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Neurotransmitter disorders are an expanding group of inherited neurometabolic syndromes that affect children

Neurotransmitters, like dopamine, support a variety of functions in the body, including cognition, emotion, and movement. Dopamine is specifically involved with decision-making, motivation, and motor control.1-3

Within a growing group of genetic conditions referred to broadly as neurotransmitter disorders, many are marked by a disruption in monoamine neurotransmitter synthesis, metabolism, and homeostasis. The disruption in synthesis leads to a range of neurological manifestations in childhood, including1,4:

  • Developmental delay
  • Motor disorders
  • Epilepsy
  • Autonomic dysfunction
  • Neuropsychiatric features

One neurotransmitter disorder is Aromatic L-amino Acid Decarboxylase (AADC) deficiency, which is a genetic disorder associated with defects in neurotransmitter synthesis that can lead to a manifestation of a broad spectrum of symptoms.

The most common symptoms of this autosomal recessive disorder are5-8:

  • Hypotonia
  • Developmental delay
  • Movement disorders, especially oculogyric crises

Many of the most common symptoms of AADC deficiency can also be attributed to a number of other conditions, resulting in potential misdiagnosis.1,4-6,9-12

Some of these conditions include1,4-6,9-12:

  • Cerebral palsy
  • Epilepsy
  • Juvenile parkinsonism

Unlike juvenile parkinsonism and certain forms of epilepsy, AADC deficiency is not neurodegenerative or multifactorial.2,5,9,13-15

WATCH: What is AADC deficiency?

Phillip Pearl, MD, and Keith Hyland, PhD, give an overview of AADC deficiency

AADC is an enzyme required for biosynthesis of dopamine and serotonin5

In AADC deficiency, mutations in the dopa decarboxylase (DDC) gene result in significant reduction or complete loss of AADC enzyme activity, leading to severe combined deficiency of dopamine, serotonin, norepinephrine, and epinephrine.5,6,16,17

The result of reduced AADC enzyme activity is an increase in L-dopa, 3-OMD, and 5-HTP, and a decrease in the neurotransmitter metabolites HVA and 5-HIAA.5,6,16,17

The clinical course of AADC Deficiency
The clinical course of AADC Deficiency

Adapted from Wassenberg 2017.5

3-OMD=3-O-methyldopa; 5-HIAA=5-hydroxyindoleacetic acid; 5-HTP=5-hydroxytryptophan; HVA=homovanillic acid; L-dopa=L-3,4-dihydroxyphenylalanine; VLA=vanillactic acid.

The putamen is a major site of dopamine activity and plays a critical role in motor function18,19

The putamen is part of the dorsal striatum, which plays a key role in corticostriatal connections that determine motor performance. It is a major site of AADC enzyme activity, and, consequently, dopamine activity.2,18,20

As an important site of dopamine signaling, a deficiency of dopamine in the putamen can lead to dopamine depletion and motor dysfunction in patients with AADC deficiency.2,19

Axial brain image of 18F-DOPA PET showing striatal uptake in both caudate and putamen nuclei
Axial brain image of 18F-DOPA PET showing striatal uptake in both caudate and putamen nuclei
Putamen

A guide to assist in diagnosing AADC deficiency

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View the Signs and Symptoms of AADC Deficiency

References: 1. Ng J, Papandreou A, Heales SJ, et al. Monoamine neurotransmitter disorders—clinical advances and future perspectives. Nat Rev Neurol. 2015;11(10):567-584. 2. Hwu PW, Kiening K, Anselm I, et al. Gene therapy in the putamen for curing AADC deficiency and Parkinson’s disease. EMBO Mol Med. 2021;13(9):e14712. doi:10.15252/emmm.202114712. 3. Neurotransmitters: What they are, functions & types. Cleveland Clinic. https://my.clevelandclinic.org/health/articles/22513-neurotransmitters#:~:text=Neurotransmitters%20are%20chemical%20messengers%20that,muscle%20cell%20or%20a%20gland. Published March 14, 2022. Accessed June 23, 2022. 4. Ng J, Heales SJR, Kurian MA. Clinical features and pharmacotherapy of childhood monoamine neurotransmitter disorders. Paediatr Drugs. 2014;16(4):275-291. doi: 10.1007/s40272-014-0079-z. 5. Wassenberg T, Molero-Luis M, Jeltsch K, et al. Consensus guideline for the diagnosis and treatment of aromatic L-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. 2017;12(1):12. doi: 10.1186/s13023-016-0522-z. 6. Brun L, Ngu LH, Keng WT, et al. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology. 2010;75(1):64-71. 7. Manegold C, Hoffmann GF, Degen I, et al. Aromatic L-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up. J Inherit Metab Dis. 2009;32(3):371-380. 8. Hwu WL, Chien YH, Lee NC, et al. Natural history of aromatic L-amino acid decarboxylase deficiency in Taiwan. JIMD Rep. 2018;40:1-6. doi: 10.1007/8904_2017_54. 9. Niemann N, Jankovic J. Juvenile parkinsonism: Differential diagnosis, genetics, and treatment. Parkinsonism Relat Disord. 2019;67:74-89. doi:10.1016/j.parkreldis.2019.06.025. 10. Kurian MA, Dale RC. Movement disorders presenting in childhood. Continuum (Minneap Minn). 2016;22(4):1159-1185. 11. Zouvelou V, Yubero D, Apostolakopoulou L, et al. The genetic etiology in cerebral palsy mimics: the results from a Greek tertiary care center. Eur J Paediatr Neurol. 2019;23(3):427-437. doi: 10.1016/j.ejpn.2019.02.001. 12. Krigger KW. Cerebral palsy: an overview. Am Fam Physician. 2006;73(1):91-100. 13. Tasch E, Cendes F, Li LM, Dubeau F, Andermann F, Arnold DL. Neuroimaging evidence of progressive neuronal loss and dysfunction in temporal lobe epilepsy. Ann Neurol. 1999;45(5):568-576. doi:10.1002/1531-8249(199905)45:5<568:: aid-ana4>3.0.co;2-p. 14. Shrimanker I, Tadi P, Sánchez-Manso JC. Parkinsonism. In: StatPearls. Treasure Island (FL): StatPearls Publishing; May 8, 2022. 15. Sirven JI. Epilepsy: A Spectrum Disorder. Cold Spring Harb Perspect Med. 2015 Sep 1;5(9):a022848. doi: 10.1101/cshperspect.a022848. PMID: 26328931; PMCID: PMC4561391. 16. Pons R, Ford B, Chiriboga CA, et al. Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis. Neurology. 2004;62(7):1058-1065. 17. Hwu WL, Lee NC, Chien YH, et al. AADC deficiency: occurring in humans, modeled in rodents. Adv Pharmacol. 2013;68:273-284. 18. Hwu W-L, Muramatsu S-i, Tseng S-H, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med. 2012;4(134):134ra61. doi:10.1126/ scitranslmed.3003640. 19. Luo X, Mao Q, Shi J, Wang X, Li CR. Putamen gray matter volumes in neuropsychiatric and neurodegenerative disorders. World J Psychiatry Ment Health Res. 2019;3(1):1020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6641567/pdf/nihms-1039924.pdf. Published May 2019. Accessed April 2022. 20. Ghandili M, Munakomi S. Neuroanatomy, Putamen. StatPearls [Internet]. StatPearls Publishing; 2022. https://www.ncbi.nlm.nih.gov/books/NBK542170. Updated February 2022. Accessed July 2022.