Aromatic L-amino acid decarboxylase (AADC) deficiency

What is AADC deficiency?

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal recessive disorder of neurotransmitter synthesis.15 It presents with a wide range of symptoms, which develop early in life and include life-limiting motor and autonomic dysfunction and developmental delay.2,3

AADC deficiency: A rare neurometabolic disease 

 This short animated video provides an overview of AADC deficiency including prevalence, red flag signs and symptoms, and the clinical tests required to confirm a diagnosis.  

 This video was developed and funded by PTC Therapeutics. All rights reserved. 

What causes AADC deficiency?

AADC deficiency results from pathogenic variants in the dopa decarboxylase gene, DDC, encoding for the AADC enzyme.1,2

There are currently around 100 disease-causing variants, with both homozygous and compound heterozygous mutations identified in patients with AADC deficiency.2,3,6,7

The most common variant is IVS6+4A>T; however, this mutation is present in less than half of known AADC deficiency cases.1,2

There is no clear association between the severity of AADC deficiency with specific known variants; most variants result in a variable clinical presentation.2

Loss of AADC enzyme activity leads to monoamine neurotransmitter deficiency and key signs/symptoms of AADC deficiency2
The loss of AADC enzyme activity results in the accumulation of serotonin and dopamine precursors (ie, 5-HTP, L-DOPA, 3-OMD) and reduced levels of downstream metabolites of serotonin and catecholamines (ie, 5-HIAA, HVA, and MHPG).1

This leads to a severe combined deficiency of dopamine, serotonin, and other catecholamines such as norepinephrine and epinephrine.1,2

In the absence of these neurotransmitters, neuronal signaling is inhibited in the central nervous system, which is required for motor development, behavior, and ​autonomic function.2

Reduced levels of neurotransmitters contribute to the spectrum of symptoms experienced by patients with AADC deficiency.8

The signs and symptoms of AADC deficiency

AADC deficiency is characterized by a wide range of clinical presentations.2,8

Patients with AADC deficiency present over a spectrum of phenotypes with motor dysfunction, failure to thrive, and limitations in attaining key developmental milestones.1,2,9 Patients with AADC deficiency may also present with autonomic dysfunction.1,2

Hypotonia, oculogyric crises, delayed motor development, and autonomic symptoms are consistently associated with AADC deficiency.2 However, severity can range from mild to severe, accounting for a wide variability in presentation.2 ​Patients with more severe forms of AADC deficiency may ​never meet developmental milestones.9

Literature review of 117 patients with AADC deficiency reporting patient characteristics where available1


Symptoms of AADC deficiency frequently appear early in life; according to published consensus guidelines:1,2

  • The age of onset of symptoms is typically within the first year of life, with the average patient showing symptoms at 2.7 months of age (n=68)
  • Despite this young age of symptom onset, the mean age at diagnosis is 3.5 years* (n=87)

AADC deficiency: identifying signs and symptoms and key diagnostic tests

Experts discuss the challenge of identifying the signs and symptoms of patients with AADC deficiency.

Nastassja Himmelreich, Bruria Ben-Zeev and Irina Anslem discuss the signs, symptoms, and key diagnostic tests for AADC deficiency; a collection of expert opinions taken from PTC-sponsored symposium presentations at the European Paediatric Neurology Society (EPNS) Congress, Child Neurological Society (CNS) Annual Meeting, and the International Symposium on Genetic Syndromes with Movement Disorders and Epilepsy (GSMDE) Annual Meeting.

This video was developed and funded by PTC Therapeutics. All rights reserved.

Watch the symposia in full:

The clinical presentation of AADC deficiency can have some similar signs and symptoms to other neurological conditions (e.g., cerebral palsy, epilepsy) and certain behavioral disorders2
AADC deficiency can present with signs and symptoms that may overlap with other conditions.2

nfographic: Clinical presentation of AADC deficiency compared to similarly presenting conditions

Differential diagnoses: distinguishing AADC deficiency from mimics such as cerebral palsy and epilepsy

Experts discuss the challenge of distinguishing AADC deficiency from mimics such as cerebral palsy and epilepsy.

The key clinically differentiating features of AADC deficiency are discussed by Warren Marks, Angeles Garcia Cazorla, and Roser Pons. View a collection of expert opinions taken from PTC-sponsored symposium presentations at the European Paediatric Neurology Society (EPNS) Congress, Child Neurological Society (CNS) Annual Meeting, and the International Symposium on Genetic Syndromes with Movement Disorders and Epilepsy (GSMDE) Annual Meeting.

This video was developed and funded by PTC Therapeutics. All rights reserved.

Watch the symposia in full:

The estimated prevalence of AADC deficiency

AADC deficiency has been documented worldwide1 and can affect patients of varying populations including:1,2

  • Asian
  • Caucasian
  • Arab
  • Iranian
  • Jewish

The term birth prevalence or newborn prevalence is used in favor of incidence, which is the number of new cases of disease in a particular time. Prevalence is the number of living individuals with a disease at a given time and is a more precise term as applied to genetic conditions in which the genotype is present at birth.17

As with many rare diseases that are underdiagnosed, estimating the prevalence of AADC deficiency is challenging, with birth prevalence estimates ranging from 1:32,000 to 1:182,000, depending on the location surveyed.2,18,19Table: survey of literature on birth prevalence of AADC deficiency

Determining an AADC deficiency diagnosis

Patients with key signs and symptoms of AADC deficiency should be tested for a neurotransmitter disorder.Diagnosis of AADC deficiency in pediatric patients with suspected neurotransmitter disorders

The 3 core diagnostic tests to confirm AADC deficiency are:1,2

  1. Genetic testing: In patients with AADC deficiency, mutations in the DDC gene are detected
    •  Current consensus guidelines recommend confirming a diagnosis of AADC deficiency with a genetic test1
  2. CSF neurotransmitter metabolite panel: Expected results in patients with AADC deficiency include:
    • Increased L-DOPA, 3-OMD and 5-HTP
    • Decreased HVA, 5-HIAA, and MHPG
    • Normal pterin levels
  3. Plasma enzyme activity: Patients with AADC deficiency show reduced AADC enzyme activity in plasma

Infographic: The 3 core diagnostic tests used to confirm AADC deficiency

Additional tests can be used to screen for AADC deficiency. These include testing 3-OMD levels in blood or plasma and urine organic acid analysis19,20,23,24

Dried blood spot testing for 3-OMD levels is a simple, rapid, minimally invasive test, that can be used to screen for AADC deficiency.4,19,23

It represents a potential option for newborn screening19,23 and may aid early diagnosis of AADC deficiency to help to bridge the delay in diagnosis of the disease.1,19

If levels of either 3-OMD or vanillactic acid are elevated, further confirmation using the core tests (plasma assay, CSF panel, genetic testing) should be performed.1

What are people asking the experts about the diagnosis of AADC deficiency?

Experts respond to questions posed during the live Q&A sessions from the symposia.

The key clinically differentiating features of AADC deficiency from Warren Marks, Angeles Garcia Cazorla, Bruia Ben-Zeev, Roser Pons, and Irina Anslem, taken from PTC-sponsored symposium presentations at the European Paediatric Neurology Society (EPNS) Congress, Child Neurological Society (CNS) Annual Meeting, and the International Symposium on Genetic Syndromes with Movement Disorders and Epilepsy (GSMDE) Annual Meeting.

This video was developed and funded by PTC Therapeutics. All rights reserved.

Watch the symposia in full:

What is the prognosis of AADC deficiency in toddlers, infants and children?

In patients with neurotransmitter disorders such as AADC deficiency, clinical symptoms can be nonspecific and diagnosis is often delayed.27 As a result, patients and carers experience a difficult path to diagnosis with frequent misdiagnoses, such as cerebral palsy, myasthenia gravis or seizure disorders before the correct diagnosis is achieved.27 In the interim, misdiagnosis or delayed diagnosis may lead to worsening of the patient’s condition.27

Patients may experience other medical complications such as orthopedic complications and possible cardiac complications.1 In addition to growth failure, patients can experience an increased risk of infections, usually as a consequence of complications with impaired feeding and swallowing, reduced mobility, and recurrent hospitalization.1

The continual need for physical assistance and the behavioral complications of AADC deficiency are expected be a great burden to caregivers1,2
Those caring for individuals with AADC deficiency report a substantial impact on their emotional wellbeing as a result of their responsibility. Some caregivers report greater impact on their mental health than their physical health due to the metal tiredness that resulted from having to manage their numerous caring responsibilities. Other commonly reported emotional impacts were sadness as a consequence of watching the individual suffer and anxiety and worry about the individual’s uncertain future. Some caregivers even reported experiencing symptoms of depression and had to see a counselor or therapist to help them cope. 28 

The patient impact in AADC deficiency has also been reported from the perspective of the caregiver. The most commonly reported emotion was frustration which would become apparent when patients were unable to do things for themselves or communicate their needs to others. 29

In AADC deficiency, the delay in diagnosis with frequent misdiagnoses is often stressful for caregivers and can result in significant financial burden to the healthcare system.27

For many patients with AADC deficiency, developmental delays, profound motor deficits and additional neurodevelopmental or psychiatric comorbidities which necessitate lifelong care as seen in other chronic diseases such as epilepsy, are associated with a high burden on caregivers and reduced quality of life.1,30,31

*Retrospective, descriptive, single-center study of patients who received a diagnosis of AADC deficiency at the National Taiwan University Hospital between 2004 and 2016

AADC, aromatic L-amino acid decarboxylase deficiency; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HTP, 5-hydroxytryptophan; 3-OMD, 3-O-methyldopa; CSF, cerebrospinal fluid; CP, cerebral palsy; CSF, cerebrospinal fluid; DDC, dopa decarboxylase; HVA, homovanillic acid; L-Dopa, L-3,4-dihydroxyphenylalanine; MHPG, 3-methoxy-4-hydroxyphenylglycol; MRI magnetic resonance imaging; VLA, vanillactic acid; VMA, vanillylmandelic acid

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References

  1. Wassenberg T, Molero-Luis M, Jeltsch K et al. Orphanet J Rare Dis 2017;12(1):12.
  2. Himmelreich N, Montioli R, Bertoldi M, et al. Mol Genet Metab 2019;127(1):12–22.
  3. Dai L, Ding C, Fang F, et al. Brain Devel 41(2):205–209.
  4. Chen PW, Lee NC, Chien YH et al. Clin Chim Acta 2014;431:19–22.
  5. Brun L, Ngu LH, Keng WT, et al. Neurology 2010;75(suppl):1–13.
  6. Monteleone B, Hyland K. BMC Neurology 2020;20:12.
  7. Micallef J, Stockler-Ipsiroglu S, van Karnebeek CD, et al. Neuropediatrics 2020; 51:229‒232.
  8. Brun L, Ngu LH, Keng WT, et al. Neurology 2010;75(1):64–71.
  9. Hwu WL, Chien C, Lee N, et al. JIMD Rep 2018;40:1–6.
  10. Manegold C, Hoffmann GF, Degen I, et al. J Inherit Metab Dis 2009;32(3):371–380.
  11. Blackburn JS, Mink JW, Augustine EF. Neurol Clin Pract 2012;2(4):311–318.
  12. Hallman–Cooper JL, et al. StatPearls. Treasure Island, FL: StatPearls Publishing; 2019. https://www.ncbi.nlm.nih.gov/books/NBK538147/. Updated July 18, 2019. Accessed September 2021.
  13. Menghi V, Bisulli F, Tinuper P, et al. Nature Sci Sleep 2018;10:317–326.
  14. Shibata M, Kato T, Yoshida T, et al. Seizure 2013;22(10):913–915.
  15. DeFilippis M, Wagner KD. Psychopharm Bull 2016;46(2):18–41.
  16. Kim JS. Korean J Pediatr 2011;54(6):229–233.​
  17. Verhaart IEC, Robertson A, Wilson IJ, et al. Orphanet J Rare Dis 2017;12(1):124.
  18. Hyland K, Reott M. Pediatr Neurol 2020;106:38–42.
  19. Chien YH, Chen PW, Lee NC, et al. Mol Genet Metab 2016;118(4):259–263.
  20. Hyland K, Clayton PT. Clin Chem 1992;38(12):2405–2410.
  21. Himmelreich N, Montioli R, Bertoldi M, et al. Mol Genet Metab. 2021. doi: 10.1016/j.ymgme.2021.06.010. [Epub ahead of print].
  22. Lee HC, Lai CK, Yau KC, et al. Clin Chim Acta 2012;413(1–2):126–130.
  23. Brennenstuhl H, Kohlmüller D, Gramer G, et al. JIMD 2019;43(3):602–610.
  24. Atwal PS, Donti TR, Cardon AL, et al. Mol Genet Metab 2015;115:91–94.
  25. Mills PB, Surtees RA, Champion MP, et al. Hum Mol Gen 2005;14(8):1077–1086.
  26. Brennenstuhl H, Garbade SF, Feyh P, et al. Mol Genet Metab 2020;131(1–2):163–170.
  27. Opladen T, Cortès-Saladelafont E, Mastrangelo M, et al. Mol Genet Metab Rep 2016;9:61–66.
  28. Skrobanski H, Williams K, Werner C et al. Curr Med Res Opin. 2021;1:1-8.
  29.  Williams K, Skrobanski H, Werner C et al. Curr Med Res Opin. 2021;37(8):1353-1361.
  30. Lai ST, Tan WY, Wo MCM, et al. Seizure 2019;71:132–139.
  31. Landfeldt E, Lindgren P, Bell CF, et al. J Neurol 2016;263:906–915.
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