Aromatic l-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up

Summary

Background

Aromatic l-amino acid decarboxylase (AADC) deficiency is a disorder of biogenic amine metabolism resulting in generalized combined deficiency of serotonin, dopamine and catecholamines. Main clinical features are developmental delay, muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Response to therapy has been variable and unsatisfactory; the overall prognosis is guarded.

Methods

To gain more insight into this rare disorder we collected clinical and laboratory data of nine German patients. All patients were clinically examined by one investigator, and their responses to different drug regimes were evaluated by the patients’ charts.

Results

Symptoms were obvious from early infancy. Later, main neurological features were truncal muscular hypotonia, hypokinesia, oculogyric crises and rigor. Three patients had single seizures. All patients presented distinct extraneurological symptoms, such as hypersalivation, hyperhidrosis, nasal congestion, sleep disturbances and hypoglycaemia. In CSF all patients revealed the pattern typical of AADC with decreased concentrations of homovanillic and 5-hydroxyindoleacetic acid and elevated concentration of 3-ortho-methyldopa. Diagnosis was confirmed by measurement of AADC activity in plasma in all patients. Drug regimes consisted of vitamin B6, dopamine agonists, MAO inhibitors and anticholinergics in different combinations. No patient achieved a complete recovery from neurological symptoms, but partial improvement of mobility and mood could be achieved in some.

Conclusion

AADC deficiency is a severe neurometabolic disorder, characterized by muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Medical treatment is challenging, but a systematic trial of the different drugs is worthwhile.

This is a preview of subscription content, access via your institution.

Fig. 1

Abbreviations

3-OMD:

3-ortho-methyldopa

5-HIAA:

5-hydroxyindoleacetic acid

5-MTHF:

5-methyltetrahydrofolate

AADC:

aromatic l-amino acid decarboxylase

CSF:

cerebrospinal fluid

HVA:

homovanillic acid

MAO:

monoamine oxidase

References

  1. Abdenur JE, Abeling NG, Specola N, etal (2006) Aromatic l-amino acid decarboxylase deficiency: unusual neonatal presentation and additional findings in organic acid analysis. Mol Gen Metab 87: 48–53. doi:10.1016/j.ymgme.2005.09.007.

    Article  CAS  Google Scholar 

  2. Abeling NG, van Gennip AH, Barth PG, van Cruchten A, Westra M, Wijburg FA (1998) Aromatic l-amino acid decarboxylase deficiency: a new case with a mild clinical presentation and unexpected laboratory findings. J Inherit Metab Dis 21: 240–242. doi:10.1023/A:1005307919767.

    PubMed  Article  CAS  Google Scholar 

  3. Anselm IA, Darras BT (2006) Catecholamine toxicity in aromatic l-amino acid decarboxylase deficiency. Pediatr Neurol 35(2): 142–144. doi:10.1016/j.pediatrneurol.2006.01.008.

    PubMed  Article  Google Scholar 

  4. Brautigam C, Wevers R, Hyland K, etal (2000) The influence of l-dopa on methylation capacity in aromatic l-amino acid decarboxylase deficiency. J Inherit Metab Dis 23: 321–324. doi:10.1023/A:1005698223186.

    PubMed  Article  CAS  Google Scholar 

  5. Brautigam C, Hyland K, Wevers R, etal (2002) Clinical and laboratory findings in twins with neonatal epileptic encephalopathy mimicking aromatic l-amino acid decarboxylase deficiency. Neuropediatrics 33: 113–117. doi:10.1055/s-2002-33673.

    PubMed  Article  CAS  Google Scholar 

  6. Burlina AB, Burlina AP, Hyland K, Bonafe L, Blau N (2001) Autistic syndrome and aromatic l-aminoacid decarboxylase deficiency. J Inherit Metab Dis 24(Supplement 1): 34. doi:10.1023/A:1012471928628.

    Google Scholar 

  7. Chang YT, Mues G, McPherson JD, etal (1998) Mutations in the human aromatic l-amino acid decarboxylase gene. JInherit Metab Dis 21: 4. doi:10.1023/A:1005467830063.

    Article  Google Scholar 

  8. Chang YT, Radhakant S, Marsh JL, etal (2004) Levodopa-responsive aromatic l-amino acid decarboxylase deficiency. Ann Neurol 55: 435–438. doi:10.1002/ana.20055.

    PubMed  Article  CAS  Google Scholar 

  9. Fiumara A, Bräutigam C, Hyland K (2002) Aromatic l-amino acid decarboxylase deficiency with hyperdopaminuria. Clinical and laboratory findings in response to different therapies. Neuropediatrics 33: 203–208. doi:10.1055/s-2002-34497.

    PubMed  Article  CAS  Google Scholar 

  10. Hyland K, Clayton PT (1990) Aromatic amino acid decarboxylase deficiency in twins. J Inherit Metab Dis 13: 301–304. doi:10.1007/BF01799380.

    PubMed  Article  CAS  Google Scholar 

  11. Hyland K, Clayton PT (1992) Aromatic l-amino acid decarboxylase deficiency: diagnostic methodology. Clin Chem 38: 2405–2410.

    PubMed  CAS  Google Scholar 

  12. Hyland K, Surtees RAH, Rodeck C, Clayton PT (1992) Aromatic l-amino acid decarboxylase: deficiency: clinical features, diagnosis and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 42: 1980–1988.

    PubMed  CAS  Google Scholar 

  13. Ito S, Nakayama T, Die S, etal (2008) Aromatic l-amino acid decarboxylase deficiency associated with epilepsy mimicking non-epileptic involuntary movements. Dev Med Child Neurol 50(11): 876–878.

    Google Scholar 

  14. Korenke GC, Christen HJ, Hyland K, Hunnemann D, Hanefeld F (1997) Aromatic l-amino acid decarboxylase deficiency: an extrapyramidal movement disorder with oculogyric crisis. Eur J Pediatr Neurol 1: 67–71.

    CAS  Google Scholar 

  15. Lee HF, Tsai CR, Chi CS, Chang TM, Lee HJ (2008) Aromatic l-amino acid decarboxylase deficiency in Taiwan. Eur J Paediatr Neurol. Jun 20. [Epub ahead of print].

  16. Malller A, Hyland K, Milstien S, Biaggioni I, Butler IJ (1997) Aromatic l-amino acid decarboxylase deficiency: clinical features, diagnosis and treatment of a second family. J Child Neurol 12: 349–354.

    PubMed  Article  CAS  Google Scholar 

  17. Mills PB, Surtees RA, Champion MP, etal (2005) Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5′-phosphate oxidase. Hum Mol Genet 14: 1077–1086.

    PubMed  Article  CAS  Google Scholar 

  18. Pons R, Ford B, Chiriboga CA, etal (2004) Aromatic l-amino acid decarboxylase deficiency: clinical features, treatment and prognosis. Neurology 62: 1058–1065.

    PubMed  CAS  Google Scholar 

  19. Swoboda KJ, Hyland K, Goldstein DS, etal (1999) Clinical and therapeutic observations in aromatic l-amino acid decarboxylase deficiency. Neurology 53: 1205–1211.

    PubMed  CAS  Google Scholar 

  20. Swoboda KJ, Saul JP, McKenna C, Speller NB, Hyland K (2003) Aromatic l-amino acid decarboxylase deficiency: overview of clinical features and outcome. Ann Neurol 54(Supplement 6): 49–55.

    Article  Google Scholar 

  21. Tay SK, Poh KS, Hyland K, etal (2007) Unusually mild phenotype of AADC deficiency in 2 siblings. Mol Genet Metab 91(4): 374–378.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgement

The authors thank Professor Keith Hyland (Horizon Molecular Medicine, Atlanta, GA, USA) and Dr Rüdiger Kläs and Dr Friedrich W. Cremer (Zentrum für Humangenetik, Mannheim, Germany) for performing molecular genetic investigations of the AADC gene.

Author information

Affiliations

Authors

Corresponding author

Correspondence to F. Hörster.

Additional information

Competing interests: None declared

References to electronic databases: Aromatic l-amino acid decarboxylase deficiency: OMIM #608643. Aromatic l-amino acid decarboxylase: EC 4.1.1.28.

Communicating editor: Michael Gibson

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Manegold, C., Hoffmann, G.F., Degen, I. et al. Aromatic l-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up. J Inherit Metab Dis 32, 371–380 (2009). https://doi.org/10.1007/s10545-009-1076-1

Download citation

Keywords

  • Levodopa
  • Dystonia
  • Bromocriptine
  • Dopamine Agonist
  • Selegiline