4 Cerebrospinal Fluid Biomarkers May Aid Diagnosis, Study Says

Four biomarkers of aromatic l-amino acid decarboxylase (AADC) deficiency have been identified in the cerebrospinal fluid of children with the condition, a new study reports.

These disease markers may aid in diagnosis when adjusted for a patient’s age, the researchers said.

The study, “Confirmation of neurometabolic diagnoses using age‐dependent cerebrospinal fluid metabolomic profiles,” was published in the Journal of Inherited Metabolic Disease. 

People with neurometabolic disorders commonly start showing symptoms at a young age. Receiving a timely and correct diagnosis is crucial so that the appropriate treatment can be started. 

Neurometabolic disorders currently are diagnosed using genetic testing combined with the analysis of a limited set of known biomarkers found in body fluids and using imaging techniques.

The specific metabolic changes associated with a neurometabolic disease often can only be detected in the cerebrospinal fluid (CSF) — the liquid surrounding the brain and spinal cord. However, this type of strategy is not designed to identify new disease biomarkers or unknown metabolic conditions. 

A technique called next‐generation metabolic screening (NGMS) allows the simultaneous measurement of hundreds of metabolites (biomarkers) in body fluids, a previous study showed. NGMS was able to diagnose several cases of inborn errors of metabolism — genetic conditions in which the body cannot properly turn food into energy.

Now, researchers at Radboud University Medical Center, in the Netherlands, have used NGMS to identify new disease biomarkers in the CSF of children with AADC deficiency or other neurometabolic disorders.

The study included CSF samples from children, ages 0-15, who were either healthy (87 persons) or had a confirmed diagnosis of a neurometabolic disorder. These diagnoses included AADC deficiency (two persons), isovaleric acidemia (one person), succinic semialdehyde dehydrogenase deficiency (two persons),  N‐acetylneuraminic acid synthase deficiency (one person), or dihydropyrimidinase deficiency (one person).

For each neurometabolic disorder, at least one specific biomarker could be identified in the CSF, confirming the diagnosis, the results showed.

“All neurometabolic diagnoses included in this study could be confirmed based on NGMS measurements in CSF samples of patients,” the researchers wrote.

In the CSF from the AADC patients specifically, four biomarkers were found to be present in altered levels compared with healthy controls. These changes included greater levels of 3‐methoxytyrosine and 5‐hydroxytryptophan, and lower levels of 5‐hydroxyindoleacetic acid and homovanillic acid.

Of note, patient age was an important factor to take into account when evaluating changes in these biomarkers. In contrast, the sex of the patient did not influence the biomarker results.

“As demonstrated by data from the AADC deficiency patients, knowledge on the age‐dependency of metabolites can be vital for making the correct diagnosis,” the team wrote. “Conversely, deviating levels of an age‐dependent metabolite can be mistakenly interpreted as perturbations caused by the disease if age is not considered when comparing patients to controls.”

The team concluded that “NGMS in CSF is a powerful tool for diagnosis of neurometabolic disorders,” and that the technique can potentially “facilitate biomarker discovery and aid in further understanding of disease mechanisms in the brain.”