NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, and Prof. Dr. Nenad Blau, Division of Metabolism, University Children's Hospital Zurich, for assistance in the preparation of this report.
Aromatic l-amino acid decarboxylase (AADC) deficiency is a very rare genetic disorder characterized by 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 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.
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 dysfunction of the autonomic nervous system. This part of the nervous system is not under voluntarily control and is notably involved in 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, 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 disease 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.
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 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 in order 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. 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 for 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.
AADC deficiency is an extremely rare disorder; fewer than 150 patients have been reported in the literature. Half of these cases are in Asian individuals, and a fifth are in individuals with Taiwanese ancestry. Males and females seem to be equally affected. AADC deficiency is probably underdiagnosed. The estimated prevalence in the U.S. based on cerebrospinal fluid (CSF) analysis and genetic testing is roughly 1-3:100,000 live newborns.
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, which 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 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 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 & Management
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 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 specialized in rehabilitation).
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 in 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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials are also posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact:
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