DDC – Aromatic L-Amino Acid Decarboxylase Deficiency

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in the DDC gene (HGNC:2719). AADC catalyzes the decarboxylation of L-DOPA to dopamine and 5-hydroxytryptophan to serotonin, and its loss leads to combined central and peripheral neurotransmitter deficits. Clinically, affected infants present with severe hypotonia (HP:0001252), oculogyric crises (HP:0010553), dystonia (HP:0001332), and global developmental delay (HP:0001263) (PMID:9309516).

Genetic evidence includes over 140 patients from more than 100 unrelated families worldwide harboring more than 80 distinct DDC variants. The variant spectrum comprises missense (e.g., c.304G>A (p.Gly102Ser)), nonsense, frameshift, splice-site, and intronic changes. Recurrent and founder alleles, such as the IVS6+4A>T splice mutation in East Asian populations, underscore population-specific risks. Case reports have documented homozygosity for c.387G>A in three siblings responsive to levodopa/carbidopa therapy ([PMID:14991824]).

Segregation data demonstrate recessive inheritance with multiple consanguineous pedigrees and affected sibships showing concordant biallelic variants and biochemical profiles. In one family, three siblings homozygous for c.387G>A segregated with severe neurotransmitter deficiency and clinical improvement under l-DOPA treatment (3 probands) [PMID:14991824].

Functional assays of recombinant variant proteins reveal markedly reduced PLP cofactor binding and catalytic efficiency. The p.Ser250Phe variant exhibits a ~7-fold drop in kcat and undergoes proteasomal degradation in cells ([PMID:23321058]). A knock-in mouse model carrying the S250F mutation displays profound serotonin deficiency, motor impairment, and autonomic dysfunction, mirroring the human phenotype ([PMID:28973165]).

Therapeutic approaches include dopamine agonists, monoamine oxidase inhibitors, pyridoxine supplementation, and recently gene therapy using AAV2-hAADC vectors, which have shown safety and improvements in motor and cognitive endpoints. Early diagnosis via CSF monoamine profiling or plasma/DBS 3-OMD screening is critical to optimize treatment timing.

References

• Journal of Child Neurology • 1997 • Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a second family PMID:9309516
• Annals of Neurology • 2004 • Levodopa-responsive aromatic L-amino acid decarboxylase deficiency. PMID:14991824
• Human Molecular Genetics • 2013 • S250F variant associated with aromatic amino acid decarboxylase deficiency: molecular defects and intracellular rescue by pyridoxine. PMID:23321058
• Human Molecular Genetics • 2017 • A pathogenic S250F missense mutation results in a mouse model of mild aromatic l-amino acid decarboxylase (AADC) deficiency. PMID:28973165

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