Semi-quantitative detection of a vanillactic acid/vanillylmandelic acid ratio in urine is a reliable diagnostic marker for aromatic L-amino acid decarboxylase deficiency.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a primary neurotransmitter defect of the biosynthesis of catecholamines and serotonin. The phenotype consists of varying degrees of neurological impairment, including motor and non-motor symptoms. Treatment outcomes correlate with the time point of diagnosis and treatment initiation; therefore, reliable diagnostic markers are necessary. Increased vanillactic acid (VLA) concentrations in the analysis of organic acids in urine have been reported in AADC deficiency. However, this elevation is often subtle and easily missed. In this study, we evaluate the semi-quantitative determination of VLA and vanillylmandelic acid (VMA) concentrations and establish the ratio of a VLA/VMA as a novel diagnostic marker for AADC deficiency. Urine samples obtained from 10,095 non-AADC deficient controls and 14 confirmed AADC deficient patients were used for organic acid analysis by liquid-liquid extraction of the acidified samples and gas chromatographic-mass spectrometric separation after trimethylsilylation. The semi-quantitative determination of VLA and VMA concentrations and the calculation of a VLA/VMA ratio were evaluated as a diagnostic marker for AADC deficiency. The mean VLA and VMA concentrations in 10,095 non-AADCD samples was 0.3 mmol/mol creatinine (SD = 1.18, range 0–57.79) and 5.59 mmol/mol creatinine (SD = 3.87, range 0.04–60.62), respectively. The mean concentration of VLA in 14 patient-derived samples was 10.24 mmol/mol creatinine, (SD = 11.58, range = 0.37–33.06) and 0.45 mmol/mol creatinine for VMA (SD = 0.29, range 0.11–1.27). The mean VLA/VMA ratio in non-AADC controls was 0.07 (SD = 0.37, range 0.0–23.24), whereas AADC deficient patients revealed a mean VLA/VMA ratio of 23.16 (SD = 22.83, range 0.97–74.1). The VLA/VMA ratio thus allows a reliable identification of patients with AADC deficiency, especially in the young age cohort as it decreases with age. To take this into account, age-adjusted thresholds have been developed. Determination of individual concentrations of VLA and VMA in urine does not allow a reliable diagnosis of AADC deficiency. In this study, we could demonstrate that a semi-quantitative analysis of organic acids in urine allows the formation of metabolite ratios and that the VLA/VMA ratio is a reliable, easily accessible, new parameter for the diagnosis of AADC deficiency. [ABSTRACT FROM AUTHOR]