Aromatic L-amino Acid Decarboxylase (AADC) Deficiency

Aromatic l-amino acid decarboxylase (AADC) deficiency is a very rare genetic autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin, dopamine, norepinephrine, and epinephrine and decreased activity of aromatic l-amino acid decarboxylase, an enzyme involved in the building (synthesis) of neurotransmitters (dopamine and serotonin), which are responsible for the communication between neurons in the nervous system. Although affected individuals can appear normal at birth, most will develop symptoms during the first months of life. AADC deficiency most commonly leads to decreased muscle tone (hypotonia), movement disorders including abnormal eyes movement (oculogyric crises), developmental delay, restricted growth (failure to thrive), and disruption of the part of the nervous system responsible for unconscious modulation of body functions such as heartbeat (autonomic nervous system). Medication is available to manage the symptoms, but the response to treatment greatly varies among affected individuals, and an optimal treatment regimen can be difficult to achieve. There is currently no cure for the disease, but gene therapy has shown potential to improve symptoms in clinical trials.

Levels of evidence according to SIGN

Levels of evidence
1++	High-quality meta-analyses, systematic reviews of RCTs or RCTs with a very low risk of bias
1+	Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias
1-	Meta-analyses, systematic reviews, or RCTs with a high risk of bias
2++	High-quality systematic reviews of case-control or cohort studies
2++	High-quality case-control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal
2+	Well-conducted case-control or cohort studies with a low risk of confounding bias and a moderate probability that the relationship is causal
2-	Case-control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal
3	Non-analytic studies, e.g. case reports, case series
4	Expert opinion

Causes

AADC deficiency is caused by mutations (changes) in a gene called DDC (which stands for DOPA decarboxylase, another name for AADC). An abnormal DDC gene leads to the production of a dysfunctional AADC enzyme that cannot accomplish its normal functions. Enzymes are a type of protein widely present in the body and their role is to facilitate and accelerate (catalyze) chemical reactions that have to take place for the body to function correctly. AADC catalyzes chemical reactions responsible for the formation (synthesis) of molecules called neurotransmitters that are essential for proper communication between neurons of the nervous system. The neurotransmitters affected by AADC deficiency are epinephrine and norepinephrine (products of dopamine and involved in the control of the sympathetic nervous system, the “fight or flight” branch of the autonomic nervous system), dopamine (involved in motor control, reward, and motivation), and serotonin (involved in sleep, memory, appetite, and mood). Serotonin is also required for the synthesis of melatonin, which is primarily involved in the regulation of the sleep-wake cycle. The deficiency of those neurotransmitters is responsible for the manifestations of AADC deficiency.

AADC deficiency is an autosomal recessive genetic disorder. This type of genetic disorder occurs when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Mutations in the DDC gene cause AADC deficiency. The DDC gene provides instructions for making the AADC enzyme, which is important in the nervous system. This enzyme helps produce dopamine and serotonin from other molecules. Dopamine and serotonin are neurotransmitters, which are chemical messengers that transmit signals between nerve cells, both in the brain and spinal cord (central nervous system) and in other parts of the body (peripheral nervous system).

Mutations in the DDC gene result in reduced activity of the AADC enzyme. Without enough of this enzyme, nerve cells produce less dopamine and serotonin. Dopamine and serotonin are necessary for normal nervous system function, and changes in the levels of these neurotransmitters contribute to the developmental delay, intellectual disability, abnormal movements, and autonomic dysfunction seen in people with AADC deficiency.

Related Disorders

The symptoms seen in AADC deficiency can be seen in numerous other disorders. Some have a very similar clinical presentation and are mostly differentiated with laboratory testing and medical imaging. Below is a list of some conditions that can present similarly to AADC deficiency, with an emphasis on neurometabolic disorders.

Tetrahydrobiopterin (BH4) deficiency is a general term for a group of disorders characterized by abnormalities in the synthesis or regeneration of BH4, a naturally occurring compound that facilitates certain chemical reactions. These disorders usually present within the first six months of life and can be diagnosed through newborn screening for phenylketonuria (elevated phenylalanine in the blood). Affected infants may not grow and gain weight as expected. In the severe forms of BH4 deficiency, symptoms include hypotonia of the trunk, hypertonia of the limbs, decreased body movement (hypokinesia), abnormal muscle contractions (athetosis), seizures, and swallowing difficulties. Small head circumference (microcephaly) is another occasional finding. (For more information on this disorder, choose “tetrahydrobiopterin deficiency” as your search term in the Rare Disease Database.)

Sepiapterin reductase deficiency (SRD) is a rare genetic disorder in BH4 metabolism characterized by abnormally low levels of certain neurotransmitters, but it presents without elevated blood phenylalanine concentrations. Symptoms usually become apparent within the first year of life and vary greatly from one person to another. Some individuals develop severe, disabling motor and cognitive deficits while others only experience mild symptoms. Common symptoms include dystonia, developmental delays, hypotonia, and oculogyric crises. Some infants may have microcephaly. (For more information on this disorder, choose “sepiapterin reductase deficiency” as your search term in the Rare Disease Database.)

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare inborn error of metabolism characterized by deficient activity of the SSADH enzyme that disrupts the metabolism of a neurotransmitter called gamma-aminobutyric acid (GABA). Affected individuals can have neurological and neuromuscular symptoms such as intellectual disability, delayed language, and motor milestones, hypotonia, seizures, and an impaired ability to coordinate voluntary movements (ataxia). (For more information on this disorder, choose “succinic semialdehyde dehydrogenase deficiency” as your search term in the Rare Disease Database.)

Tyrosine hydroxylase deficiency is a rare genetic disorder that involves the synthesis of dopamine and is characterized by a wide spectrum of severity ranging from a mild movement disorder to a life-threatening, neurological disorder. Symptoms of the severe form of tyrosine hydroxylase deficiency are obvious early in infancy and include poor control of voluntary muscles, delays in achieving motor milestones, hypertonia, abnormal rigidity of the arms and legs, hypokinesia, and involuntary muscle spasms that result in slow, stiff movements of the limbs (spasticity). (For more information on this disorder, choose “tyrosine hydroxylase deficiency” as your search term in the Rare Disease Database.)

Cerebral palsy is a neurological movement disorder characterized by a lack of muscle control and impairment in the coordination of movements. This disorder is usually a result of injury to the brain during early development in the uterus, at birth, or in the first two years of life. Affected infants have muscle weakness, hypotonia, and, later, muscle stiffness (spasticity) and lack of coordination. They may experience developmental delays during the first or second year of life. As with AADC deficiency, this condition is not progressive.

Symptoms

AADC deficiency is a disorder that manifests early in life. The symptoms can begin during the neonatal period or when the child is a few months old. There is a wide range of possible symptoms and the severity of the disease varies among affected individuals. The two most common symptoms are hypotonia in the trunk and oculogyric crises. These crises are characterized by abnormal rotation of the eyeballs and gaze deviation, uncontrolled movements of the head and neck, muscle spasms, agitation, and irritability. They can last several hours and tend to recur every 2 to 5 days. Other movement disorders can be present such as decreased movements (hypokinesia), increased muscle tone (hypertonia) in the limbs, sustained muscle contraction and abnormal postures (dystonia), involuntary writhing movements (athetosis), involuntary and irregular movements of the hands and feet (chorea), and tremors.

Another prominent feature of AADC deficiency is the dysfunction of the autonomic nervous system. This part of the nervous system is not under voluntary control and is notably involved in the self-regulation of the body. Dysfunction of the autonomic nervous system can lead to symptoms such as excessive sweating and salivation (hypersalivation), droopy eyelids (ptosis), nasal congestion, temperature instability, and low blood pressure (hypotension), and low blood sugar (hypoglycemia). Less common symptoms include seizures, behavioral problems such as irritability and excessive crying, decreased or increased sleep (insomnia and hypersomnia, respectively), and decreased or increased reflexes (hyporeflexia and hyperreflexia, respectively).

Another relatively common non-neurologic manifestation is gastrointestinal problems such as diarrhea, constipation, and reflux. Because of the disease itself and as a consequence of the numerous possible symptoms, children with AADC deficiency have developmental delay and are not able to reach normal milestones such as walking and talking, have feeding difficulties and decreased growth (failure to thrive), and are prone to many medical complications. Patients might also have difficulty adapting to those complications as their autonomic nervous system is dysfunctional and can react inappropriately to stressors such as surgery or infections. Many affected children, unfortunately, do not live through childhood, but some with milder diseases do reach adulthood. Importantly, the condition of people living with the disease can deteriorate because of complications, but the symptoms themselves do not tend to worsen with time. Some patients eventually develop cerebral palsy.

In this case, babies with severe aromatic L-amino acid decarboxylase deficiency usually present during the first few months of life. Symptoms can include:

Hypotonia (floppiness)
Developmental delay
Oculogyric crises^[rx]
Difficulty with initiating and controlling movements
Dystonia and dyskinesia
Gastrointestinal dysmotility can present at as vomiting, gastro-oesophageal reflux, diarrhea and/or constipation
Autonomic symptoms include difficulties controlling temperature and blood sugar, excessive sweating, and nasal congestion

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.^[rx]

Diagnosis

AADC deficiency is a very rare and complex disease with features that overlap with many other disorders (see above). A complete clinical evaluation and a high index of suspicion are required to make the diagnosis. The evaluation of a child with neurodevelopmental delay starts with a perinatal and developmental history and a complete physical examination. Although many tests, such as a complete blood count, measurement of electrolyte levels, and magnetic resonance imaging of the brain are usually performed in the diagnostic workup of a child presenting with neurodevelopmental delay, the laboratory diagnosis of AADC deficiency is centered about four specific tests:

1) A lumbar puncture is a procedure where a needle is placed in the spinal column of the patient to collect cerebrospinal fluid (CSF). The CSF is then analyzed to identify abnormal levels of certain substances (metabolites) involved in the molecular pathways of neurotransmitter synthesis. The synthesis of neurotransmitters involves a cascade of numerous chemical reactions. In patients with AADC deficiency, the cascade stops where AADC is usually required to catalyze the chemical reactions. As a result, in cases of enzyme deficiency, the metabolites “before” AADC in the chemical reaction cascade will be increased, and those “after” will be decreased.
2) Measurement of a specific metabolite 3-O-methyl-dopa (3OMD) in plasma or dried blood spots, which will be increased in patients with the disease.
3) Measurement of the activity level of the AADC enzyme in the blood (serum), which will be reduced in patients with the disease.
4) Genetic testing that can identify disease-causing (pathogenic) mutations in the DDC gene.

Treatment

Although there is currently no cure for AADC deficiency, numerous medications can help manage the symptoms. The optimal medication regimen greatly varies among affected individuals. There is limited scientific evidence for the efficacy of most treatment options due to the rarity of the disease. Each patient needs to have a personalized approach and should be followed by a pediatric neurologist and potentially many other physicians to assist in trials of medications to determine the best combination on a case-by-case basis. Some of the most commonly used treatments include medications to increase the concentration of dopamine in the nervous system (dopamine agonists) or to decrease its degradation (monoamine oxidase B [MAO-B] inhibitors). Vitamin B6 (pyridoxine) or its active form, pyridoxal phosphate (PLP), are often tried, as PLP normally assists AADC in its role as a cofactor and might therefore increase the residual activity of the enzyme. Other medications might be considered depending on the patient. For example, melatonin can be tried for sleep disturbances, and benzodiazepines (a class of medication that acts as central nervous system depressants), or anticholinergics (which counteract the activity of acetylcholine, a neurotransmitter) might help patients with oculogyric crises and other motor symptoms.

A key factor for the optimal management of AADC deficiency is to adopt a multidisciplinary approach to address the specific needs of the affected individual. Members of the team commonly include physiotherapists, speech therapists, dieticians, psychologists, social workers, and physiatrists (physicians specializing in rehabilitation).

Individuals will require physiotherapy, occupational therapy, and speech and language therapy. Some will need enteral feeding (for example, a gastrostomy or jejunostomy) due to difficulties with chewing and swallowing.

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. Individuals may also need to take a range of other medications to control dyskinesia, constipation, and other symptoms.^[rx]

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. As of May 2022, the gene therapy product eladocagene exuparvovec is recommended for approval by the European Commission.

Recommended drugs and doses for AADC deficiency

	Class	Drug	Mechanism	Dose recommendation	Precaution/comments
FIRST-LINE TREATMENT AGENTS	Vitamin B6	Pyridoxine (Vit B6)	The cofactor, optimizes residual AADC activity	Start: 100 mg/d in 2 doses Max 200 mg/d	It May be preferred over pyridoxal 5-phosphate because of cost and availability Maintain for 1 year, then discontinue when in stable circumstances. If no deterioration, leave discontinued. Chronic use in high doses can cause severe sensorimotor polyneuropathy Side effects: generally well tolerated, sometimes nausea, vomiting.
	Vitamin B6	Pyridoxal 5-Phosphate	The cofactor, optimizes residual AADC activity	Start:100 mg/d in 2 doses. Max 200 mg/d	Consider a trial of pyridoxine gives too many side effects or is not effective. Chronic use in high doses can cause severe sensorimotor polyneuropathy
	Dopamine agonists	Pramipexole	Non-ergot derived D2-agonist with a preference for D3 receptor subtype.	Start 0.005 – 0.010 mg/kg/d of BASE in 1-3 divided doses, increase every 3-7* days by 0.005 mg/kg/d, max 0.075 mg/kg or 3.3 mg/d of BASE	The distinction in salt and base content. Take tablets with water, optional with food High risk of drug-induced dyskinesias
		Ropinirole	Non-ergot derived D2-agonist with a preference for D3-receptor subtype.	Suggestion: Start 0.25 mg/d 1 daily 2 h before bedtime; increase every 3-7* days to 0.5-4.0 mg/d in 3 divided doses, max 0.3 mg/kg/d or 24 mg/d	Do not use in severe kidney failure Take tablets with food With very limited experience in AADC deficiency, physicians should extrapolate and titrate carefully. Probably high risk of drug-induced dyskinesias as in other dopamine agonists.
		Rotigotine patch	Non-ergot-derived D2 agonist with a preference for D3; also effect on D2, D1, and D5; and α2B and 5HT1A agonist.	>12 years and >15 kg: Start 2 mg/d; weekly increase by 2 mg, max 8 mg/d.	No data available for use in children <12y/ <15 kg. Do not cut patches. Drug-induced dyskinesias require a lower dose and/ or slower increase Skin reactions occur often (about 30 %). Sulfite can lead to allergic reactions Remove patch during MRI/ electro cardioversion (aluminum content)
		Bromocriptine	Ergot-derived D2-agonist with D1 receptor antagonist effect	Start 0.1 mg/kg/d (max 1.25 mg/d); increase weekly by 0.1 mg/kg/d (max 1.25 mg/d) up to 0.5 mg/kg/d (max 30 mg/d) in 2-3 divided doses.	Non-ergot-derived dopamine agonists are preferred Take tablets with food Small risk of fibrotic complications, consider cardiac screening before and during use. Higher risk with a higher dose, dose restricted to 30 mg/d in adults. Maintain the lowest effective dose.
		Pergolide or cabergoline	Ergot-derived	None	Do not use it because of the higher risk of fibrotic complications
	MAO-inhibitors	Selegiline	MAO-B inhibitor (non-selective in very high doses)	Start 0.1 mg/kg/d in 2-3 divided doses. Increase every 2 weeks by 0.1 mg/kg/d up to 0.3 mg/kg/d or 10 mg/d	Dose at breakfast and lunch, avoid night-time doses if insomnia is experienced. Does sublingual preparations much lower
	MAO-inhibitors	Tranylcypromine	Non-selective MAO-A and -B inhibitor	Start 0.1 mg/kg/d in 2 doses. Increase every 2 weeks by 0.1 mg/kg/d up to 0.5 mg/kg/d (max 30 mg)	Dose at breakfast and lunch, and avoid night-time doses if insomnia is experienced. The occurrence of the ‘cheese effect’ (hypertensive crises when foods with high content of tyramine are ingested) is very unlikely in patients with AADC deficiency due to their low levels of dopamine, norepinephrine, and epinephrine.
ADDITIONAL SYMPTOMATIC TREATMENT	Anticholinergics (dystonia/ autonomic symptoms)	Trihexyphenidyl	Anticholinergic agents, restores neurotransmitter disbalance	<15 kg: start 0.5-1 mg/d in 1 dose; increase every 3-7* days by 1 mg/d in 2-4 doses/d >15 kg: start 2 mg/d in 2 doses; increase every 3-7* days by2mg/d in 2-4 divided doses. Effective dose highly variable (6-60 mg) Maximum dose: <10 kg 30 mg/d; >10 kg 60 mg/d	In general, the younger, the better tolerated; dosages often exceed recommended dose for adults (15 mg/d). The maximum dose is dictated by side effects: e.g. dry mouth, dry eyes, blurred vision (mydriasis), urine retention, constipation. Sedation in high doses.
	Anticholinergics (dystonia/ autonomic symptoms)	Benztropine	Centrally acting anticholinergic agent. Also dopaminergic effect by inhibiting presynaptic reuptake	Start 1 mg in 2 divided doses, increase weekly up to 4 mg/d	Anticholinergic side effects: e.g. dry mouth, dry eyes, blurred vision (mydriasis), urine retention, obstipation. Sedation in high doses.
	Nasal congestion	Oxymetazoline or xylometazoline nosedrops	α-adrenergic agonist leading to local vasoconstriction	Use general dose guidelines for age, try to use the lowest available dose in chronic use	Try to include intermittent weeks without treatment to prevent habituation Hypertensive crises if used concomitantly with MAO-inhibitors are very unlikely in patients with AADC deficiency due to their levels of dopamine, norepinephrine, and epinephrine
	Sleeping problems	Melatonin	Regulates onset of sleep and day/night cycling	Start 3 mg/d, given 4 h before the onset of sleep. Max dose 5-8 mg/d	Transient night terrors on initial treatment can occur (personal experience) Availability differs between countries.
	Irritability/ sleep disturbance	Clonidine	Centrally acting antihypertensive drug; imidazoline (I1-) and α2-agonist	Start 0.1 mg/d ante Noctum, increase to max 3 mg/d ante Noctum	Monitor blood pressure in a higher dose Sedative, therefore gives AN
SPECIAL CASES ONLY	L-Dopa binding site variant	L-Dopa without carbidopa	Substrate for AADC to form dopamine; effective in certain binding site variants	Start 0.5-1 mg/kg/d in 3 divided doses, increase 2 weekly by 1 mg/kg to 5 mg/kg/d. Only if clinical effective, further increase to max 15 mg/kg/d	Start as a first-line treatment only if known binding site variant. Otherwise, consider a third-line treatment trial for 2 months (or less if deterioration) when in a stable clinical situation. Monitor CSF during treatment, including 5-MTHF
SPECIAL CASES ONLY	Low 5-MTHF in CSF	Folinic acid (calcium folinate)	Methylation of excessive amounts of L-Dopa in AADCD may cause depletion of methyl donors.	1-2 mg/kg/d, max 20 mg/ d	Only supply if 5-MTHF is low in CSF Monitor 5-MTHF in CSF during treatment with L-Dopa

Investigational Therapies

Current research and clinical trials in AADC deficiency are mostly focused on gene therapy, which aims to replace the non-working gene. This is performed using a virus as a vector. Viruses can insert part of their genetic material into human cells and use the human cellular machinery to replicate. If the virus is genetically engineered so that the genetic material it inserts in human cells contains the functional DDC gene, a more functional AADC enzyme could be produced. Researchers have developed such viruses and injected them into specific regions of the brain of children with AADC deficiency. The results have been promising and many patients improved, but additional research is needed before this therapy is approved for clinical use.