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Aromatic L-amino acid decarboxylase deficiency | |
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Other names | AADC deficiency |
Specialty | Neurology ![]() |
Symptoms | Dystonia, oculogyric crises, developmental delay, parkinsonism, dysautonomia |
Usual onset | Infancy |
Causes | Autosomal recessive DDC mutation |
Diagnostic method | Lumbar puncture for neurotransmitter analysis; enzyme assay; genetic testing |
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.
Babies with severe aromatic L-amino acid decarboxylase deficiency usually present during the first few months of life. Symptoms can include:
Some people may develop cerebral folate deficiency, because O-methylation of the excessive amounts of L-Dopa can deplete methyl donors such as S-adenosyl methionine and levomefolic acid. This deviation can be detected by measuring the levels of levomefolic acid in the cerebrospinal fluid, and can be corrected by folinic acid. [1]
Aromatic L-amino acid decarboxylase deficiency is an autosomal recessive condition, meaning an individual needs to have two faulty copies of the DDC gene in order to be affected. Usually, one copy is inherited from each parent. [3]
The aromatic L-amino acid decarboxylase deficiency enzyme is involved in the synthesis of dopamine and serotonin, both of which are important neurotransmitters.
There are three core diagnostic tools: [1]
To establish the diagnosis of AADCD, patient must have positive genetic testing (1st criterion) while also fulfilling either one of the other two criterions.
Elevated 3-OMD levels in serum can be used as a simple and sensitive screening test, positive result of which must be confirmed by the diagnostic criteria above. [1]
There is no cure for aromatic L-amino acid decarboxylase deficiency, but medical and multidisciplinary treatment can relieve some of the symptoms.[ medical citation needed ] Individuals will require physiotherapy, occupational therapy, and speech and language therapy.[ medical citation needed ] Some will need enteral feeding (for example, a gastrostomy or jejunostomy) due to difficulties with chewing and swallowing.[ medical citation needed ]
Various medications can help compensate for the missing neurotransmitters. Dopamine agonists such as rotigotine or pramipexole and monoamine oxidase inhibitors such as selegiline are commonly used.[ medical citation needed ] Individuals may also need to take a range of other medications to control dyskinesia, constipation and other symptoms. [1]
In July 2021, results of a small gene therapy phase I study reported observation of dopamine restoration on seven participants between 4 and 9 years old. [4] [5] [6]
In July 2022, the gene therapy product eladocagene exuparvovec was approved in the European Union for use in patients aged 18 months or older. [7]
A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.
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.
Aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme, located in region 7p12.2-p12.1.
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.
Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure. It is one of the preferred treatments for high blood pressure in pregnancy. For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred. It can be given by mouth or injection into a vein. Onset of effects is around 5 hours and they last about a day.
Benserazide is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier.
Oculogyric crisis (OGC) is a rare sudden, paroxysmal, dystonic reaction that may manifest in response to specific drugs, particularly neuroleptics, or medical conditions, such as movement disorders. This neurological phenomenon is characterized by a sustained dystonic, conjugate, involuntary upward deviation of both eyes lasting seconds to hours. The term oculogyric is applied in reference to the simultaneous upward movement of both eyes, although the reaction may encompass a variety of additional responses. The reaction is not life-threatening.
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.
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).
An aromatic amino acid is an amino acid that includes an aromatic ring.
PTC Therapeutics is a US pharmaceutical company focused on the development of orally administered small molecule drugs and gene therapy which regulate gene expression by targeting post-transcriptional control (PTC) mechanisms in orphan diseases.
Droxidopa is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitter norepinephrine (noradrenaline). Unlike norepinephrine, droxidopa is capable of crossing the protective blood–brain barrier (BBB).
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.
Dopamine-responsive dystonia (DRD) also known as Segawa syndrome (SS), is a genetic movement disorder which usually manifests itself during early childhood at around ages 5–8 years.
Sepiapterin reductase deficiency is an inherited pediatric disorder characterized by movement problems, and most commonly displayed as a pattern of involuntary sustained muscle contractions known as dystonia. Symptoms are usually present within the first year of age, but diagnosis is delayed due to physicians lack of awareness and the specialized diagnostic procedures. Individuals with this disorder also have delayed motor skills development including sitting, crawling, and need assistance when walking. Additional symptoms of this disorder include intellectual disability, excessive sleeping, mood swings, and an abnormally small head size. SR deficiency is a very rare condition. The first case was diagnosed in 2001, and since then there have been approximately 30 reported cases. At this time, the condition seems to be treatable, but the lack of overall awareness and the need for a series of atypical procedures used to diagnose this condition pose a dilemma.
Gene therapy in Parkinson's disease consists of the creation of new cells that produce a specific neurotransmitter (dopamine), protect the neural system, or the modification of genes that are related to the disease. Then these cells are transplanted to a patient with the disease. There are different kinds of treatments that focus on reducing the symptoms of the disease but currently there is no cure.
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.
Dihydropteridine reductase deficiency (DHPRD) is a genetic disorder affecting the tetrahydrobiopterin (BH4) synthesis pathway, inherited in the autosomal recessive pattern. It is one of the six known disorders causing tetrahydrobiopterin deficiency, and occurs in patients with mutations of the QDPR gene.
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.