Introduction:

Cerebrospinal fluid (CSF) is used for measuring reliable Brain serotonin levels. However, it involves an invasive procedure especially for Monoamine Oxidase Deficient (MAOD) children. Audhya et al. (2012) reported that blood platelet serotonin level is well correlated with CSF serotonin level more than blood plasma serotonin. For measuring serotonin levels (a crucial biomarker) in MAOD children CLIA-compliant test is required. Unfortunately, CLIA-compliant blood platelet serotonin test referred by Audhya et al. (2012) is not available. Currently, CLIA compliant Whole Blood Tests are available with Quest Diagnostics (Test #818X), Mayo Clinic (Test #SERWB) and LabCorp (Test #120089). Similarly, CLIA-compliant Serum Tests for serotonin are also available with these companies. Our goal is to choose the best CLIA-compliant clinical serotonin test which would give us more realistic correlation with brain serotonin levels in a child with MAO-A or MAO-A/B deficiency. I would recommend whole blood serotonin over Serum serotonin test.

Here are the companies with available CLIA compliant serotonin test:

1. Mayo Clinic Laboratories – Serotonin, Blood (SERWB)
   • Whole blood EDTA collected into a specialized serotonin transport tube
   • LC-MS/MS assay
   • Because nearly all circulating serotonin resides in platelets, whole blood is the preferred specimen over platelet-poor plasma.
2. LabCorp – Serotonin, Whole Blood (120089)
   • LC-MS/MS
   • Available through the LabCorp network
   • Measures serotonin in whole blood rather than plasma.
3. Quest Diagnostics, Whole Blood (818X)
   • LC-MS/MS assay
   • Also measures serotonin in whole blood.

How does the paper by Audhya et al. 2012 help to choose Whole blood over Serum test?

The Audhya paper found that platelet serotonin had a much stronger correlation with CSF serotonin than plasma serotonin. Because whole blood serotonin is overwhelmingly derived from platelet serotonin, whole blood is much closer to what the paper supports than plasma testing.

No commercial CLIA laboratory offers the specialized platelet serotonin extraction protocol used in the Audhya study. Clinical laboratories generally perform whole blood serotonin, which is practical and standardized, but it is not identical to the research platelet assay used in that paper. In the absence of CLIA compliant specialized platelet serotonin test the preference would be: Whole blood serotonin test Between whole blood serotonin and serum serotonin, I would choose whole blood serotonin test.

Here’s why?

Advantages of Whole blood serotonin test:

• Measures serotonin in the entire blood sample, where the vast majority (over 95%) of serotonin is contained within platelets.
• Better reflects the body’s total circulating serotonin stores.
• Less affected by how much serotonin is released from platelets during clotting.
• More standardized for evaluating disorders involving serotonin metabolism, including neuroendocrine disorders.

Disadvantages of Serum serotonin test:

Serum is obtained after the blood has clotted. During clotting, platelets become activated and release serotonin into the serum. As a result:

• The measured value depends not only on how much serotonin is present in platelets, but also on how completely the platelets release it during clotting.
• Results can vary with clotting time, sample handling, platelet activation, and processing.
• Serum serotonin is often used in specific contexts (such as evaluating certain neuroendocrine tumors), but it is generally not the preferred specimen when you’re trying to understand serotonin biology itself.

How does the Audhya paper inform this choice?

Although the study did not directly compare whole blood versus serum, it supports the principle that the platelet serotonin pool is the informative compartment. Whole blood preserves that platelet pool, whereas serum reflects serotonin released from platelets during clotting rather than serotonin stored within them.

Although all three labs (Mayo Clinic Laboratories, LabCorp, Quest Diagnostics) offer both whole blood serotonin and serum serotonin tests, I would recommend whole blood serotonin over serum serotonin, regardless of whether we use Mayo, LabCorp, or Quest because of the following reasons.

Feature	Whole Blood	Serotonin Serum Serotonin
Includes platelet serotonin	✅ Yes	Indirectly (released during clotting)
Reflects total circulating serotonin	✅ Better	Less directly
More stable physiologically	✅ Yes	More affected by clotting conditions
Most consistent with the biology discussed in the Audhya paper	✅ Yes	No

Why whole blood is the better choice?

The Audhya paper found that platelet serotonin had an exceptionally high correlation with CSF serotonin (r = 0.97), whereas plasma serotonin did not. Whole blood serotonin is dominated by serotonin contained within platelets because platelets store the overwhelming majority of serotonin in blood. Serum serotonin, in contrast, is measured after clotting, when platelets have released their serotonin into the serum. That means the serum result depends not only on the amount of serotonin present but also on how the specimen clotted and was processed.

For a disorder like MAO deficiency, where we are interested in serotonin levels in blood rather than the effects of platelet activation during serum separation, whole blood is the more direct measure for serotonin.

MAODF continues to make important progress in identifying potential treatments for MAO Deficiency. Following an AI-driven screening of approximately 40,000 compounds conducted by Unravel Biosciences, 14 promising drug candidates were selected for further testing. These compounds are currently being evaluated in Unravel’s Xenopus (frog) model of MAO Deficiency.

At the same time, MAODF is collaborating with University of Radbound in the Netherlands to test both Unravel’s lead candidates and seven known neurotransmitter-related compounds in patient-derived nerve cell models. These studies examine whether the compounds can improve the abnormal nerve cell activity associated with MAO Deficiency and restore cellular function toward normal levels.

Early results have been very encouraging. Three of the seven neurotransmitter-related compounds tested so far, L-pCPA, Ketanserin and Tetrabenazine significantly improved disease-related abnormalities in patient-derived neurons, bringing their activity closer to that seen in cells from an unaffected parent.

While additional testing is still underway, these findings represent an exciting step forward and provide hope that effective treatments for MAO deficiency can be identified. We look forward to sharing further updates as results from the remaining compounds become available.

Over the past three years, MAODF has been working with research teams at University of Texas Southwestern Medical Center and The Ohio State University to develop a gene therapy approach for patients with Monoamine Oxidase Deficiency (MAOD). Gene therapy is considered a promising long- term strategy because it may one day provide a more permanent correction of the underlying disease.

In the early stages of the project, researchers tested a commonly used AAV9 gene therapy delivery system together with an MAOD mouse model developed from the laboratory of Jean Shih in California. Although these studies provided important information, the mouse model did not consistently show the behavioral features needed to fully evaluate treatment success. To improve the research, Jackson Laboratory recently developed a new MAOD mouse model that appears to better reflect the disease. However, the new model is proving difficult to breed in large numbers required for treatment studies.

At the same time, advances in the gene therapy field continue to provide new hope. Researchers at the Broad Institute (MIT and Harvard) have recently developed newer AAV capsids that may improve delivery of gene therapies to the brain and central nervous system. MAODF is therefore exploring the possibility of restarting its gene therapy program in the future using these next-generation delivery systems together with improved MAOD animal models developed through ongoing research collaborations.