Aromatic l-amino acid decarboxylase deficiency diagnosed by clinical metabolomic profiling of plasma

Elucidation of the complex metabolic profile of cerebrospinal fluid using an untargeted biochemical profiling assay

“…Correlation of the levels of each of the 188 molecules in CSF to those in plasma revealed a range of values (Figure 5 and Supplemental Table 4). 3-methoxytyrosine, identified as a marker for aromatic amino acid decarboxylase deficiency [22], showed a high correlation between CSF and plasma (r = 0.88), and biochemicals linked to nutritional intervention, including pyridoxate (Vitamin B 6 ; r = 0.97), carnitine (r = 0.61), and trimethylamine N-oxide (r = 0.77), showed positive correlations (Figure 5). The lysine degradation metabolite glutaroylcarnitine showed the strongest negative association between the two matrices (r = −0.42).…”

“…As observed in Figure 6, when the necessary co-substrate tetrahydrobiopterin is insufficient, as is the case in dihydropteridine reductase deficiency, upstream metabolites such as phenylalanine and phenyllactate are elevated, whereas downstream metabolites such as homovanillate are decreased. Several neurotransmitters, as well as some of their metabolites, were detected across all three matrices (Table 1), such as 3-methoxytyrosine a biomarker for aromatic amino acid decarboxylase deficiency [22,32]. Therefore, the ability to monitor the metabolism neurotransmitters in CSF could be important to identify IEMs associated with the synthesis of neurotransmitters such as dopamine, GABA, and others.…”

“…Compound heterozygous variants of unknown significance were revealed in the DDC gene by WES. Follow-up neurotransmitter testing of CSF from a subsequent lumber puncture showed a prominent elevation of the L-DOPA metabolite 3-methoxytyrosine and undetectable levels of homovanillic acid and 5-hydroxyindoleacetic acid that confirmed the homozygous VUS present in the DDC gene caused genuine disease and confirmed the diagnosis of AADC deficiency [22]. Subsequent metabolomic profiling of plasma revealed that 3-methyoxytyrosine levels were markedly elevated (Z-score +6.1) and pointed to the utility of untargeted global metabolomic phenotyping to aid in the identification and accelerated diagnosis of IEMs.…”

“…Genomic-level testing, such as clinical whole exome sequencing (WES), is a well-established means to identify IEM disease variants [15–21], but the application of similar broad-based phenotype screening technologies lag behind genomic and genetic testing approaches. Genomic methods like WES identify variants of unknown significance (VUS) with some frequency, and metabolomic analysis has proven to be a useful source of functional data to determine whether the variant is pathogenic [22]. Newborn screening can identify a small subset of IEMs, but many IEMs are not included in newborn screening panels.…”

“…This approach identified and assisted in the diagnosis of aromatic amino acid decarboxylase deficiency through the metabolomic and genomic analyses of plasma [22]. Prior to untargeted metabolomic analysis, the child was subjected to an extensive series of tests including (but not limited to) very long-chain fatty acid profiling, lysosomal storage disorders panel, urine mucopolysaccharide screening, chromosomal microarray, CSF amino acid analysis, urine organic acid profiling, plasma acylcarnitine determination, and serial MRIs – all of which failed to reveal the underlying diagnosis.…”