Aromatic L-amino acid decarboxylase (AADC) deficiency (OMIM entry #608643) is an autosomal recessive inherited metabolic disease caused by mutations in the AADC gene (Official Symbol: DDC; Gene ID. 1644). The AADC enzyme (EC: 220.127.116.11) converts L-dihydroxyphenylalanine (L-dopa) to dopamine and 5-hydroxytryptophan (5-HTP) to serotonin. Dopamine and serotonin are central neurotransmitters but in addition are precursors for noradrenaline, adrenaline and melatonin. Consequently, AADC deficiency results in a deficit of each of these key signalling molecules.
The clinical picture is variable between patients but the two most commonly reported symptoms of AADC deficiency are hypotonia and oculogyric crises. Other common symptoms include hypokinesia, developmental delay, dystonia, limb hypertonia, choreoathetosis, insomnia, irritability, dysarthria/speech difficulties, feeding/ swallowing difficulties and gastroesophageal reflux. Autonomic symptoms are also common including hypotension, hypoglycaemia, ptosis, excessive sweating, temperature instability, nasal congestion and hypersalivation. The majority of patients present with symptoms during infancy or childhood.
Please see the following clinical review articles for more information:
Brun L et al. (2010) Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology75, 64-71.
Pons R., Ford B., Chiriboga C. A., Clayton P. T., Hinton V., Hyland K., Sharma R. and De Vivo D. C. (2004) Aromatic L-amino acid decarboxylase deficiency: Clinical features, treatment, and prognosis. Neurology62, 1058-1065.
The clinical picture in AADC deficiency is similar to that of tyrosine hydroxylase (TH) deficiency, guanosine triphosphate cyclohydrolase (GTPCH) deficiency, sepiapterin reductase (SR) deficiency as well as other dopamine related diseases. Therefore AADC deficiency is diagnosed by biochemical analysis of CSF neurotransmitters. The serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid (HVA) and the L-dopa alternative metabolite 3-O-methyldopa (3OMD; 3-methoxytyrosine) are measured by HPLC with electrochemical detection. 5-HTP may also be measured. Due to the metabolic block at AADC the characteristic pattern of AADC deficiency is low 5-HIAA and HVA as well as high 3OMD and 5-HTP (if measured). Diagnosis can be confirmed by measuring AADC activity in plasma and by molecular analysis to determine pathogenic mutations. High vanillactic acid in urine, high 3OMD in plasma and high prolactin in serum can also be indicative of AADC deficiency.
A list of laboratories that provide testing for AADC deficiency can be found here:
Patients with AADC deficiency are most commonly treated with a combination of a dopamine agonist, a monoamine oxidase inhibitor and vitamin B6. A dopamine agonist is administered in an attempt to replace dopamine neurotransmission and stimulate dopamine receptors. A monoamine oxidase inhibitor is given to prevent the breakdown of dopamine and serotonin and so boost the residual levels of these neurotransmitters. The active form of vitamin B6, pyridoxal 5’-phosphate is the cofactor of AADC and so vitamin B6 (in the form of pyridoxine or pyridoxal 5’-phosphate) is administered to boost residual enzyme activity. Folinic acid is also commonly administered in AADC deficiency due to the potential for depletion of the methyl donor pool by increased methylation of L-dopa to 3OMD. Other medications that have also been administered in AADC deficiency include the anticholinergic trihexyphenidyl and melatonin. Unfortunately, the response of patients to medication in the majority of cases is unsatisfactory with many patients showing little improvement.
L-dopa (levodopa) has been administered in some cases of AADC deficiency. However it should be noted that these patients have a specific mutation that alters the affinity of the AADC enzyme for the substrate L-dopa and this treatment is unlikely to be effective in the majority of cases.
Clinical guidelines for AADC deficiency are currently being developed as part of the iNTD project. More information on the project can be found here:
Multiple research programmes are ongoing into different aspects of AADC deficiency with particular emphasis on improving treatment. A gene therapy clinical trial for AADC deficiency is in preparation due to take place at the National Institutes of Health (NIH) in Bethesda, USA. The iNTD project is compiling a clinical database of patients with AADC deficiency and developing clinical guidelines for the disorder. The effect of individual mutations on the AADC enzyme and the consequences for cellular function and patient treatment is being investigated in Italy. As well as this, in London induced pluripotent stem cells (iPSCs) are being generated from AADC deficiency patient skin fibroblasts to be differentiated into dopaminergic neurons to investigate functional changes and potential new treatments.
For more information on any of these projects please visit the following pages of our website: