Aromatic L-amino acid decarboxylase deficiency

Aromatic L-amino acid decarboxylase deficiency (AADC deficiency) is a rare genetic disorder caused by mutations in the DDC gene, which encodes an enzyme called aromatic L-amino acid decarboxylase.

Signs and symptoms

Biosynthesis and breakdown of serotonin and the catecholamines, and the metabolic block in AADC deficiency, Wassenberg et al., 2017.

Babies with severe AADC deficiency usually present during the first few months of life. Symptoms can include:

• Hypotonia (floppiness)
• Developmental delay
• Oculogyric crises
• Difficulty with initiating and controlling movements
• Dystonia and dyskinesia
• Gastointestinal dysmotility which can present at as vomiting, gastro-oesophageal reflux, diarrhoea and/or constipation
• Autonomic symptoms including difficulties controlling temperature and blood sugar, excessive sweating and nasal congestion

Some patients may develop cerebral folate deficiency, because O-methylation of the excessive amounts of L-Dopa can deplete methyl donors such as SAM and 5-MTHF. This deviation can be detected by measuring the levels of 5-MTHF in the cerebrospinal fluid, and can be corrected by folinic acid.

Genetics

AADC deficiency has an autosomal recessive pattern of inheritance

AADC deficiency is an autosomal recessive condition, meaning an individual needs to have two faulty copies of the DDC gene in order to be affected. Usually, one copy is inherited from each parent.

Pathophysiology

The AADC enzyme is involved in the synthesis of dopamine and serotonin, both of which are important neurotransmitters.

Diagnosis

Once there is a clinical suspicion of the diagnosis, neurotransmitters can be analysed in cerebrospinal fluid from a lumbar puncture. If these show the pattern of abnormalities typical for AADC deficiency, the diagnosis can be confirmed by genetic testing and/or measurement of enzyme activity.

Treatment

There is currently no cure for AADC deficiency, but medical and multidisciplinary treatment can relieve some of the symptoms. Patients will require physiotherapy, occupational therapy, and speech and language therapy. Some will need enteral feeding (for example, a gastrostomy or jejunostomy) due to difficulties with chewing and swallowing.

Various medications can help compensate for the missing neurotransmitters. Dopamine agonists such as rotigotine or pramipexole and monoamine oxidase inhibitors such as selegiline are commonly used. Patients may also need to take a range of other medications to control dyskinesia, constipation and other symptoms.