Philip L. Pearl, MD, Director, Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital, William G. Lennox Chair and Professor of Neurology, Harvard Medical School, Boston, MA discusses aromatic L-amino acid decarboxylase (AADC) deficiency and the recently published paper in Molecular Genetics and Metabolism: “Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes.”
AADC deficiency is a rare, genetic disorder that affects the central nervous systems of young patients. Defect in the dopa decarboxylase (DDC) gene, which leads to a reduction in the critical neurotransmitters dopamine, norepinephrine, epinephrine, and melatonin in the brain causes AADC deficiency.
As a result, the functions and cellular communication controlled by these individual neurotransmitters can be affected. For example, patients with AADC deficiency experience varying symptom severity which includes developmental delay (sit, crawl, stand, walk), oculogyric crisis, and moving disorders (such as hypotonia). The additional symptoms associated with AADC deficiency are related to the poor production of the other neurotransmitters.
Signs and symptoms usually appear in affected children before their first birthday. Patients often start to display severe developmental disabilities, and have difficulty gaining muscle strength and coordination. Vital motor function, including breathing, swallowing, and feeding, can all be affected. Patients generally require lifelong care, and those with severe symptoms rarely survive beyond 10 years of age. Symptom severity is dependent on the phenotype of the disease; some patients survive into adulthood, and in these cases, may only need assistance in limited areas (e.g., mobility). For patients with moderate symptoms, survival into adulthood is possible, but clearer information on the natural history of these patients is not yet available.
PATHOPHYSIOLOGY AND EPIDEMIOLOGY
The DDC gene creates an enzyme that is required for the production of the neurotransmitters dopamine, epinephrine, norepinephrine, serotonin, and melatonin. Therefore, when the enzyme is not present, the levels of all of these neurotransmitters are far lower than normal, interfering in several ways with intercellular communication. The abnormal neurotransmitter levels inhibit motor and muscle development, as described above.
This genetic disorder is passed down through autosomal recessive heredity; meaning that only children receiving a mutated DDC gene from both parents can express symptoms. Those receiving only one copy of a mutation will have normal DDC gene function but are carriers of the recessive, defective gene. Yet, over 80 variants of the DDC gene have been recorded, which probably explains the spectrum of symptoms seen in patients.
AADC deficiency is an extremely rare disorder: From 1990 to 2020, case series of 120 to 130 patients have been published. Interestingly, a new study asserts that AADC deficiency may be a bit more common: Researchers announced findings in 2020 that AADC deficiency may be associated with some neurologic disorders in children. They believe that perhaps 1 in 900 patients (up to 20 years old) with undiagnosed neurotransmitter disorders may be attributable to AADC deficiency.
AADC deficiency has been documented all over the world, but the highest prevalence is seen in the Asian population due to the founder effect. Based on the case series, the average age when symptoms first appear is 2.7 months, but mean age at time of first diagnosis is age 3.5 years.
SIGNS AND SYMPTOMS
The first sign of the disease is usually hypotonia (e.g., the neck muscles are too weak to hold the baby’s head up). Other neurological problems, including developmental delay (e.g., walking and talking), movement disorders (e.g., involuntary movements), and autonomic issues (e.g., excessive sweating, chronic nasal congestion, hypotension, uncontrolled heart rate, and ptosis), are common; patients may have one or more of these signs. Other reported signs in AADC deficiency are frequent sleep disturbances, which are caused by the melatonin abnormalities, general lack of energy, and poor appetite. Chronic diarrhea was noted in a case series of 10 French children with the disorder.
One movement disturbance that can be extremely concerning to caregivers of patients with AADC deficiency is a syndrome called oculogyric crisis, prolonged involuntary upward deviation of the eyes. Symptoms tend to worsen with fatigue and improve after the patient sleeps.[5]
Once suspected, a diagnosis is challenging: analysis of metabolites in cerebrospinal fluid, assessment of plasma AADC activity, and/or DNA sequence analysis is required. Blood testing and cerebrospinal fluid analysis will show very low levels of specific chemicals (e.g., 5-hydroxyindoleacetic acid) related to the production of the neurotransmitters dopamine and serotonin. Blood tests can measure the activity of the enzyme that is encoded by the DDC gene. Genetic testing for DDC mutations will confirm the diagnosis.
To learn more about this rare genetic disorder, visit our AADC Deficiency Learning Page.
REFERENCE
Corrigendum to: Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes. Mol Genet Metab. 2023 Aug;139(4):107647. doi: 10.1016/j.ymgme.2023.107647. Epub 2023 Jul 7. https://pubmed.ncbi.nlm.nih.gov/37453860/
