Diagnosis of AADC Deficiency

Aromatic l-amino acid decarboxylase (AADC) deficiency is a genetic condition caused by mutations in the DDC gene, which results in low levels of neurotransmitters, or signaling molecules, in the brain. Affected neurotransmitters include dopamine, norepinephrine, epinephrine, and serotonin, so that AADC deficiency leads to severe problems in mobility, eye movement, and in autonomic nervous system functions.

Diagnostic tests to confirm AADC deficiency include measuring dopamine, norepinephrine, epinephrine, and serotonin levels in the cerebrospinal fluid (CSF), testing for AADC enzyme activity in the blood, and screening the DDC gene for mutations. Two test results indicating AADC deficiency are usually necessary to confirm a diagnosis.

Lumbar puncture

AADC is an enzyme that decarboxylates or removes a carboxyl group from either L-dopa or 5-hydroxytryptophan to generate the neurotransmitters dopamine (L-dopa) or serotonin (5-hydroxytryptophan). Dopamine is also used to make norepinephrine and epinephrine.

When the AADC enzyme is deficient, levels of dopamine, serotonin, norepinephrine, and epinephrine are significantly lower in the CSF.

Cerebrospinal fluid from people suspected of having AADC deficiency is obtained mostly through a lumbar puncture, or spinal tap. The typical confirmatory diagnosis will show:

  1. Low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG). 5-HIAA is a breakdown product of serotonin, and its levels are low because serotonin levels are insufficient. HVA is a metabolite produced in the brain from dopamine. Because dopamine levels are low or non-existent, HVA levels are low. MHPG is a degradation product of norepinephrine, which is not sufficiently produced because of low levels of dopamine.
  1. High levels of 3-O-methyldopa (3-OMD), L-Dopa and 5-OH tryptophan (5-HTP). L-dopa is the substrate of the AADC enzyme that is converted into dopamine. Because of AADC deficiency, levels of L-dopa are high. 5-HTP is the substrate of the AADC enzyme, which is converted into serotonin. It builds up in the CFS of patients with AADC deficiency. 3-OMD is generated from L-dopa. When dopamine levels are low, levels of L-dopa are high, which can be converted into 3-OMD and increase its levels.
  1. Normal levels of pterins, such as neopterin, dihydrobiopterin, and tetrahydrobiopterin. Pterins are naturally occurring small molecules that are required by the AADC enzyme to produce dopamine and serotonin. Their normal levels rule out the possibility of tetrahydrobiopterin disorder, which can also cause low levels of dopamine and serotonin.

Blood tests

The AADC enzyme is normally found in blood and elsewhere. Its activity can be monitored in the plasma, or liquid portion of the blood. Deficient AADC enzyme activity in the blood plasma can confirm AADC deficiency.

An AADC enzyme assay of blood plasma samples is used to confirm AADC deficiency. Commercially available L-dopa or 5-HTP is used as substrates. The expected outcome of the assay, a test or analysis, is either significantly low or absent AADC enzyme activity.

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.

At least 50 disease-causing mutations in the DDC gene that encodes for the AADC enzyme have been reported. Since the sequence of the entire 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.


Last updated: Sept. 11, 2019


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