Aromatic L-Amino Acid Decarboxylase Deficiency

Clinical characteristics: Individuals with aromatic L-amino acid decarboxylase (AADC) deficiency typically have complex symptoms, including motor, behavioral, cognitive, and autonomic findings. Symptom onset is in early infancy, typically within the first six months of life. The most common initial symptoms are often nonspecific, and include feeding difficulties, hypotonia, and developmental delay. More specific symptoms include oculogyric crises (which occur in the vast majority of affected individuals, typically starting in infancy), movement disorders (especially dystonia), and autonomic dysfunction (excessive sweating, temperature instability, ptosis, nasal congestion, hypoglycemic episodes). Sleep disturbance is present in a majority of affected individuals and can include insomnia, hypersomnia, or both. Mood disturbance, including irritability and anxiety, are also common. Brain MRI is typically either normal or may demonstrate nonspecific abnormalities, such as mild diffuse cerebral atrophy or delayed myelination. Seizures are an uncommon finding, occurring in fewer than 5% of affected individuals.

Diagnosis/testing: The diagnosis of AADC deficiency is established in a proband who has the following core diagnostic testing results: biallelic pathogenic variants in DDC identified by molecular genetic testing OR cerebrospinal fluid (CSF) or plasma neurotransmitter profile consistent with AADC deficiency AND significantly reduced AADC enzyme activity in plasma.

Management: Targeted therapies: Treatments can include the use of dopamine agonists (pramipexole, ropinirole, rotigotine patch, or bromocriptine), MAO inhibitors (selegiline or tranylcypromine), vitamin B₆ (pyridoxine, pyridoxal phosphate), folinic acid, and (in rare cases) levodopa in a preparation without carbidopa. Putaminal delivery of eladocagene exuparvovec (Upstaza^®) was approved in the European Union and United Kingdom for the treatment of individuals aged 18 months and older with a clinical, molecular, and genetically confirmed diagnosis of AADC deficiency with a severe phenotype (i.e., individuals who cannot sit, stand, or walk); this treatment is not currently FDA approved for use in the United States.

Supportive care: Feeding therapy with consideration of gastrostomy tube placement or jejunal feeding; anticholinergic drugs and/or sleep induction for movement disorders / oculogyric crisis; xylometazoline or oxymetazoline nasal drops for autonomic dysfunction; melatonin or clonidine for sleep disturbance; and standard therapies for epilepsy, developmental delay / intellectual disability, musculoskeletal issues, bowel dysfunction (constipation, diarrhea, or gastroesophageal reflux disease), strabismus, visual impairment, obstructive sleep apnea, hypoglycemia, and hearing loss.

Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status and safety of oral intake; monitor frequency and severity of oculogyric crises and movement disorders; assess for new manifestations, such as seizures, changes in tone, and movement disorders; monitor developmental progress and educational needs; monitor for behavioral issues and symptoms of anxiety, ADHD, ASD, aggression, & self-injury; clinical assessment for kyphoscoliosis and hip dislocation; monitor for constipation, diarrhea, gastroesophageal reflux, and abdominal discomfort or pain; and monitor for evidence of aspiration, respiratory insufficiency, sleep disturbance, and frequency of respiratory infections. Annually: obtain hip and spinal radiographs (until skeletal maturity); consider cardiology evaluation; consider continuous glucose monitoring, especially in younger affected individuals. Per treating clinicians: ophthalmology evaluation; monitor for cardiac function and rhythm defects; monitor for symptoms of obstructive sleep apnea and nasal congestion. In those on levodopa treatment: monitor CSF neurotransmitters, including 5-methyltetrahydrofolate levels, as clinically indicated to assess for secondary folate deficiency, particularly if neurologic symptoms worsen. In those on bromocriptine therapy: echocardiogram and EKG every 6-12 months to monitor for vavlulopathy caused by valve fibrosis (the risk is lower than with other ergot-derived dopamine agonists such as pergolide, but not absent).

Agents/circumstances to avoid: Ergot-derived dopamine agonists with strong serotonergic (5-HT2B) agonist action (pergolide and cabergoline) due to risk of cardiac valvulopathy and other fibrotic complications; levodopa in most affected individuals who do not have ligand binding site pathogenic variants; dopamine receptor antagonists (e.g., metoclopramide, antipsychotic medications), which may worsen primary disease symptoms.

Evaluation of relatives at risk: Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of AADC deficiency. Molecular genetic testing is recommended if the pathogenic variants in the family are known; measurement of CSF neurotransmitters (to evaluate for the characteristic profile) and plasma AADC enzyme activity is recommended if the pathogenic variants in the family are not known.

Pregnancy management: Successful pregnancy has been documented in an affected woman with a mild phenotype who took low-dose pramipexole and selegiline during pregnancy.

Genetic counseling: AADC deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a DDC pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. If both DDC pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.