AADCd for Clinicians/Scientists

AADC Deficiency

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: 4.1.1.28) 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.

Clinical Presentation

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. Neurology 75, 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. Neurology 62, 1058-1065.
Helman, G., Pappa, M. B. and Pearl, P. L. (2014). Widening Phenotypic Spectrum of AADC Deficiency, a Disorder of Dopamine and Serotonin Synthesis. JIMD Reports, 17, 23–7. Free full text available.
 
 

Diagnosis

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 (High-Performance Liquid Chromatography) with electrochemical detection. 5-HTP may also be measured. Due to the metabolic block of AADC enzyme, the characteristics pattern of AADCd shows low level of 5-HIAA and HVA, but, hight level of 30MD 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.

UK

Simon Heales PhD

Neurometabolic Unit

National Hospital

Queen Square

London

WC1N 3BG

UK

 

Tel: +44  207837 3611 ext. 3844

email: sheales@ion.ucl.ac.uk

Germany

Professor Nenad Blau 

Senior Consultant in Biochemical Genetics

Division of Inborn Metabolic Diseases

University Childrens Hospital

Department of General Pediatrics

Im Neuenheimer Feld 430

D-69120 Heidelberg

Germany

Tel: + 41 1 266 7544

email: nenad.blau@kispi.unizh.ch

Spain

Rafael Artuch or Aida Ormazabal

Laboratorio de Bioquimica

Hospital Sant Joan de Deu 2

08950 Espluques de Llobreqat

Barcelona

Spain

 

 

Tel: + 34 93 280616900

email: rartuch@hsjdbcn.org

USA

DNA Analysis Only

Keith Hyland PhD

Director, Department Of Neurochemistry

Horizon Molecular Medicine

1 Dunwoody Park

Suite 250

Atlanta

GA 30338USA

Tel: + 1 678 597 5659

email: khyland@horizonmedicine.com

Australia

Dr Sushil Bandodkar

Principal Scientist and Acting Head Biochemistry and Neurolochemistry Department

The Children's Hospital at Westmead

Westmead

New South Wales (NSW)

2145 Australia

Tel: + 61 298453289

email: susgil.bandodkar@health.nsw.gov.au

Taiwan

DNA Analysis Available

Wang-Tso Lee, MD,PhD

Director of Child Neurology

National Taiwan University Hospital

7 Chung-Shan South Road

Taipei

Taiwan

 

 

Tel: + 886 2 23123456 ext 9501495

email: leeped@hotmail.com

Germany

Georg F Hoffmann MD

University of Heidelberg

Im Neuenheimer Feld 153

69120 Heidelberg

Germany

 

 

Tel: + 49 06 221 562302

email: Georg.Hoffmann@med.uni-heidelberg.de

The Netherlands

Marcel Verbeek

Neurochemist

Radbound University

Nijmegen Medical Centre

Department of Neurology

Laboratory of Paediatrics & Neurology

830 LKN

P.O. Box 9101

6500 HB Nijmegen

The Netherlands

Tel: + 31 24 3615192/3624567 ext. 2309

email: m.verbeek@cukz.umcn.nl

France

Laurence Christa PhD

Metabolic Biochemical Laboratory

Necker Hospital

149-161 Rue de Sevres

75743 Paris Cedex 15

France

 

 

 

Tel: + 33 1 44 38 15 54

email: Laurence.christa@parisdescartes.fr

Treatment

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 AADCd enzyme for the substrate L-dopa and this treatment is unlikely to be effective in the majority of cases.

Brun L et al. (2010) Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology 75, 64-71.

Since publication of the above article transdermal rotigotine (dopamine agonist) patches have been administered in AADC deficiency. Please see the following publication for more information:

Mastrangelo, M. et al (2013). Transdermal rotigotine in the treatment of aromatic L-amino acid decarboxylase deficiency. Movement Disorders, 28, 556–7.

Clinical guidelines for AADC deficiency are currently being developed as part of the iNTD project.

Research

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.

Please see the following clinical review articles for more information:

Gene therapy clinical trials
AADC Induced Pluripotent Stem Cell (iPSC) Research
Analysis of pathogenic mutations in AADC deficiency:
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iNTD database and clinical guideline development:

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