Aromatic L-amino acid decarboxylase

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Aromatic L amino acid decarboxylase (DOPA decarboxylase)
DOPA decarboxylase dimer 1JS3.png
Ribbon diagram of a DOPA decarboxylase dimer. [1]
Identifiers
EC no. 4.1.1.28
CAS no. 9042-64-2
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
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PMC articles
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NCBI proteins
DOPA decarboxylase (aromatic L-amino acid decarboxylase)
3rbf.jpg
Aromatic L-amino acid decarboxylase homodimer, Human
Identifiers
SymbolDDC
NCBI gene 1644
HGNC 2719
OMIM 107930
RefSeq NM_000790
UniProt P20711
Other data
EC number 4.1.1.28
Locus Chr. 7 p11
Search for
Structures Swiss-model
Domains InterPro

Aromatic L-amino acid decarboxylase (AADC or AAAD), also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme (EC 4.1.1.28), located in region 7p12.2-p12.1.

Contents

Mechanism

The enzyme uses pyridoxal phosphate (PLP), the active form of vitamin B6, as a cofactor. PLP is essential to the mechanism of decarboxylation in AADC. In the active enzyme, PLP is bound to lysine-303 of AADC as a Schiff base. Upon substrate binding, Lys-303 is displaced by the substrate's amine. This positions the carboxylate of the substrate within the active site such that decarboxylation is favored. Decarboxylation of the substrate produces a quinonoid intermediate, which is subsequently protonated to produce a Schiff base adduct of PLP and the decarboxylated product. Lys-303 can then regenerate the original Schiff base, releasing the product while retaining PLP. [2]

Probing this PLP-catalyzed decarboxylation, it has been discovered that there is a difference in concentration and pH dependence between substrates. DOPA is optimally decarboxylated at pH 6.7 and a PLP concentration of 0.125 mM, while the conditions for optimal 5-HTP decarboxylation were found to be pH 8.3 and 0.3 mM PLP. [3]

Mechanism of aromatic L-amino acid decarboxylase AADC mechanism.png
Mechanism of aromatic L-amino acid decarboxylase

Structure

Aromatic L-amino acid decarboxylase is active as a homodimer. Before addition of the pyridoxal phosphate cofactor, the apoenzyme exists in an open conformation. Upon cofactor binding, a large structural transformation occurs as the subunits pull closer and close the active site. This conformational change results in the active, closed holoenzyeme. [4]

In PLP-deficient murine models, it has been observed that dopamine levels do not significantly deviate from PLP-supplemented specimens; however, the concentration of serotonin in the deficient brain model was significant. This variable effect of PLP-deficiency indicates possible isoforms of AADC with differential substrate specificity for DOPA and 5-HTP. Dialysis studies also suggest that the potential isoform responsible for DOPA decarboxylation has a greater binding affinity for PLP than that of 5-HTP decarboxylase. [3]

Regulation

AADC regulation, especially as it relates to L-DOPA decarboxylation, has been studied extensively. AADC has several conserved protein kinase A (PKA) and protein kinase G recognition sites, with residues S220, S336, S359, T320, and S429 all as potential phosphate acceptors. In vitro studies have confirmed PKA and PKG can both phosphorylate AADC, causing a significant increase in activity. [5] [6] In addition, dopamine receptor antagonists have been shown to increase AADC activity in rodent models, while activation of some dopamine receptors suppresses AADC activity. [7] Such receptor mediated regulation is biphasic, with an initial short term activation followed by long term activation. The short term activation is thought to proceed through kinase activation and subsequent phosphorylation of AADC, while the sensitivity of long term activation to protein translation inhibitors suggests regulation of mRNA transcription. [8]

Reactions

AADC catalyzes several different decarboxylation reactions: [9]

However, some of these reactions do not seem to bear much or any biological significance. For example, histamine is biosynthesised strictly via the enzyme histidine decarboxylase in humans and other organisms. [10] [11]

Human serotonin biosynthesis pathway Serotonin biosynthesis.svg
Human serotonin biosynthesis pathway

Clinical relevance

In normal dopamine and serotonin (5-HT) neurotransmitter synthesis, AADC is not the rate-limiting step in either reaction. However, AADC becomes the rate-limiting step of dopamine synthesis in patients treated with L-DOPA (such as in Parkinson's disease), and the rate-limiting step of serotonin synthesis in people treated with 5-HTP (such as in mild depression or dysthymia).[ citation needed ] AADC is inhibited by carbidopa outside of the blood brain barrier to inhibit the premature conversion of L-DOPA to dopamine in the treatment of Parkinson's.

In humans, AADC is also the rate-limiting enzyme in the formation of trace amines. Aromatic l-amino acid decarboxylase deficiency is associated with various symptoms as severe developmental delay, oculogyric crises and autonomic dysfunction. The molecular and clinical spectrum of AAAC deficiency is heterogeneous. The first case of AADC deficiency was described in twin brothers 1990. Patients can be treated with dopamine agonists, MAO inhibitors, and pyridoxine (vitamin B6). [15] Clinical phenotype and response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype–phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD). [16]

Immunohistochemical studies have revealed that AADC is expressed in various neuronal cell types such as serotonergic and catecholaminergic neurons. Neurons that express AADC but are not considered classical monoaminergic cell neurons are termed D cells. Cells that are immunoreactive for AADC have also been found in the human brainstem. These cells include melanin-pigmented cells that are typically designated as catecholaminergic and may also be serotonergic. Significant localization of dopaminergic cells that are also immunoreactive for AADC is reported in the substantia nigra, ventral tegmental area, and the mesencephalic reticular formation. Unlike previous reports on animal models, nonaminergic (D cells) are unlikely to be observed in the human brain. [17]

Genetics

The gene encoding the enzyme is referred to as DDC is located on chromosome 7 in humans. [18] It consists of 15 exons encoding a protein of 480 amino acids. [19] Single nucleotide polymorphisms and other gene variations have been investigated in relation to neuropsychiatric disorders, for example, a one-base pair deletion at 601 and a four-base pair deletion at 722–725 in exon 1 in relation to bipolar disorder [20] and autism. No direct correlation between gene variation and autism was found. [21]

More than 50 mutations of DDC have been correlated with AADC deficiency [22] This condition is most prevalent in Asia, presumably due to the founder effect. [23]

Alternative splicing events and promoters have been observed that lead to various forms of the AADC enzyme. Unique usage of certain promoters leads to transcription of only the first exon to produce an extra-neuronal isoform, and splicing of exon 3 leads to a product devoid of enzymatic activity. Analyses via porcine specimens have elucidated two AADC isoforms – resulting from exclusion of exon 5 and exons 5 and 6 – that lack a portion of the decarboxylating domain. [19]

See also

Related Research Articles

<span class="mw-page-title-main">Dopamine</span> Organic chemical that functions both as a hormone and a neurotransmitter

Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Phenethylamine</span> Organic compound, a stimulant in humans

Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.

<small>L</small>-DOPA Chemical compound

l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine. l-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, l-DOPA itself mediates neurotrophic factor release by the brain and CNS. In some plant families, l-DOPA is the central precursor of a biosynthetic pathway that produces a class of pigments called betalains. l-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

<span class="mw-page-title-main">Pyridoxal phosphate</span> Active form of vitamin B6

Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent activities, corresponding to ~4% of all classified activities. The versatility of PLP arises from its ability to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates.

<span class="mw-page-title-main">Carbidopa</span> Chemical compound

Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–brain barrier for central nervous system effect, instead of being peripherally metabolised into substances unable to cross said barrier.

The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons. It transports monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrine, and histamine – into the vesicles, which release the neurotransmitters into synapses, as chemical messages to postsynaptic neurons. VMATs utilize a proton gradient generated by V-ATPases in vesicle membranes to power monoamine import.

<span class="mw-page-title-main">Benserazide</span> Chemical compound

Benserazide is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier.

<span class="mw-page-title-main">Histidine decarboxylase</span> Enzyme that converts histidine to histamine

The enzyme histidine decarboxylase is transcribed on chromosome 15, region q21.1-21.2, and catalyzes the decarboxylation of histidine to form histamine. In mammals, histamine is an important biogenic amine with regulatory roles in neurotransmission, gastric acid secretion and immune response. Histidine decarboxylase is the sole member of the histamine synthesis pathway, producing histamine in a one-step reaction. Histamine cannot be generated by any other known enzyme. HDC is therefore the primary source of histamine in most mammals and eukaryotes. The enzyme employs a pyridoxal 5'-phosphate (PLP) cofactor, in similarity to many amino acid decarboxylases. Eukaryotes, as well as gram-negative bacteria share a common HDC, while gram-positive bacteria employ an evolutionarily unrelated pyruvoyl-dependent HDC. In humans, histidine decarboxylase is encoded by the HDC gene.

<span class="mw-page-title-main">Tyrosine hydroxylase</span> Enzyme found in Homo sapiens that converts l-tyrosine to l-dopa, the precursor of cathecolamines

Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).

<span class="mw-page-title-main">Tryptophan hydroxylase</span> Class of enzymes

Tryptophan hydroxylase (TPH) is an enzyme (EC 1.14.16.4) involved in the synthesis of the monoamine neurotransmitter serotonin. Tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase together constitute the family of biopterin-dependent aromatic amino acid hydroxylases. TPH catalyzes the following chemical reaction

<span class="mw-page-title-main">Arginine decarboxylase</span>

The enzyme Acid-Induced Arginine Decarboxylase (AdiA), also commonly referred to as arginine decarboxylase, catalyzes the conversion of L-arginine into agmatine and carbon dioxide. The process consumes a proton in the decarboxylation and employs a pyridoxal-5'-phosphate (PLP) cofactor, similar to other enzymes involved in amino acid metabolism, such as ornithine decarboxylase and glutamine decarboxylase. It is found in bacteria and virus, though most research has so far focused on forms of the enzyme in bacteria. During the AdiA catalyzed decarboxylation of arginine, the necessary proton is consumed from the cell cytoplasm which helps to prevent the over-accumulation of protons inside the cell and serves to increase the intracellular pH. Arginine decarboxylase is part of an enzymatic system in Escherichia coli, Salmonella Typhimurium, and methane-producing bacteria Methanococcus jannaschii that makes these organisms acid resistant and allows them to survive under highly acidic medium.

<span class="mw-page-title-main">Aromatic L-amino acid decarboxylase inhibitor</span>

An aromatic L-amino acid decarboxylase inhibitor is a medication of type enzyme inhibitor which inhibits the synthesis of dopamine by the enzyme aromatic L-amino acid decarboxylase. It is used to inhibit the decarboxylation of L-DOPA to dopamine outside the brain, i.e. in the blood. This is primarily co-administered with L-DOPA to combat Parkinson's disease. Administration can prevent common side-effects, such as nausea and vomiting, as a result of interaction with D2 receptors in the vomiting center located outside the blood–brain barrier.

Reverse transport, or transporter reversal, is a phenomenon in which the substrates of a membrane transport protein are moved in the opposite direction to that of their typical movement by the transporter. Transporter reversal typically occurs when a membrane transport protein is phosphorylated by a particular protein kinase, which is an enzyme that adds a phosphate group to proteins.

<i>meta</i>-Tyramine Chemical compound

meta-Tyramine, also known as m-tyramine and 3-tyramine, is an endogenous trace amine neuromodulator and a structural analog of phenethylamine. It is a positional isomer of para-tyramine, and similarly to it, has effects on the adrenergic and dopaminergic systems.

3-<i>O</i>-Methyldopa Chemical compound

3-O-Methyldopa (3-OMD) is one of the most important metabolites of L-DOPA, a drug used in the treatment of the Parkinson's disease.

Aromatic L-amino acid decarboxylase deficiency, also known as AADC deficiency, is a rare genetic disorder caused by mutations in the DDC gene, which encodes an enzyme called aromatic L-amino acid decarboxylase.

<span class="mw-page-title-main">Monoamine precursor</span>

Monoamine precursors are precursors of monoamines and monoamine neurotransmitters in the body. The amino acids L-tryptophan and L-5-hydroxytryptophan are precursors of serotonin and melatonin, while the amino acids L-phenylalanine, L-tyrosine, and L-DOPA (levodopa) are precursors of dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline). Administration of monoamine precursors can increase the levels of monoamine neurotransmitters in the body and brain. Monoamine precursors may be used in combination with peripherally selective aromatic L-amino acid decarboxylase inhibitors such as carbidopa and benserazide. Carbidopa/levodopa is used to increase brain dopamine levels in the treatment of Parkinson's disease while carbidopa/oxitriptan (EVX-101) is under development as an antidepressant for possible use in the treatment of depression.

Eladocagene exuparvovec, sold under the brand name Upstaza, is a gene therapy product for the treatment of aromatic L‑amino acid decarboxylase (AADC) deficiency. It infuses the gene encoding for the human AADC enzyme into the putamen region of the brain. The subsequent expression of AADC results in dopamine production and, as a result, development of motor function in patients with AADC deficiency.

References

  1. ↑ PDB: 1JS3 ​; Burkhard P, Dominici P, Borri-Voltattorni C, Jansonius JN, Malashkevich VN (November 2001). "Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase". Nature Structural Biology. 8 (11): 963–7. doi:10.1038/nsb1101-963. PMID   11685243. S2CID   19160912.
  2. ↑ Bertoldi M (March 2014). "Mammalian Dopa decarboxylase: structure, catalytic activity and inhibition". Archives of Biochemistry and Biophysics. 546: 1–7. doi:10.1016/j.abb.2013.12.020. PMID   24407024.
  3. 1 2 Siow YL, Dakshinamurti K (1985). "Effect of pyridoxine deficiency on aromatic L-amino acid decarboxylase in adult rat brain". Experimental Brain Research. 59 (3): 575–81. doi:10.1007/BF00261349. PMID   3875501. S2CID   22286973.
  4. ↑ Giardina G, Montioli R, Gianni S, Cellini B, Paiardini A, Voltattorni CB, Cutruzzolà F (December 2011). "Open conformation of human DOPA decarboxylase reveals the mechanism of PLP addition to Group II decarboxylases". Proceedings of the National Academy of Sciences of the United States of America. 108 (51): 20514–9. Bibcode:2011PNAS..10820514G. doi: 10.1073/pnas.1111456108 . PMC   3251144 . PMID   22143761.
  5. ↑ Duchemin AM, Berry MD, Neff NH, Hadjiconstantinou M (August 2000). "Phosphorylation and activation of brain aromatic L-amino acid decarboxylase by cyclic AMP-dependent protein kinase". Journal of Neurochemistry. 75 (2): 725–31. doi:10.1046/j.1471-4159.2000.0750725.x. PMID   10899948. S2CID   19636477.
  6. ↑ Duchemin AM, Neff NH, Hadjiconstantinou M (July 2010). "Aromatic L-amino acid decarboxylase phosphorylation and activation by PKGIalpha in vitro". Journal of Neurochemistry. 114 (2): 542–52. doi:10.1111/j.1471-4159.2010.06784.x. PMID   20456015. S2CID   205622115.
  7. ↑ Hadjiconstantinou M, Neff NH (2008). "Enhancing aromatic L-amino acid decarboxylase activity: implications for L-DOPA treatment in Parkinson's disease". CNS Neuroscience & Therapeutics. 14 (4): 340–51. doi:10.1111/j.1755-5949.2008.00058.x. PMC   6494005 . PMID   19040557.
  8. ↑ Berry MD, Juorio AV, Li XM, Boulton AA (September 1996). "Aromatic L-amino acid decarboxylase: a neglected and misunderstood enzyme". Neurochemical Research. 21 (9): 1075–87. doi:10.1007/BF02532418. PMID   8897471. S2CID   19823573.
  9. ↑ "AADC". Human Metabolome database. Retrieved 17 February 2015.
  10. ↑ Huang H, Li Y, Liang J, Finkelman FD (2018). "Molecular Regulation of Histamine Synthesis". Frontiers in Immunology. 9: 1392. arXiv: 1802.02540 . doi: 10.3389/fimmu.2018.01392 . PMC   6019440 . PMID   29973935.
  11. ↑ chikawa A, Tanaka S (2012). "Histamine Biosynthesis and Function". eLS. American Cancer Society. doi:10.1002/9780470015902.a0001404.pub2. ISBN   9780470015902.
  12. ↑ Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacology & Therapeutics. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID   19948186.
  13. ↑ Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends in Pharmacological Sciences. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID   15860375.
  14. ↑ Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". European Journal of Pharmacology. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID   24374199.
  15. ↑ Pons R, Ford B, Chiriboga CA, Clayton PT, Hinton V, Hyland K, Sharma R, De Vivo DC (April 2004). "Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis". Neurology. 62 (7): 1058–65. doi:10.1212/WNL.62.7.1058. PMID   15079002. S2CID   12374358.
  16. ↑ "Patient registry".
  17. ↑ Kitahama K, Ikemoto K, Jouvet A, Araneda S, Nagatsu I, Raynaud B, et al. (October 2009). "Aromatic L-amino acid decarboxylase-immunoreactive structures in human midbrain, pons, and medulla". Journal of Chemical Neuroanatomy. 38 (2): 130–40. doi:10.1016/j.jchemneu.2009.06.010. PMID   19589383. S2CID   20759513.
  18. ↑ Scherer LJ, McPherson JD, Wasmuth JJ, Marsh JL (June 1992). "Human dopa decarboxylase: localization to human chromosome 7p11 and characterization of hepatic cDNAs". Genomics. 13 (2): 469–71. doi:10.1016/0888-7543(92)90275-W. PMID   1612608. S2CID   37950853.
  19. 1 2 Blechingberg J, Holm IE, Johansen MG, Børglum AD, Nielsen AL (January 2010). "Aromatic l-amino acid decarboxylase expression profiling and isoform detection in the developing porcine brain". Brain Research. 1308: 1–13. doi:10.1016/j.brainres.2009.10.051. PMID   19857468. S2CID   8292103.
  20. ↑ Børglum AD, Bruun TG, Kjeldsen TE, Ewald H, Mors O, Kirov G, et al. (November 1999). "Two novel variants in the DOPA decarboxylase gene: association with bipolar affective disorder". Molecular Psychiatry. 4 (6): 545–51. doi: 10.1038/sj.mp.4000559 . PMID   10578236.
  21. ↑ Lauritsen MB, Børglum AD, Betancur C, Philippe A, Kruse TA, Leboyer M, Ewald H (May 2002). "Investigation of two variants in the DOPA decarboxylase gene in patients with autism". American Journal of Medical Genetics. 114 (4): 466–70. doi:10.1002/ajmg.10379. PMC   4826443 . PMID   11992572.
  22. ↑ Wassenberg T, Molero-Luis M, Jeltsch K, Hoffmann GF, Assmann B, Blau N, et al. (January 2017). "Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency". Orphanet Journal of Rare Diseases. 12 (1): 12. doi: 10.1186/s13023-016-0522-z . PMC   5241937 . PMID   28100251.
  23. ↑ Lee HF, Tsai CR, Chi CS, Chang TM, Lee HJ (March 2009). "Aromatic L-amino acid decarboxylase deficiency in Taiwan". European Journal of Paediatric Neurology. 13 (2): 135–40. doi:10.1016/j.ejpn.2008.03.008. PMID   18567514.
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