Diagnosis of AADC Deficiency

Last updated Jan. 7, 2022, by Marisa Wexler, MS

✅ Fact-checked by Inês Martins, PhD

Aromatic l-amino acid decarboxylase (AADC) deficiency is a genetic condition caused by mutations in the DDC gene, which provides instructions for making an enzyme called AADC.

This enzyme is needed to make certain neurotransmitters — the chemical messengers that nerve cells use to communicate with each other — including serotonin, dopamine, and the related norepinephrine and epinephrine.

In AADC deficiency, DDC mutations lead to a lack of functional AADC enzyme, ultimately resulting in insufficient production of these neurotransmitters, which causes symptoms such as developmental delay and autonomic dysfunction.

Diagnostic tests for AADC deficiency broadly involve examining the levels of the affected neurotransmitters and related molecules, measuring AADC activity in the blood, and looking for mutations in the DDC gene. Two test results indicating AADC deficiency are usually necessary to confirm a diagnosis.

Analysis of cerebrospinal fluid

Cerebrospinal fluid, or CSF, is the liquid that surrounds the brain and spinal cord. It is usually collected through a lumbar puncture, also called a spinal tap, which involves inserting a needle through the spine.

When the AADC enzyme is deficient, levels of the neurotransmitters this enzyme helps to make (including dopamine, serotonin, norepinephrine, and epinephrine) are significantly lower in the CSF.

People with AADC deficiency have lower-than-normal CSF levels of molecules that are produced from these neurotransmitters. These include 5-hydroxyindoleacetic acid (5-HIAA), a metabolic product of serotonin; homovanillic acid (HVA), a metabolite produced from dopamine; and 3-methoxy-4-hydroxyphenylglycol (MHPG), a degradation product of norepinephrine and epinephrine.

AADC deficiency also is characterized by higher-than-normal levels of AADC’s substrates, the raw materials that the enzyme uses to produce the neurotransmitters. These include 5-hydroxytryptophan (5-HTP), which is used to make serotonin, as well as 3-O-methyldopa (3-OMD) and L-Dopa, both of which are precursors of dopamine.

Another characteristic CSF finding in AADC deficiency is normal levels of pterins, a group of molecules that the AADC enzyme uses to help make neurotransmitters. Normal levels of pterins are important for distinguishing between AADC deficiency and tetrahydrobiopterin deficiency, another neurological disorder that also results in abnormally low serotonin and dopamine levels, but due to a different underlying cause.

Blood tests

One place that the AADC enzyme is normally found is in the blood. The enzyme’s activity can be monitored in the plasma, or liquid portion of the blood.

Blood tests generally involve taking a sample and adding substrates — the raw materials that the AADC enzyme uses to make neurotransmitters, most notably L-dopa for dopamine and 5-HTP for serotonin. The test can assess how well the AADC enzyme in the sample is able to convert these substrates into the active neurotransmitter, indicating its activity.

In people with AADC deficiency, the enzyme’s activity will be well below the lower limit of what is considered normal; in many patients, the enzyme has no detectable activity in plasma.

While not routinely implemented, blood tests can also be used to measure certain molecules that are usually detected in the CSF analyses — such as 3-OMD and 5-HTP. Examining these metabolites in dried blood spots, which are essentially drops of blood collected on filter paper, has been considered feasible in newborn screening studies.

Genetic testing

Since AADC deficiency is caused by genetic mutations in the DDC gene, sequencing a DNA sample can confirm the diagnosis of AADC deficiency. This is often the last confirmation step because results may come only a few months after the sample is taken.

At least 79 disease-causing mutations in the DDC gene have been reported. As the sequence of the entire healthy gene is known, sequencing analysis of either short portions of the gene or the entire gene can be used to confirm a diagnosis of AADC deficiency if the mutated region(s) can be identified.


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