A female toddler presents to her pediatrician with liver dysfunction, mild developmental delay, and behavioral changes. What lab testing makes sense and why?

With the advent of next-generation sequencing, there has been an onslaught of fast and affordable molecular genetic test offerings. As such, clinicians are turning to molecular tests earlier and more frequently in the diagnostic process. Where does biochemical testing fit in the new test paradigm? To answer this question, it is important to understand the nature of metabolic disorders and the unique advantages of biochemical analysis in the diagnosis and monitoring of these conditions.

Inherited metabolic disorders (IMD), also known as inborn errors of metabolism (IEM), are a group of disorders that affect metabolic pathways. The majority of disorders in this group are caused by enzyme deficiencies. If an enzyme does not function properly, then the pathway is stalled, components before that block build-up and components after the block diminishes. Consequences of a block may include toxic buildup or deficiencies in critical compounds. An example would be phenylalanine buildup in phenylketonuria (PKU). Common IMDs include aminoacidopathies, organic acidurias, disorders of carbohydrate metabolism, and disorders of fatty acid oxidation. Symptoms and age of onset vary depending on the enzyme impacted.

Who should get biochemical testing?
The most well-known way to identify someone with an IMD is via newborn screening. In cases where newborn screening indicates possible IMD, follow-up biochemical testing is sent right away. This may provide a biochemical diagnosis within days of life, allowing treatment to begin quickly. Newborn screening programs do not, however, capture all people affected by an IMD. It may be that a disorder is not included on a state’s newborn screening panel or the screen failed to detect it.

Some affected patients present with clinical symptoms. These may be acute, such as metabolic decompensation, acidosis, hypoglycemia, hyperammonemia, vomiting, altered mental status, liver dysfunction, or seizures. Or, they may be chronic, such as developmental delay, neurologic abnormalities, muscle problems, or other multi-system issues. Circling back to the case of the female toddler with liver dysfunction, mild delay, and behavioral changes: After nondiagnostic workups, she was evaluated for a possible liver transplant. Biochemical testing was finally done at that time, with results consistent with a urea cycle disorder. Treatment was started, and liver transplantation was no longer needed for this patient.

In addition to diagnosis, biochemical testing plays a role in monitoring treatments. It also has clinical utility in diagnosis and monitoring non-IEM conditions such as nutritional deficiency, and vitamin deficiencies (such as B12 deficiency).

When should a clinician order biochemical testing?
Biochemical tests investigate these metabolic pathways, such as amino acids, organic acids, and fatty acids, using sample types such as blood and urine. In concert with other chemistries, they create a window into the patient’s metabolic systems in near real-time. If a patient presents in an acute episode, it is critical that biochemical tests be performed during the symptomatic event. It is during these symptomatic episodes that the biochemical abnormalities are most apparent. Once they resolve, these critical values may diminish or disappear.

For diagnostic purposes, it may be valuable to consider molecular genetic testing as well. While both may facilitate diagnosis, only biochemical testing can provide insight into the patient’s state of health, the level of biochemical dysfunction, biochemical baseline, and response to treatment. It may also provide critical phenotype information for variant analysis of molecular results. The molecular and biochemical approaches are valuable companions.

Why send biochemical testing to Quest?
Whether to resolve an abnormal newborn screen result for a new baby, help diagnose or rule out IMD in a patient presenting in the hospital, or monitor a patient living with an IMD, biochemical testing remains a critical part of a provider’s toolkit. Biochemical tests partner with molecular and enzymatic test approaches to create the fullest picture possible for a patient and his or her family.

High-level interpretation and commitment to patients with inherited metabolic disorders are what make a Biochemical Genetics Lab unique. Almost 25 years ago, Quest Diagnostics opened our Biochemical Genetics Laboratory. Our team includes board-certified geneticists and genetic counselors, scientists, and laboratory staff, who remain active in learning, publishing, and advancing the latest thinking in metabolic disorders. Visit our website or call Quest Genomics Client Services at 1.866.GENE INFO (1.866.436.3463) with your questions about testing.