Aromatic L-amino Acid Decarboxylase Deficiency via the DDC Gene

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare disorder of neurotransmitter metabolism that results in a severe deficit of serotonin and catecholamines. The majority of patients with this disorder display initial clinical symptoms during infancy or early childhood, although a few reported cases did not present until adolescence or adulthood (Brun et al. 2010). Affected individuals may exhibit severe developmental delays, oculogyric crises, hypotonia, dystonia, hypokinesia, difficulties with feeding and speech, and autonomic symptoms such as excessive sweating and/or temperature instability (Brun et al. 2010; Wassenberg et al. 2017). Less frequently, ptosis and/or insomnia have been observed. Individuals with a milder disease course have also been described (Leuzzi et al. 2015).

Aromatic L-amino acid decarboxylase (AADC) deficiency is inherited in an autosomal recessive manner due to defects in the DDC gene. DDC encodes for a homodimeric, pyridoxal phosphate-dependent enzyme responsible for the second step in the catecholamine biosynthetic pathway that results in synthesis of the neurotransmitter dopamine. In addition, DDC can also decarboxylate 5-hydroxytryptophan into serotonin (Montioli et al. 2014). As dopamine acts as a precursor for the metabolites epinephrine and norepinephrine, patients lacking DDC activity exhibit a combined deficiency of serotonin, dopamine, epinephrine, and norepinephrine (Wassenberg et al. 2017). At least thirty missense variants, several splicing variants, and several small insertions/deletions have been reported as causative for AADC deficiency (Human Gene Mutation Database).

Due to a founder mutation that results in defective splicing (c.714+4A>T), AADC deficiency may be more prevalent in certain Asian populations, such as the Taiwanese (Lee et al. 2009).

The clinical sensitivity of this test is expected to be high for patients with a biochemical diagnosis of AADC deficiency. In a cohort of 49 patients with biochemically-diagnosed disease, two probable causative variants in the DDC gene were identified in 46/49 patients (93.9%; Brun et al. 2010). In the remaining three patients, one probable causative variant was identified in DDC.

This test provides full coverage of all coding exons of the DDC gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).