Aromatic L-amino acid decarboxylase (AADC) deficiency is an inherited neurometabolic disease caused by mutations in the DDC gene. This gene provides instructions for the production of an enzyme called L-amino acid decarboxylase (AADC), which is required for the production of the neurotransmitters (or cell signaling molecules) dopamine and serotonin.
Mutations in the DDC gene lead to the AADC enzyme not functioning properly and reducing the levels of dopamine and serotonin being produced, which in turn impairs the communication between the brain and other organs.
Blood tests measuring AADC enzyme activity in plasma (the liquid portion of blood) and 3-O-methyldopa levels in dried blood spots can help to confirm the diagnosis of AADC deficiency, together with findings from other diagnostic tests.
AADC enzyme activity
The primary blood test to diagnose AADC deficiency is the measurement of AADC enzyme activity in the plasma. The AADC enzyme converts L-dopa into the neurotransmitter dopamine, and 5-hydroxytryptophan (5-HTP) into serotonin.
In this procedure, a blood sample is collected, and the plasma is separated from blood cells. The samples may be processed immediately or frozen at –80° C for later analysis.
AADC enzyme activity is assayed using either L-dopa or 5-HTP as a substrate although L-dopa is preferred due to its higher sensitivity. In patients with AADC deficiency, the AADC enzyme activity is often below the detection limit or significantly lower than normal. The activity of the enzyme is moderately lower in carriers of the disease than in healthy individuals.
Unlike conventional blood collection methods, dried blood spots (DBS) testing requires a small volume of blood (30 to 100 microliter per spot) and is particularly useful in taking blood samples from newborns. DBS involves blotting and drying a sample of blood on filter paper. These samples can be easily transported, are highly stable for long periods of time, and can be subjected to several analytical tests.
3-O-methyldopa (3-OMD) is a product of L-dopa metabolism and its levels are known to be elevated in patients with AADC deficiency. A clinical study in Taiwan screened 127,987 newborns for AADC deficiency over a period of two years. DBS analysis in four newborns showed a significantly elevated level of 3-OMD levels in the blood, which correlated with genetic tests showing both copies of the DDC gene to be mutated. Six of the newborns with slightly elevated levels of 3-OMD were confirmed to be carriers.
While DBS testing drastically reduces the disease screening time for newborns, the consensus guideline for diagnosis and treatment of AADC deficiency recommends further investigation into the accuracy and cost-effectiveness of this test.
Levels of prolactin (a hormone that promotes breast-milk production) are often elevated in the blood when dopamine production is affected, which is the case in AADC deficiency and other neurometabolic disorders. However, normal prolactin levels do not indicate the absence of AADC deficiency, and further research is needed before levels of prolactin can be used as a diagnostic tool.
3-OMD testing using conventional blood samples instead of DBS is also possible. PTC Therapeutics, in partnership with MNG Laboratories, is offering AADC deficiency testing at no cost to determine 3-OMD levels in blood. The results of the test are usually available in about 10 to 14 days.
Last updated: Sept. 16, 2019
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