AADC deficiency is caused by biallelic pathogenic variants in the DDC gene, which encodes the aromatic L-amino acid decarboxylase enzyme. This enzyme catalyzes the decarboxylation of L-DOPA to dopamine and 5-hydroxytryptophan to serotonin. Loss-of-function variants in DDC impair both reactions, producing global monoamine neurotransmitter deficiency with accumulation of precursor metabolites detectable in cerebrospinal fluid and urine.

The condition follows an autosomal recessive inheritance pattern: both copies of the DDC gene must carry a pathogenic variant for an individual to be affected. Parents who are each carriers of one pathogenic variant are typically unaffected; each pregnancy of two carrier parents carries a 25% probability of producing an affected child. As described in the GeneReviews chapter for this condition, no clinically relevant genotype-phenotype correlations for DDC have been established, with rare exception (a single reported individual with a specific variant near the substrate binding pocket showed levodopa responsiveness, though this has not been broadly established). Because two pathogenic copies are required, the condition may be more prevalent in families where parents share a common ancestor, as this increases the probability that both parents carry the same rare DDC variant.

Diagnosis of AADC deficiency requires biochemical and molecular confirmation in the setting of a characteristic clinical presentation. Cerebrospinal fluid neurotransmitter analysis is central to diagnosis and typically demonstrates markedly reduced homovanillic acid (HVA, the primary dopamine metabolite) and 5-hydroxyindoleacetic acid (5-HIAA, the serotonin metabolite), with elevated L-DOPA and 5-hydroxytryptophan. Plasma AADC enzyme activity is substantially reduced or absent in affected individuals. Urine catecholamine profiles may show characteristic biochemical abnormalities. Molecular genetic testing of the DDC gene identifies biallelic pathogenic variants and provides definitive confirmation.

Diagnosis is typically considered in the setting of a neonate or infant presenting with severe hypotonia, movement disorder, oculogyric crises, and autonomic dysfunction. Published clinical practice consensus guidelines for AADC deficiency specify recommended evaluations following initial diagnosis across multiple organ systems, including comprehensive neurologic assessment (full neurologic examination, consideration of brain MRI, EEG if seizures are a concern), developmental evaluation, gastrointestinal and nutritional assessment including evaluation for aspiration risk and need for feeding support, ophthalmologic evaluation for ptosis and other ocular findings, cardiovascular evaluation including consideration of echocardiogram and Holter monitoring, and respiratory and sleep assessment.

Treatment of AADC deficiency includes both disease-modifying and symptomatic management strategies. Eladocagene exuparvovec-tneq (brand name: Kebilidi) is an FDA-approved treatment for AADC deficiency, having received regulatory approval in November 2024 via a Biologics License Application (BLA); it carries active market status. This product is an adeno-associated virus-based gene transfer therapy delivering a functional copy of the gene encoding the AADC enzyme to targeted brain regions, aiming to restore dopamine biosynthesis. Eligibility criteria, procedural details, and post-treatment management are determined by the treating clinical team in the context of individual patient assessment.

Symtomatic and supportive management is a central component of care and encompasses multiple domains. Strategies addressing monoamine neurotransmitter deficiency may include pharmacologic approaches targeting dopamine and serotonin pathways as guided by the clinical team. Oculogyric crises and dystonic episodes require individualized management. Multidisciplinary supportive care incorporates physical therapy to address gross motor function, occupational therapy for fine motor skills and activities of daily living, speech-language therapy, and comprehensive feeding and nutritional support. Gastrointestinal manifestations including gastroesophageal reflux, constipation, and diarrhea typically require ongoing management. Respiratory complications including apnea are evaluated and managed as clinically indicated; consideration of chest physiotherapy and respiratory precautions may be warranted. Ophthalmologic and cardiovascular monitoring are recommended components of ongoing surveillance per published guidelines.

Additional investigational gene therapy approaches are under active clinical study, including several AAV-based gene transfer strategies currently in Phase 1 and Phase 2 trials.

The natural history of AADC deficiency without intervention is characterized by severe impairment of motor function and marked developmental delay from early infancy. Most affected individuals demonstrate substantially limited voluntary movement, severe hypotonia, prominent movement disorder, and significant functional dependence. Oculogyric crises may be prolonged and severely disruptive. Nutritional challenges and gastrointestinal complications are common throughout the disease course. Respiratory vulnerability and susceptibility to infections represent ongoing concerns.

The emergence of disease-modifying gene therapy represents a significant development in the prognostic landscape for this condition; individual treatment responses vary. The GeneReviews chapter notes that the full phenotypic spectrum of DDC-related disease, including whether milder presentations exist, continues to be characterized. Individual outcomes depend on the severity of the underlying enzyme deficiency, the nature and extent of complications, timing of diagnosis and initiation of treatment, and access to specialized multidisciplinary care.

AADC deficiency is an active area of clinical investigation, with gene therapy and novel therapeutic approaches representing the dominant published research type across the 37 classified publications in the research landscape. Case reports, review articles, and biomarker studies are also represented. Three clinical trials are currently active, including a Phase 1 gene therapy dose-escalation study and Phase 2 studies of novel AAV-based gene transfer strategies, with completion dates extending through 2037. The AADC Family Network maintains a patient registry supporting longitudinal research efforts. The approval of eladocagene exuparvovec has catalyzed ongoing research into delivery optimization, long-term safety monitoring, and outcome characterization. Individuals interested in current clinical trials may search ClinicalTrials.gov.