AROMATIC L-AMINO ACID DECARBOXYLASE DEFICIENCY (AADC)
Aromatic L-amino acid decarboxylase deficiency (AADC) is a rare, neurometabolic disorder resulting from the loss of dopa decarboxylase (DDC) function required to synthesize neurotransmitters (dopamine and serotonin). Symptomatology of AADC begins in the first 6 months of life and includes developmental delay, cognitive issues (intellectual disability), behavioral issues (anxiety, autistic features), and motor issues (dystonia, hypokinesia, oculogyric crises) as well as autonomic dysfunction (temperature instability, hypoglycemia). Diagnosis of AADC is based on three key diagnostic elements (Wassenberg et al., 2017). The first element is a specific biochemical profile on cerebrospinal fluid (CSF) analysis*. The second element is genetic testing revealing pathogenic DDC gene variants. The third element is a decreased plasma AADC enzyme activity. Mild diffuse atrophy and/or delayed myelination can be seen on brain MRI. AADC symptoms can range from mild to severe. Most individuals with AADC have the severe form and have a high risk of death by 5 to 6 years of age due to severe motor dysfunction (Blau et al., 2023). AADC is an autosomal recessive condition. This means AADC results when two copies of the DDC gene (dopa decarboxylase gene) are inherited with disease-causing mutations. Incidence of AADC is estimated to be one to three per 1,000,000 live births (Blau et al., 2024). Half of the cases occur in those of Asian ancestry and many of those cases occur in individuals with Taiwanese ancestry. There are no disease-modifying treatments for AADC other than supportive care. Therapies aimed at increasing neurotransmitter production or decreasing destruction of neurotransmitters (inhibition of monoamine oxidase) have been tried but without much success.
*CSF biochemical profile suggestive of AADC: low 5-HIAA [5-hydroxyindoleacetic acid], HVA [homovanillic acid], and MHPG [3-methoxy-4- hydroxyphenylglycol], normal pterins and elevated 3-OMD [3-O-methyldopa], L-Dopa [L-3,4-hihydoxyphenylalanine], 5-HTP [5-hydroxytryptophan].
Symptoms of AADC deficiency typically begin shortly after birth 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 hypokinesia, hypertonia in the limbs, dystonia, athetosis, chorea, and tremors. Dysfunction of the
autonomic nervous system can lead to excessive sweating, hypersalivation, ptosis, nasal congestion, temperature
instability, hypotension, and hypoglycemia. Gastrointestinal symptoms including gastric reflux, constipation, or
diarrhea are common. Because of the disease itself and because of the numerous possible symptoms, children with
AADC deficiency have developmental delays and are not able to reach normal milestones such as walking and
talking; they have feeding difficulties and generally have a failure to thrive. They are prone to many medical complications
and 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.
The 2017 consensus guidelines for the diagnosis and treatment of AADC deficiency state that confirmation of disease
involves three core diagnostic tests: a lumbar puncture showing CSF with low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), and high
concentrations of 3-O-methyldopa (3-OMD), L-Dopa, and 5-OH tryptophan (5-HTP); genetic testing showing
mutations in the DCC gene; and decreased AADC enzyme activity in the plasma. If genetic diagnosis is performed
as the first step, functional confirmation should be completed by measuring AADC enzyme activity in the plasma
and/or neurotransmitter metabolites in CSF. Guidelines recommend performing all three diagnostic tests to
confirm diagnosis.
Until now, there have been no disease modifying therapies available for the treatment of AADC deficiency.
Management has included a multidisciplinary approach to address the specific needs of the affected individual.
Numerous medications can help manage symptoms although the most appropriate treatment 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. First-line treatments include dopamine agonists, monoamine oxidase B [MAO-B] inhibitors, and
vitamin B6. Guidelines prefer the use of non–ergot-derived dopamine agonists including pramipexole, ropinirole, and
rotigotine, and state that they should be tried. Guidelines also recommend a trial of MAO-B inhibitors, although literature
support for use is minimal. Vitamin B6 is considered due to its use as a cofactor for the AADC enzyme and the
possibility it may increase residual enzyme activity. Other medications, such as melatonin, benzodiazepines, or anticholinergics, may also be considered for an individual with specific symptoms.
ELADOCAGENE EXUPARVOVEC-TNEQ (KEBILIDI)
Eladocagene exuparvovec-tneq (Kebilidi) is a FDA-approved viral vector–based gene therapy using the recombinant adeno-associated viral vector serotype 2 (rAAV2) to deliver a functional copy of the dopa decarboxylase gene to an individual. It is the first approved gene therapy administered directly to the brain via stereotactic surgery. Once infused into the putamen, the AADC enzyme is expressed, and dopamine production occurs. The FDA's accelerated approval was based in part on positive outcomes from a phase I/II study of eladocagene exuparvovec-tneq (Kebilidi) in 10 individuals with severe AADC deficiency. The primary endpoint, Peabody Development Motor Scales, second edition [PDMS-2]), showed meaningful improvement in all trial participants receiving the therapy (Tai et al., 2021; Chien et al., 2017). Per the manufacturer, the procedure for gene therapy delivery is approximately 8 hours and individuals remain in the hospital for 3 to 4 days postoperatively.
RELIABLE EVIDENCE
The primary source of data for accelerated FDA approval was clinical trial PTC-AADC-GT-002 [NCT04903288]. This was a single arm, open-label study with ages ranging from 16 months to 10 years. The median age was 2.8 years. Thirteen individuals received eladocagene exuparvovec-tneq (Kebilidi), 12 of which had a severe phenotype: no motor milestone achievement at baseline and no response to standard therapies. Milestones were assessed at baseline and at week 48. One individual dropped out prior to week 48. Of the 12 remaining participants, eight acquired a new gross motor milestone at week 48; the four individuals who were unable to make gains were treated between ages 2.8 and 10 (FDA package insert, 2024). None of the external controls had achieved new motor milestones at last assessment (age range, 2–19 years). Other trials described below have noted additional gains 24 months posttreatment.
A long-term study (Tai et al., 2021) assessed the safety and efficacy of eladocagene exuparvovec-tneq (Kebilidi) treatment in AADC by combining data from three trials (compassionate use [AADC-CU/1601], phase I/II [NCT01395641], and phase IIb [NCT02926066]). All trials were single-arm, open-label trials. The primary difference among the trials was in the phase IIb trial that limited enrollment to individuals aged 6 years or younger and shifted to a higher dose of eladocagene exuparvovec-tneq (Kebilidi) by 33%. The compassionate use study involved eight individuals, the phase I/II trial enrolled 10 individuals, and the phase IIb trial enrolled eight individuals. A combined total of 26 individuals with severe AADC (without head control) received bilateral intraputaminal infusions of eladocagene exuparvovec-tneq (Kebilidi) at a mean age of 4.1 years (range, 1.7–8.5 years); mean follow-up was 5.4 years (range, 2.0–10.2 years). Eladocagene exuparvovec-tneq (Kebilidi) therapy showed rapid improvements in motor and cognitive function within 12 months that were sustained over 5 years. The clinical improvements included significant increases in motor function scores as measured by PDMS-2 and Alberta Infant Motor Scale (AIMS) scores. Baseline PDMS-2 was 10.4, which improved to 80.5 by year 1 and 116.1 by year 5 (P<0.01) post–eladocagene exuparvovec-tneq (Kebilidi) therapy. The AIMS score increased from 1.8 to 24.5 at year 5 posttreatment. Three individuals achieved independent walking. Also statistically significant were improved cognitive and language abilities per Bayley III scores. One individual developed speech capabilities. Body weight gain improved from 26% in first year compared with 9.4% pretreatment. Lastly, oculogyric crises decreased as did excessive sweating and temperature instability. Laboratory data improvements included increased CSF HVA levels (from 6.6 to 30.2 nmol/L at 12 months), enhanced dopamine production shown through PET imaging, and sustained AADC enzyme activity in the putamen. Eleven individuals from these three combined trials, who had been followed for more than 5 years, showed sustained improvements as noted by maintenance of motor and cognitive gains and stable PET imaging results at 5 years.
There were two deaths reported among the trial participants. One individual experienced encephalitis secondary to influenza B 11 months after receiving eladocagene exuparvovec-tneq (Kebilidi) therapy and died. There was an endemic outbreak of influenza B at the time and this death was reported to be unrelated to the therapy. The other individual died of probable aspiration 5 years after receiving eladocagene exuparvovec-tneq (Kebilidi) therapy. The most common side effects were dyskinesia (24 individuals), pyrexia, upper respiratory tract infections, and CSF leakage related to surgery and were treated with standard therapy. Most dyskinesia events resolved within months and are believed to be related to dopamine receptor sensitivity after prolonged deficiency of dopamine. There were no new significant safety concerns in long-term follow-up. Prognostic factors suggesting a better response to eladocagene exuparvovec-tneq (Kebilidi) were younger age at treatment and higher pretreatment HVA levels. There was no correlation between dosage and treatment outcomes. In addition to individual benefit, caregivers reported improved quality of life across multiple domains including physical health, psychological well-being, and social relationships. Of note, there was only one adult (19 years old) treated in any of the clinical trials. An economic modeling study comparing best supportive care (n=49) versus eladocagene exuparvovec-tneq (Kebilidi) therapy (n=30) was reported in 2023 (Simons et al., 2023). Best supportive therapies included dopamine agonists, monoamine oxidase inhibitors, pyridoxal phosphate/pyridoxine, anticholinergic agents, folic acid, L-dopa (with or without carbidopa), 5-hydroxytryptophan, benzodiazepines, melatonin, and selective serotonin-reuptake inhibitors. The best supportive care was delivered via guidelines developed by the international working group on neurotransmitter-related disorders. Two of 49 individuals gained more than one motor milestone, but otherwise, the standard of care approach did not appear to improve motor function or help individuals attain milestones. Estimates suggest an additional 25.25 life years were gained and 20.21 quality-of-life benefits were gained for the eladocagene exuparvovec-tneq (Kebilidi) group compared with the best-supportive-care group.
One additional clinical trial (NCT04903288) not yet completed is a long-term extension study designed to capture long-term safety and efficacy data from participants treated with eladocagene exuparvovec-tneq (Kebilidi).
National/Specialty Organizations
The National Institute for Health and Care Excellence (NICE) published guidelines recommend eladocagene exuparvovec-tneq (Kebilidi) for people with severe AADC at 18 months of age and over. “The clinical evidence suggests that eladocagene exuparvovec improves motor development, and that these improvements will last."
The National Organization of Rare Disorders published guidelines for the treatment of AADC (Wassenberg et al., 2017). However, at the time of guideline publication in 2017, eladocagene exuparvovec-tneq (Kebilidi) was not yet available.
