AADC Patients Experience Severe Symptoms from Infancy to Adulthood, Study Reveals

Inês Martins, PhD avatar

by Inês Martins, PhD |

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Most patients with aromatic l-amino acid decarboxylase (AADC) deficiency experience a combination of severe motor symptoms and prominent non-motor symptoms that persist from childhood to adulthood, according to findings from a recent study.

Some older patients, however, have milder forms of the disease and are able to walk and sit independently, attend school, and participate in work activities.

The study, “AADC Deficiency From Infancy to Adulthood: Symptoms and Developmental Outcome in an International Cohort of 63 Patients,” was published in the Journal of Inherited Metabolic Disease.

AADC deficiency is caused by mutations in the DDC gene, which carries the instructions for making an enzyme that is essential for the production of neurotransmitters (chemical factors that allow communication between nerve cells). AADC patients typically experience developmental delays, movement disorders, muscle weakness, as well as sleep disorders, and problems in controlling blood pressure, heart rate, and body temperature.

Since the condition was first described in 1990, more than 135 patients have been reported in research literature, most of whom have a severe disease course with profound motor impairment. Only a few patients exhibited mild disease and had good responses to treatment.

Studies to date, however, have provided information mostly about symptoms at disease onset. Little is known about how symptoms evolve over the course of disease, as well as developmental outcomes and mortality among those with AADC deficiency.

To address this question, an international team of researchers examined the symptoms and outcomes of AADC patients included in the International Working Group of Neurotransmitter-Related Disorders (iNTD) patient registry and in the AADC Research Trust.

The study, funded by the Pediatric Neurotransmitter Disease Association and the National Institute of Neurological Disorders and Stroke, included 63 patients from 23 countries. Most were from Europe (27 patients) and North America (16), followed by Asia, (12), South America (4), and Middle East (4).

Information about each patient was provided via a questionnaire completed by the physician and/or the patient’s parents. At the time of the analysis, patients had a median age of 7, ranging from 6 months to 36.8 years. Patients were mostly female (60%) and their median age at the time of initial symptoms was 3 months (range 0–12 months).

The time from initial symptoms to an AADC diagnosis varied greatly, but younger patients tended to be diagnosed faster than those older than 10 at the time of the analysis, the researchers reported. This likely reflects advances in newborn screenings in more recent years.

The most common initial symptoms were low muscle tone (hypotonia, 75%), involuntary upward eye movement (oculogyric crises, 62%), developmental delay (62%), and feeding problems (54%). Patients also presented with non-motor symptoms such as sleepiness (50%), irritability (44%), excessive sweating (44%), and stuffy nose (42%).

At the time of the questionnaire, participants across different ages were asked to classify symptoms as major, minor, or absent. Insomnia affected a large proportion of patients from age 2 to older than 18, but was particularly more burdensome at ages 6–12, with half of the children in this age range reporting it as a major problem.

Irritability also affected most children (85%) in this age range (6‐12), while excessive sleepiness and excessive sweating mostly affected children younger than 2. Excessive sweating and irritability also were common in patients across other age groups.

Regarding oculogyric crises, about 98% of patients reported such episodes, but these appeared to be more common, more severe, and to last longer in younger patients. In retrospect, respondents believed these episodes had been most problematic at ages ranging from infancy to 5. Episodes lasting more than four hours also were much more common in patients younger than 6 (84%), compared to older patients (43%).

The researchers, however, noted that some of the older patients have milder disease and the ability to walk without assistance, which may explain the reduced frequency of oculogyric crises in adolescents and adults.

Among patients 12 months or older, 33% had head control and 22% could walk and sit independently. Overall, younger patients had more severe motor symptoms, with none of the 19 patients younger than 6 being able to sit or walk independently. But researchers do not believe this is a delay in milestone attainment, as most older patients who could walk did so before reaching age 6.

“Rather, the data suggest that a greater proportion of the older patients in this cohort had a milder disease phenotype,” researchers wrote.

Other problems found in these patients were difficulties in eating, reported in 75% of patients as either a past or current problem. Nearly half of patients (45%) had a feeding tube in their stomach for nutritional support.

Among the 38 patients 5 or older, four were completely independent, seven were partially independent, and the remaining 71% were completely dependent. Notably, 62% of patients up to age 18 attended school, and two of the eight young adults older than 18 worked outside their homes.

Regarding treatment, dopamine agonists were the most commonly used medications and the most likely to ease symptoms, but they were associated with dose-limiting side effects — including dyskinesia (abnormal, uncontrollable, involuntary movements), insomnia, irritability, and vomiting — that led to discontinuation of therapies 25% of the time.

At the time of the questionnaire, five patients had died, but parents responded to the survey. Two patients died at age 2, one at 7, one at 13, and the other at 21. Causes of death included pneumonia, complications during an oculogyric crisis, and heart attack.

Overall, “the age distribution of our cohort (70% of subjects under age 13 years) and the observation of a greater proportion of patients with a more severe disease phenotype in the younger compared to the older patients, both suggest a significant mortality risk during childhood for patients with severe disease,” the researchers wrote.

The team also noted that the “findings illustrate that AADCD is associated with severe functional impairment in the majority of patients, and that prominent non‐motor and autonomic symptoms occur throughout the lifespan. Disease features are refractory to existing medical therapies, particularly in severe cases, which motivates the search for novel effective therapeutic strategies.”