Top

Published in:

Open Access 01-12-2017 | Review

Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency

Authors: Tessa Wassenberg, Marta Molero-Luis, Kathrin Jeltsch, Georg F. Hoffmann, Birgit Assmann, Nenad Blau, Angeles Garcia-Cazorla, Rafael Artuch, Roser Pons, Toni S. Pearson, Vincenco Leuzzi, Mario Mastrangelo, Phillip L. Pearl, Wang Tso Lee, Manju A. Kurian, Simon Heales, Lisa Flint, Marcel Verbeek, Michèl Willemsen, Thomas Opladen

Published in: Orphanet Journal of Rare Diseases | Issue 1/2017

Abstract

Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine. Onset is early in life, and key clinical symptoms are hypotonia, movement disorders (oculogyric crisis, dystonia, and hypokinesia), developmental delay, and autonomic symptoms.

In this consensus guideline, representatives of the International Working Group on Neurotransmitter Related Disorders (iNTD) and patient representatives evaluated all available evidence for diagnosis and treatment of AADCD and made recommendations using SIGN and GRADE methodology. In the face of limited definitive evidence, we constructed practical recommendations on clinical diagnosis, laboratory diagnosis, imaging and electroencephalograpy, medical treatments and non-medical treatments. Furthermore, we identified topics for further research. We believe this guideline will improve the care for AADCD patients around the world whilst promoting general awareness of this rare disease.

Available only for authorised users

Hyland K, Clayton PT. Aromatic amino acid decarboxylase deficiency in twins. J Inherit Metab Dis. 1990;13(3):301–4.CrossRefPubMed

Brun L, Ngu LH, Keng WT, Ch'ng GS, Choy YS, Hwu WL, et al. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology. 2010;75(1):64–71. doi:10.1212/WNL.0b013e3181e620ae.CrossRefPubMed

Alfadhel M, Kattan R. Aromatic amino Acid decarboxylase deficiency not responding to pyridoxine and bromocriptine therapy: case report and review of response to treatment. J Cent Nerv Syst Dis. 2014;6:1–5. doi:10.4137/JCNSD.S12938.CrossRefPubMedPubMedCentral

Lee HF, Tsai CR, Chi CS, Chang TM, Lee HJ. Aromatic L-amino acid decarboxylase deficiency in Taiwan. Eur J Paediatr Neurol. 2009;13(2):135–40.CrossRefPubMed

Leuzzi V, Mastrangelo M, Polizzi A, Artiola C, van Kuilenburg AB, Carducci C et al. Report of two never treated adult sisters with aromatic L-amino acid decarboxylase deficiency: a portrait of the natural history of the disease or an expanding phenotype? JIMD Rep. 2014. doi:10.1007/8904_2014_295.

Ng J, Papandreou A, Heales SJ, Kurian MA. Monoamine neurotransmitter disorders-clinical advances and future perspectives. Nat Rev Neurol. 2015;11(10):567–84. doi:10.1038/nrneurol.2015.172.CrossRefPubMed

Chang YT, Sharma R, Marsh JL, McPherson JD, Bedell JA, Knust A, et al. Levodopa-responsive aromatic L-amino acid decarboxylase deficiency. Ann Neurol. 2004;55(3):435–8.CrossRefPubMed

INTD. International Working Group on Neurotransmitter Related Disorders. 2013. www.intd-online.org.

INTD. International working group on neurotransmitter related disorders Patient Registry. 2013. https://intd-registry.org.

10.

AADC research trust. The AADC research trust literature database. 2015. http://www.aadcresearch.org/page/by-leading-author/. Accessed 09 Feb 2016.

11.

WHO. International clinical trials registry platform. 2016. http://apps.who.int/trialsearch/. Accessed Feb 2016.

12.

NIH. ClinicalTrials.gov, a service of the U.S. National Institutes of Health. 2015. https://clinicaltrials.gov/. Accessed Feb 2016.

13.

SIGN. Scottish Intercollegiate Guideline Network. 2014. http://www.sign.ac.uk.

14.

Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. doi:10.1016/j.jclinepi.2010.04.026.CrossRefPubMed

15.

Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol. 2011;64(4):395–400. doi:10.1016/j.jclinepi.2010.09.012.CrossRefPubMed

16.

Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401–6. doi:10.1016/j.jclinepi.2010.07.015.CrossRefPubMed

17.

Guyatt GH, Oxman AD, Schunemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011;64(4):380–2. doi:10.1016/j.jclinepi.2010.09.011.CrossRefPubMed

18.

Arnoux JB, Damaj L, Napuri S, Serre V, Hubert L, Cadoudal M, et al. Aromatic L-amino acid decarboxylase deficiency is a cause of long-fasting hypoglycemia. J Clin Endocrinol Metab. 2013;98(11):4279–84. doi:10.1210/jc.2013-2740.CrossRefPubMed

19.

Barth M, Serre V, Hubert L, Chaabouni Y, Bahi-Buisson N, Cadoudal M, et al. Kinetic analyses guide the therapeutic decision in a novel form of moderate aromatic Acid decarboxylase deficiency. JIMD Rep. 2012;3:25–32. doi:10.1007/8904_2011_43.CrossRefPubMed

20.

Graziano C, Wischmeijer A, Pippucci T, Fusco C, Diquigiovanni C, Noukas M, et al. Syndromic intellectual disability: a new phenotype caused by an aromatic amino acid decarboxylase gene (DDC) variant. Gene. 2015;559(2):144–8. doi:10.1016/j.gene.2015.01.026.CrossRefPubMed

21.

Gucuyener K, Kasapkara CS, Tumer L, Verbeek MM. Aromatic L-amino acid decarboxylase deficiency: a new case from Turkey with a novel mutation. Ann Indian Acad Neurol. 2014;17(2):234–6. doi:10.4103/0972-2327.132652.CrossRefPubMedPubMedCentral

22.

Helman G, Pappa MB, Pearl PL. Widening phenotypic spectrum of AADC deficiency, a disorder of dopamine and serotonin synthesis. JIMD Rep. 2014. doi:10.1007/8904_2014_327.

23.

Lee HC, Lai CK, Yau KC, Siu TS, Mak CM, Yuen YP, et al. Non-invasive urinary screening for aromatic L-amino acid decarboxylase deficiency in high-prevalence areas: a pilot study. Clin Chim Acta. 2012;413(1-2):126–30. doi:10.1016/j.cca.2011.09.008.CrossRefPubMed

24.

Hwu WL, Muramatsu S, Tseng SH, Tzen KY, Lee NC, Chien YH, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med. 2012;4(134):134ra61. doi:10.1126/scitranslmed.3003640.CrossRefPubMed

25.

Molero-Luis M, Serrano M, Ormazabal A, Perez-Duenas B, Garcia-Cazorla A, Pons R, et al. Homovanillic acid in cerebrospinal fluid of 1388 children with neurological disorders. Dev Med Child Neurol. 2013;55(6):559–66. doi:10.1111/dmcn.12116.CrossRefPubMed

26.

Wassenberg T, Willemsen MA, Geurtz PB, Lammens M, Verrijp K, Wilmer M, et al. Urinary dopamine in aromatic L-amino acid decarboxylase deficiency: the unsolved paradox. Mol Genet Metab. 2010;101(4):349–56. doi:10.1016/j.ymgme.2010.08.003.CrossRefPubMed

27.

Wassenberg T, Monnens LA, Geurtz BP, Wevers RA, Verbeek MM, Willemsen MA. The paradox of hyperdopaminuria in aromatic L-amino Acid deficiency explained. JIMD Rep. 2012;4:39–45. doi:10.1007/8904_2011_84.CrossRefPubMed

28.

Haliloglu G, Vezir E, Baydar L, Onol S, Sivri S, Coskun T, et al. When do we need to perform a diagnostic lumbar puncture for neurometabolic diseases? Positive yield and retrospective analysis from a tertiary center. Turk J Pediatr. 2012;54(1):52–8.PubMed

29.

Vutskits L, Menache C, Manzano S, Haenggeli CA, Habre W. Anesthesia management in a young child with aromatic l-amino acid decarboxylase deficiency. Paediatr Anaesth. 2006;16(1):82–4. doi:10.1111/j.1460-9592.2005.01605.x.CrossRefPubMed

30.

Berkowitz DH, Ganesh A. Combined general and regional anesthetic in a child with aromatic L-amino acid decarboxylase deficiency. Anesth Analg. 2006;103(6):1630–1. doi:10.1213/01.ane.0000247197.78421.93.CrossRefPubMed

31.

Burlina AB, Burlina AP, Hyland K, Bonafé L, Blau N. Autistic syndrome and aromatic L-amino acid decarboxylase (AADC) deficiency. J Inherit Metab Dis. 2001;24(S1):34.

32.

Choy YS, Ngu LH, Chen BC, Ong LC, Blau N. Variable manifestations and therapeutic response of aromatic l-amino acid decarboxylase deficiency. JIMD. 2006;29(144):15.1.

33.

Chang YT, Mues G, McPherson JD, Bedell JA, Marsh JL, Hyland K. Mutations in the human aromatic l-amino acid decarboxylase gene. J Inherit Metab Dis. 1998;21(S2):4.

34.

Fiumara A, Brautigam C, Hyland K, Sharma R, Lagae L, Stoltenborg B, et al. Aromatic L-amino acid decarboxylase deficiency with hyperdopaminuria. Clinical and laboratory findings in response to different therapies. Neuropediatrics. 2002;33(4):203–8.CrossRefPubMed

35.

Tay SK, Poh KS, Hyland K, Pang YW, Ong HT, Low PS, et al. Unusually mild phenotype of AADC deficiency in 2 siblings. Mol Genet Metab. 2007;91(4):374–8.CrossRefPubMed

36.

Ide S, Sasaki M, Kato M, Shiihara T, Kinoshita S, Takahashi JY, et al. Abnormal glucose metabolism in aromatic l-amino acid decarboxylase deficiency. Brain Dev. 2010;32:506–10.CrossRefPubMed

37.

Menache C, Manzano S, Cruzado D, Mirabeau M, Haenggeli CA. Aromatic l-amino acid decarboxylase deficiency in two siblings. Ann Neurol. 2002;52(3S):S159–S60.

38.

Ito S, Nakayma T, Ide S, Ito Y, Oguni H, Goto YI, et al. Aromatic l-amino acid decarboxylase deficiency associated with epilepsy mimicking non-epileptic involuntary movements. Dev Med Child Neur. 2008;50:876–8.CrossRef

39.

Anselm IA, Darras BT. Catecholamine toxicity in aromatic L-amino acid decarboxylase deficiency. Pediatr Neurol. 2006;35(2):142–4.CrossRefPubMed

40.

Manegold C, Hoffmann GF, Degen I, Ikonomidou H, Knust A, Laass MW, et al. Aromatic L-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up. J Inherit Metab Dis. 2009;32(3):371–80.CrossRefPubMed

41.

Pons R, Ford B, Chiriboga CA, Clayton PT, Hinton V, Hyland K, et al. Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis. Neurology. 2004;62(7):1058–65.CrossRefPubMed

42.

Korenke GC, Christen HJ, Hyland K, Hunneman DH, Hanefeld F. Aromatic L-amino acid decarboxylase deficiency: an extrapyramidal movement disorder with oculogyric crises. Eur J Paediatr Neurol. 1997;1(2-3):67–71.CrossRefPubMed

43.

Abeling NG, Brautigam C, Hoffmann GF, Barth PG, Wevers RA, Jaeken J, et al. Pathobiochemical implications of hyperdopaminuria in patients with aromatic L-amino acid decarboxylase deficiency. J Inherit Metab Dis. 2000;23(4):325–8.CrossRefPubMed

44.

Hyland K, Surtees RA, Rodeck C, Clayton PT. Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology. 1992;42(10):1980–8.CrossRefPubMed

45.

Swoboda KJ, Saul JP, McKenna CE, Speller NB, Hyland K. Aromatic L-amino acid decarboxylase deficiency: overview of clinical features and outcomes. Ann Neurol. 2003;54 Suppl 6:S49–55.CrossRefPubMed

46.

Knust A. Aromatischer L-aminosauredecarboxylasemangel: charakterisierung und therapiestudie einer ‘neuen’ neurometabolischen erkrankung der dopamin- und serotoninbiosynthese [Human Medicine]. Marburg: Phillips-Universitat Marburg; 2002.

47.

Brautigam C, Wevers RA, Hyland K, Sharma RK, Knust A, Hoffman GF. The influence of L-dopa on methylation capacity in aromatic L-amino acid decarboxylase deficiency: biochemical findings in two patients. J Inherit Metab Dis. 2000;23(4):321–4.CrossRefPubMed

48.

Montioli R, Dindo M, Giorgetti A, Piccoli S, Cellini B, Voltattorni CB. A comprehensive picture of the mutations associated with aromatic amino acid decarboxylase deficiency: from molecular mechanisms to therapy implications. Hum Mol Genet. 2014;23(20):5429–40. doi:10.1093/hmg/ddu266.CrossRefPubMed

49.

Mills PB, Surtees RA, Champion MP, Beesley CE, Dalton N, Scambler PJ, et al. Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase. Hum Mol Genet. 2005;14(8):1077–86. doi:10.1093/hmg/ddi120.CrossRefPubMed

50.

Brautigam C, Hyland K, Wevers R, Sharma R, Wagner L, Stock GJ, et al. Clinical and laboratory findings in twins with neonatal epileptic encephalopathy mimicking aromatic L-amino acid decarboxylase deficiency. Neuropediatrics. 2002;33(3):113–7.CrossRefPubMed

51.

Surtees R, Hyland K. L-3,4-dihydroxyphenylalanine (levodopa) lowers central nervous system S-adenosylmethionine concentrations in humans. J Neurol Neurosurg Psychiatry. 1990;53(7):569–72.CrossRefPubMedPubMedCentral

52.

Hyland K. Clinical utility of monoamine neurotransmitter metabolite analysis in cerebrospinal fluid. Clin Chem. 2008;54(4):633–41. doi:10.1373/clinchem.2007.099986.CrossRefPubMed

53.

Verbeek MM, Geurtz PB, Willemsen MA, Wevers RA. Aromatic L-amino acid decarboxylase enzyme activity in deficient patients and heterozygotes. Mol Genet Metab. 2007;90(4):363–9.CrossRefPubMed

54.

Blau N. PNDdb: locus-specific database of gene variants causing BH4 deficiencies and other PND (formerly BIOMDB). 2016. http://www.biopku.org/home/pnddb.asp.

55.

Atwal PS, Donti TR, Cardon AL, Bacino CA, Sun Q, Emrick L, et al. Aromatic L-amino acid decarboxylase deficiency diagnosed by clinical metabolomic profiling of plasma. Mol Genet Metab. 2015;115(2-3):91–4. doi:10.1016/j.ymgme.2015.04.008.CrossRefPubMed

56.

Swoboda KJ, Hyland K, Goldstein DS, Kuban KC, Arnold LA, Holmes CS, et al. Clinical and therapeutic observations in aromatic L-amino acid decarboxylase deficiency. Neurology. 1999;53(6):1205–11.CrossRefPubMed

57.

Chen PW, Lee NC, Chien YH, Wu JY, Wang PC, Hwu WL. Diagnosis of aromatic l-amino acid decarboxylase deficiency by measuring 3-O-methyldopa concentrations in dried blood spots. Clin Chim Acta. 2014;431C:19–22. doi:10.1016/j.cca.2014.01.034.CrossRef

58.

Abeling NG, van Gennip AH, Barth PG, van CA, Westra M, Wijburg FA. Aromatic L-amino acid decarboxylase deficiency: a new case with a mild clinical presentation and unexpected laboratory findings. J Inherit Metab Dis. 1998;21(3):240–2.CrossRefPubMed

59.

Lee LK, Cheung KM, Cheng WW, Ko CH, Lee HH, Ching CK, et al. A rare cause of severe diarrhoea diagnosed by urine metabolic screening: aromatic L-amino acid decarboxylase deficiency. Hong Kong Med J. 2014;20(2):161–4. doi:10.12809/hkmj133922.CrossRefPubMed

60.

Antonini A, Poewe W. Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson’s disease. Lancet Neurol. 2007;6(9):826–9. doi:10.1016/S1474-4422(07)70218-1.CrossRefPubMed

61.

(EMA) EMA. Amendments to be included in the relevant sections of the summaryor product characteristics for bromocriptine containing medicinal products..In: Union E, editor. London; 2009. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Ergot_derived_dopamine_agonists_31/WC500011454.pdf.

62.

Andersohn F, Garbe E. Cardiac and noncardiac fibrotic reactions caused by ergot-and nonergot-derived dopamine agonists. Mov Disord. 2009;24(1):129–33. doi:10.1002/mds.22385.CrossRefPubMed

63.

Katzenschlager R, Sampaio C, Costa J, Lees A. Anticholinergics for symptomatic management of Parkinson’s disease. Cochrane Database Syst Rev. 2003;2:CD003735. doi:10.1002/14651858.CD003735.

64.

Jankovic J. Medical treatment of dystonia. Mov Disord. 2013;28(7):1001–12. doi:10.1002/mds.25552.CrossRefPubMed

65.

Abdenur JE, Abeling N, Specola N, Jorge L, Schenone AB, van Cruchten AC, et al. Aromatic l-aminoacid decarboxylase deficiency: unusual neonatal presentation and additional findings in organic acid analysis. Mol Genet Metab. 2006;87(1):48–53. doi:10.1016/j.ymgme.2005.09.007.CrossRefPubMed

66.

Manji H, Howard RS, Miller DH, Hirsch NP, Carr L, Bhatia K, et al. Status dystonicus: the syndrome and its management. Brain. 1998;121(Pt 2):243–52.CrossRefPubMed

67.

Allen NM, Lin JP, Lynch T, King MD. Status dystonicus: a practice guide. Dev Med Child Neurol. 2014;56(2):105–12. doi:10.1111/dmcn.12339.CrossRefPubMed

68.

Christine CW, Starr PA, Larson PS, Eberling JL, Jagust WJ, Hawkins RA, et al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology. 2009;73(20):1662–9. doi:10.1212/WNL.0b013e3181c29356.CrossRefPubMedPubMedCentral

69.

San Sebastian W, Kells AP, Bringas J, Samaranch L, Hadaczek P, Ciesielska A et al. Safety and tolerability of MRI-guided infusion of AAV2-hAADC into the mid-brain of non-human primate. Mol Ther Methods Clin Dev. 2014;3. doi:10.1038/mtm.2014.49.

70.

Fidika A, Salewski C, Goldbeck L. Quality of life among parents of children with phenylketonuria (PKU). Health Qual Life Outcomes. 2013;11:54. doi:10.1186/1477-7525-11-54.CrossRefPubMedPubMedCentral

71.

Newton K, Lamarche K. Take the challenge: strategies to improve support for parents of chronically ill children. Home Healthc Nurse. 2012;30(5):E1–8. doi:10.1097/NHH.0b013e318252c3d5.CrossRefPubMed

72.

Racine E, Bell E, Yan A, Andrew G, Bell LE, Clarke M, et al. Ethics challenges of transition from paediatric to adult health care services for young adults with neurodevelopmental disabilities. Paediatr Child Health. 2014;19(2):65–8.PubMedPubMedCentral

73.

Camfield P, Camfield C. Transition to adult care for children with chronic neurological disorders. Ann Neurol. 2011;69(3):437–44. doi:10.1002/ana.22393.CrossRefPubMed

74.

Hyland K, Clayton PT. Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology. Clin Chem. 1992;38(12):2405–10.PubMed

75.

Kuo SJ, Ma GC, Chang SP, Wu HH, Chen CP, Chang TM, et al. Preimplantation and prenatal genetic diagnosis of aromatic L-amino acid decarboxylase deficiency with an amplification refractory mutation system-quantitative polymerase chain reaction. Taiwan J Obstet Gynecol. 2011;50(4):468–73. doi:10.1016/j.tjog.2011.10.012.CrossRefPubMed

76.

Chen HF, Chang SP, Wu SH, Lin WH, Lee YC, Ni YH, et al. Validating a rapid, real-time, PCR-based direct mutation detection assay for preimplantation genetic diagnosis. Gene. 2014;548(2):299–305. doi:10.1016/j.gene.2014.07.039.CrossRefPubMed

77.

Hoffmann GF, Assmann BE. Aromatic l-amino acid decarboxylase deficiency. In: Hoffmann GF, Blau N, editors. Congenital neurotransmitter disorders: a clinical approach. 1 ed. New York: Nova Science Publishers; 2014. p. 65-80.

Title: Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency
Authors: Tessa Wassenberg
Marta Molero-Luis
Kathrin Jeltsch
Georg F. Hoffmann
Birgit Assmann
Nenad Blau
Angeles Garcia-Cazorla
Rafael Artuch
Roser Pons
Toni S. Pearson
Vincenco Leuzzi
Mario Mastrangelo
Phillip L. Pearl
Wang Tso Lee
Manju A. Kurian
Simon Heales
Lisa Flint
Marcel Verbeek
Michèl Willemsen
Thomas Opladen
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2017
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-016-0522-z

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2017

Incidence, disease onset and short-term outcome in urea cycle disorders –cross-border surveillance in Germany, Austria and Switzerland

The cost of severe haemophilia in Europe: the CHESS study

Central nervous system manganese induced lesions and clinical consequences in patients with hereditary hemorrhagic telangiectasia

Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

Prevalence, incidence and carrier frequency of 5q–linked spinal muscular atrophy – a literature review

Pulmonary hypertension in lymphangioleiomyomatosis: prevalence, severity and the role of carbon monoxide diffusion capacity as a screening method