The Skill Checkup series provides a quick, case-style interactive quiz highlighting key guidelines- and evidence-based information to inform clinical practice.
A 6-month-old boy of Taiwanese descent has history of seizure-like episodes, dystonia, and ongoing nasal congestion. His caregivers report feeding and sleeping difficulties as well as irritability with increased startle to noises and sudden movements. The infant had been diagnosed with cerebral palsy; however, the caregivers are requesting a second opinion.
At presentation, the infant weighs 6.1 kg (13.4 lb; < 2%), is 57.2 cm long (22.5 in; < 2%), and is afebrile. Marked developmental delay is noted, as the patient has not reached any age-appropriate milestones. Physical exam is notable for bilateral ptosis, right-sided head deviation, and truncal muscular hypotonia. You observe sustained upward deviation of the eyes with backward neck flexion. Hypersalivation and tongue thrusting are seen.
Aromatic L-amino acid decarboxylase (AADC) deficiency (OMIM #608643) is an extremely rare autosomal recessive inherited disorder caused by pathogenic variants in the dopa decarboxylase gene (DDC). DDC is mapped to the short arm of chromosome 7 (7p12.2-p12.1), which encodes the enzyme aromatic L-amino acid decarboxylase. AADC is involved in the biosynthesis of the monoamine neurotransmitters serotonin and dopamine. Because dopamine is the precursor for norepinephrine and epinephrine, AADC deficiency, or dopa decarboxylase deficiency, results in a severe combined deficiency of all four of these neurotransmitters: serotonin, dopamine, norepinephrine and epinephrine.
To date, less than 150 cases of AADC deficiency have been described in the medical literature. There is an increased prevalence in Southeast Asia, particularly among Taiwanese and Japanese populations. AADC deficiency is characterized by marked neurological and vegetative symptoms that usually begin in infancy. Symptoms are most frequently reported within the first year of life (average age of onset is about 3 months of age).
The diagnosis of AADC deficiency should be considered in infants presenting with early-onset muscular hypotonia, movement disorders (eg, oculogyric crisis, dystonia), and developmental delay. Autonomic nervous system dysfunction also occurs, such as hypersalivation, excessive sweating, ptosis, nasal congestion, and temperature instability. Other clinical features, such as sleep disorders and gastrointestinal dysfunction, are also observed owing to serotonin deficiency.
The genetic and clinical spectrum of AADC deficiency is heterogeneous and varies among patients. Diagnosis is based on a characteristic cerebrospinal fluid neurotransmitter metabolite profile, low or absent plasma AADC enzyme activity, and identification of pathologic variants in the DDC.
Pyridox(am)ine 5-phosphate deficiency differs from AADC deficiency in that it presents with a severe neonatal epileptic encephalopathy. The cerebrospinal fluid profile of AADC deficiency may be similar to that of pyridox(am)ine 5-phosphate deficiency; however, increased glycine and threonine in cerebrospinal fluid and a very low proteolipid protein level distinguish pyridox(am)ine 5-phosphate deficiency.
Both tetrahydrobiopterin deficiency and phenylketonuria are inherited as autosomal recessive disorders. These rare genetic disorders are classified as inborn errors of metabolism amino, resulting in accumulation of phenylalanine in the body. To prevent clinical deterioration, low-phenylalanine diets are prescribed in infancy. These genetic conditions can be detected early through newborn metabolic screening programs.
A progressive deteriorating clinical course is not a hallmark of AADC deficiency and should prompt suspicion for other neurodevelopmental diseases with a thorough diagnostic workup.
Epileptic seizures and features of autism have been described in patients diagnosed with AADC deficiency. On neurologic examination, deep tendon reflexes may be decreased, normal, or increased. Pathologic reflexes such as the Babinski sign may be seen in patients older than 2 years. Sleep disturbances (both insomnia and hypersomnia) due to serotonin deficiency also occur. Patients with AADC can suffer from severe sleep apnea, a potential life-threatening situation.
The core diagnostic tests for AADC deficiency are cerebrospinal fluid, plasma AADC activity, and genetic testing showing compound heterozygous or homozygous disease-causing variants in DDC. At least two of these three core diagnostic test results should be positive to confirm diagnosis.
AADC deficiency has a characteristic cerebrospinal fluid neurotransmitter metabolite profile. These measurements are:
- Reduced homovanillic acid, 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol
- Elevated 3-O-methyldopa, levodopa, and 5-hydroxytryptophan levels
- Normal levels of cerebrospinal fluid pterins (neopterin, dihydrobiopterin, and tetrahydrobiopterin)
Of note, normal levels of cerebrospinal fluid pterins are critical to diagnosis because they clearly differentiate AADC deficiency from the tetrahydrobiopterin disorders, in which levels of pterins are abnormal. Decreased plasma AADC enzyme activity is also seen in AADC deficiency. In fact, even in heterozygous carriers, plasma AADC activity is reduced.
Because AADC deficiency has no distinctive MRI pattern, imaging is generally not beneficial in the workup for this condition. However, imaging should be performed in patients with neurodevelopmental delay to exclude other conditions in the differential diagnosis.
Increased urine vanillactic acid levels, as measured by urine organic acid analysis, should prompt suspicion of AADC deficiency, but this elevation is often subtle and can be missed if not explored in a laboratory with expertise. Normal levels do not exclude diagnosis. Dopamine, homovanillic acid, and vanillylmandelic acid in urine are also unreliable biomarkers.
Although elevated serum prolactin has been seen in patients, normal levels do not exclude AADC deficiency.
In general, first-line treatment agents for AADC deficiency are selective dopamine agonists, monoamine oxidase inhibitors, and pyridoxine. Although monoamine oxidase inhibitors are not associated with evidence of clear clinical benefit, a trial period of therapy is recommended. Non–ergot-derived agonists should be used to treat AADC deficiency because ergot-derived agonists confer a risk for cardiac valvulopathy and other fibrotic complications.
Levodopa is first-line treatment only for patients with levodopa binding-site variants (ie, G102S, R347Q, R160Wl). Patients with AADC deficiency already have elevated levels of levodopa, and a sustained effect of therapy has been seen in patients with these relevant binding-site variants. Specifically, levodopa without carbidopa is recommended. In patients without proven levodopa binding-site variants, a levodopa trial can be considered if other treatment options do not show benefit. Cerebrospinal fluid 5-methyltetrahydrofolate levels should be determined before and during levodopa therapy.
Gene therapy is currently under investigation for the treatment of AADC deficiency, with patient recruitment ongoing for clinical trials in Taiwan, Japan, the United States, and Europe. Although modest improvements in motor and mental function have been reported in limited numbers of patients, further research is needed before this therapeutic modality can be recommended.
Anticholinergic agents can be considered in AADC deficiency, especially to treat autonomic symptoms, dystonia, and oculogyric crisis. In addition, other possible medications are melatonin when sleep disturbances arise and benzodiazepines for intermittent use for sustained oculogyric or dystonic crises.
Likewise, certain medications should be avoided. Centrally acting dopamine antagonists should be avoided because they may worsen dopamine deficiency. 5-hydroxytryptophan has been used as AADC deficiency therapy, but its benefit has not yet been proven and current recommendations advise against its use. Finally, based on current evidence, the use of selective serotonin reuptake inhibitors in AADC deficiency is not recommended.
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