Aromatic L-amino acid decarboxylase (AADC) deficiency

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited disorder of neurotransmitter synthesis resulting from a mutation in the dopa decarboxylase (DDC) gene.¹ Mutations in the DDC gene result in a significant reduction, or complete loss, of AADC enzyme activity, leading to a deficiency in key neurotransmitters, including dopamine, serotonin, epinephrine and norepinephrine.^1–3

A reduction in neurotransmitters affects neuronal signaling in the central nervous system, which is required for motor and behavioral development and autonomic function.^1,2 AADC deficiency can present with a broad range of symptoms, which usually appear around 3 months of age, and vary from patient to patient.¹ The most common symptoms are associated with reduced neurotransmitter levels and include motor and autonomic dysfunction and developmental delay.^1,4

AADC deficiency is an autosomal recessive disorder caused by mutations in the DDC gene, resulting in impaired activity of the AADC enzyme.¹ The AADC enzyme synthesizes several neurotransmitters – such as dopamine, serotonin, adrenaline and noradrenaline – the production of which is affected in patients with AADC deficiency.¹

​Impaired AADC enzyme activity is also associated with the accumulation of serotonin and dopamine precursors                            (i.e. 5-hydroxytryptophan [5-HTP], L-3,4-dihydroxyphenylalanine [L-Dopa], and 3-O-methyldopa [3-OMD]) and reduced levels of downstream metabolites (i.e. 5-hydroxyindoleacetic acid [5-HIAA], homovanillic acid [HVA] and 3-methoxy-4-hydroxyphenylglycol [MHPG]).¹

AADC deficiency can present with a broad range of symptoms that vary from patient to patient.^2,5 Symptoms can appear quite early in life, around 2.7 months of age.¹

Key clinical signs and symptoms of AADC deficiency include:^1,5

• Hypotonia
• Movement disorders such dystonia and hypokinesia
• Oculogyric crisis
• Developmental delays
• Autonomic dysfunction including ptosis, excessive sweating and nasal congestion
• Diurnal variation – with symptoms worsening toward the end of the day and improving with sleep

AADC deficiency is a rare neurometabolic condition with an estimated global prevalence of 1:32,000 to 1:90,000 live births.⁶ A founder mutation has been defined in patients of southern Chinese descent, especially from Taiwan, and the prevalence in Taiwan has been estimated to be 1:32,000 live births.^1,7

AADC deficiency may be challenging to diagnose as patients can present with signs and symptoms that overlap with other, more common conditions, including epilepsy, cerebral palsy or neuromuscular disorders.^1,4,8–10

The clinical presentation of AADC deficiency can have some similar signs and symptoms to other neurological conditions          (e.g. cerebral palsy, epilepsy) and certain behavioral disorders²

It is recommended that any patient presenting with clinical signs of AADC deficiency should be tested for neurotransmitter disorder.¹

Preliminary diagnostic tests

Newborn screening provides the opportunity to identify inherited or congenital metabolic or endocrine disorders in newborns.¹¹ There are 2 preliminary diagnostic tests that can be used to identify suspected cases of AADC deficiency:

1. Dried blood spot analysis: Elevated 3-OMD concentrations is highly predictive for AADC deficiency and may prompt earlier referral of patients for diagnostic tests¹²
2. Urinary testing: Analysis of urine vanillactic acid to vanillylmandelic acid ratio is also a reliable approach for screening for AADC deficiency.¹³ If a screening test raises suspicion of an AADC deficiency diagnosis then further confirmation is needed by performing core diagnostic tests.^1,6,7

Core diagnostic tests

To confirm a diagnosis of AADC deficiency, a positive genetic test is needed alongside one other positive diagnostic test.¹ There are 3 core diagnostic tests that could be performed to confirm an AADC deficiency diagnosis: genetic test, plasma enzyme assay or cerebrospinal fluid (CSF) neurometabolite panel.¹

• Gene sequencing: to confirm the presence of a mutation in the DDC gene
• Plasma enzyme assay: a patient with AADC deficiency will have reduced AADC enzyme activity in the plasma
• CSF metabolite panel: a typical CSF panel shows:
  • Increased levels of L-Dopa, 5-HTP and 3-OMD
  • Reduced levels of HVA, 5-HIAA, and MHPG
  • Normal pterins

In patients with neurotransmitter disorders such as AADC deficiency, clinical symptoms can be nonspecific and diagnosis is often delayed.¹⁴ As a result, patients and carers experience possible differential diagnosis before achieving a definitive diagnosis of AADC deficiency.¹⁴

Muscle and joint symptoms can have an impact on many aspects of a patient’s life, including motor function, energy-related symptoms and the ability to communicate.⁶ Caregivers of patients with AADC report that patients also experience issues with feeding, pain, and impaired cognitive function.⁶ These symptoms relate to each other and have a wide impact on a patient’s daily activities, emotions, behavior and ability to socialise.⁶

Patients with AADC deficiency have a substantial burden of living.⁶

Caregiver burden is high^1,2

Given that most AADC patients have motor and developmental delays, there is a need for life-long care, and one survey found that up to 71% of patients are completely dependent on a caregiver.¹⁵ Caregivers report a burden that includes a need to provide 24-hour supervision, administering medication, frequent hospital visits, work disruption and sleep disturbances.¹⁵

Caregivers have reported mental tiredness as a result of providing care alongside other mental health symptoms such as depression or anxiety.¹⁵