AADC Deficiency

Overview

Aromatic L-amino acid decarboxylase (AADC) deficiency is an ultra-rare, inherited neurometabolic disorder caused by mutations in the DDC gene, leading to impaired synthesis of dopamine and serotonin. This results in severe motor, developmental, and autonomic symptoms, often beginning in infancy. Clinical features include:

• Developmental delay and hypotonia

• Oculogyric crises (upward eye deviation episodes)

• Autonomic dysfunction (ptosis, sweating, nasal congestion)

• Movement disorders (dystonia, hypokinesia)

• Sleep disturbances and irritability

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Treatment Options

Because AADC deficiency is a neurotransmitter synthesis disorder, therapy focuses on:

1. Enhancing neurotransmitter synthesis/release

2. Bypassing defective metabolic pathways

3. Symptomatic management

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1. Dopamine Agonists

Used to stimulate dopamine receptors since dopamine itself cannot be replaced effectively.

• Pramipexole: 0.125 mg orally 2–3 times daily; titrate slowly to effect, max ~1.5 mg/day (dose individualized).

• Ropinirole: Start 0.25 mg orally TID; gradual titration; usual therapeutic range 3–12 mg/day.

• Rotigotine: Transdermal patch, starting at 2 mg/24h, titrated based on tolerance.

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2. Monoamine Oxidase Inhibitors (MAO-B inhibitors)

To prevent breakdown of residual dopamine and serotonin.

• Selegiline: 0.1–0.3 mg/kg/day orally (divided doses).

• Rasagiline: 0.5–1 mg once daily (off-label use in children, more commonly reported in adults).

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3. Pyridoxine (Vitamin B6)

AADC enzyme uses pyridoxal phosphate (active vitamin B6) as a cofactor. Supplementation may help, particularly in mild mutations.

• Pyridoxine hydrochloride: 10–200 mg/day orally (dose adjusted individually).

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4. 5-Hydroxytryptophan (5-HTP)

Precursor of serotonin; bypasses the AADC defect partially.

• 5-HTP: 2–15 mg/kg/day orally in divided doses (careful titration needed due to risk of dyskinesia).

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5. Gene Therapy (Eladocagene exuparvovec – Upstaza®)

• Approved in the EU/UK (not yet widely available elsewhere).

• One-time intracerebral infusion of adeno-associated viral vector delivering a functional DDC gene to restore dopamine synthesis.

• Dose: delivered surgically into putamen; not expressed as mg but as viral vector particles (clinical specialist procedure).

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6. Other Supportive/Adjunct Therapies

• Melatonin (1–3 mg orally at night) → for sleep disturbances.

• Benzodiazepines (e.g., diazepam 0.1–0.3 mg/kg PO/IV q6–8h as needed) → for oculogyric crises, dystonia.

• Anticholinergics (e.g., trihexyphenidyl 0.1 mg/kg/day divided TID, titrated) → for dystonia.

• Physiotherapy, occupational therapy, speech therapy → to support motor and developmental function.

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Key Considerations

• Levodopa is usually ineffective and may worsen symptoms, unlike in classic dopamine deficiency syndromes.

• Drug responses vary greatly between patients; therapy must be carefully titrated under specialist supervision.

• Genetic confirmation is essential for diagnosis and for eligibility for gene therapy.

• Supportive multidisciplinary care (neurology, gastroenterology, nutrition, respiratory therapy) is crucial.