiracial cohort. Metabolites, 11(12), 885.
• Vianey-Saban, C., Fouilhoux, A., Vockley, J., Acquaviva-Bourdain, C., & Guffon, N. (2023). Improving diagnosis of mitochondrial fatty-acid oxidation disorders. European Journal of Human Genetics, 1-8.

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