Aromatic L-amino acid decarboxylase deficiency

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Aromatic L-amino acid decarboxylase deficiency
Synonyms	N/A
Pronounce	N/A
Specialty	N/A
Symptoms	Hypotonia, oculogyric crises, dystonia, developmental delay, parkinsonism, autonomic dysfunction
Complications	Cerebral folate deficiency, gastrointestinal dysmotility, feeding difficulties
Onset	Infancy
Duration	Lifelong
Types
Causes	Mutations in the DDC gene
Risks	Family history of AADC deficiency
Diagnosis	Lumbar puncture, neurotransmitter analysis, enzyme assay, genetic testing
Differential diagnosis	Cerebral palsy, dopamine transporter deficiency syndrome, mitochondrial disease
Prevention	Genetic counseling
Treatment	Dopamine agonists, monoamine oxidase inhibitors, folinic acid, supportive therapies
Medication	Rotigotine, pramipexole, selegiline, trihexyphenidyl
Prognosis	Variable; improved with early diagnosis and multidisciplinary care
Frequency	Very rare (estimated <1 per 100,000 births)
Deaths

Aromatic L-amino acid decarboxylase deficiency (AADC deficiency) is a rare, inherited neurometabolic disorder that affects the biosynthesis of key neurotransmitters including dopamine, serotonin, epinephrine, and norepinephrine. It results from mutations in the DDC gene, which encodes the aromatic L-amino acid decarboxylase enzyme, also known as AADC.

Overview

AADC deficiency disrupts the final step in the synthesis of several monoamine neurotransmitters. This leads to a wide range of neurological and autonomic symptoms, primarily presenting in infancy or early childhood. The condition follows an autosomal recessive inheritance pattern and is categorized among inborn errors of neurotransmitter metabolism.

Signs and Symptoms

Metabolic block in the biosynthesis of serotonin and catecholamines in AADC deficiency.

Clinical features vary in severity, but common symptoms include:

• Hypotonia (reduced muscle tone)
• Developmental delay
• Oculogyric crises – episodes of sustained upward deviation of the eyes
• Dystonia and dyskinesia – involuntary muscle contractions and abnormal movements
• Parkinsonism – tremors, rigidity, and bradykinesia
• Autonomic dysfunction – excessive sweating, nasal congestion, temperature instability, drooling, and hypoglycemia
• Feeding difficulties, reflux, and constipation

Secondary complications such as cerebral folate deficiency may occur due to depletion of methyl donors like SAM and 5-MTHF from altered neurotransmitter metabolism. This is detected by low 5-MTHF in cerebrospinal fluid and can be treated with folinic acid supplementation.

Genetics

AADC deficiency results from biallelic pathogenic variants in the DDC gene located on chromosome 7. Inheritance is autosomal recessive, meaning both parents must be carriers for an affected child. Carrier status is typically asymptomatic.

Pathophysiology

The AADC enzyme catalyzes the decarboxylation of:

• L-DOPA to dopamine
• 5-hydroxytryptophan (5-HTP) to serotonin

Deficiency results in significantly reduced levels of dopamine, serotonin, and downstream catecholamines, affecting motor control, mood regulation, and autonomic functions.

Diagnosis

Diagnosis is confirmed through a combination of:

• Analysis of neurotransmitter metabolites in cerebrospinal fluid (via lumbar puncture)
• Measurement of AADC enzyme activity in plasma or fibroblasts
• Genetic testing for DDC mutations

Characteristic CSF findings include:

• Low levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA)
• Elevated 3-O-methyldopa (3-OMD) and L-DOPA

Differential Diagnosis

Conditions with overlapping features include:

• Cerebral palsy
• Severe hypotonia of infancy
• Other monoamine neurotransmitter disorders
• Mitochondrial encephalopathy

Treatment

There is currently no cure, but symptoms may be managed with:

Pharmacologic therapy

• Dopamine agonists (e.g., rotigotine, pramipexole)
• Monoamine oxidase inhibitors (e.g., selegiline) to reduce neurotransmitter degradation
• Anticholinergic agents for dystonia (e.g., trihexyphenidyl)
• Folinic acid to treat secondary folate deficiency

Supportive care

• Physiotherapy, speech and language therapy, and occupational therapy
• Nutritional support including enteral feeding via gastrostomy if required

Prognosis

The clinical course is variable. Early intervention and multidisciplinary care can improve outcomes and quality of life. Some children with mild forms may achieve partial motor and cognitive milestones, while others may remain severely affected.

Epidemiology

AADC deficiency is extremely rare, with fewer than 200 cases reported worldwide. Prevalence is estimated at less than 1 in 100,000 live births. It is likely underdiagnosed due to phenotypic overlap with other neurological disorders.

Research

Gene therapy trials using adeno-associated virus (AAV) vectors have shown promise in clinical studies, aiming to restore AADC enzyme function in the central nervous system.

See also

• Monoamine neurotransmitter disorders
• Hypotonia
• Neurometabolic disorder
• Genetic counseling

External links

• AADC Research Trust
• Genetic and Rare Diseases Information Center – AADC deficiency