Abstract
BackgroundPrevious work has identified age-related negative correlations for γ-hydroxybutyric acid (GHB) and γ-aminobutyric acid (GABA) in plasma of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD). Using plasma and dried blood spots (DBS) collected in an ongoing natural history study, we tested the hypothesis that other biomarkers would follow a similar age-related negative correlation as seen for GHB/GABA. Samples (mixed sex) included: patients (n = 21 unique samples, 1–39.5 yrs) and parallel controls (n = 9 unique samples, 8.4–34.8 yrs). Archival control data (DBS only; n = 171, 0.5–39.9 yrs) was also included.ResultsMetabolites assessed included amino acids (plasma, DBS) and acylcarnitines, creatine, creatinine, and guanidinoacetate (DBS only). Age-related negative correlations for glycine (plasma, DBS) and sarcosine (N-methylglycine, plasma) were detected, accompanied by elevated proline and decreased levels of succinylacetone, argininosuccinate, formaminoglutamate, and creatinine. Significantly low acylcarnitines were detected in patients across all chain lengths (short-, medium- and long-chain). Significant age-dependent positive correlations for selected acylcarnitines (C6-, C12DC(dicarboxylic)-, C16-, C16:1-, C18:1-, C18:2OH-carnitines) were detected in patients and absent in controls. Receiver operating characteristic (ROC) curves for all binary comparisons revealed argininosuccinate and succinylacetone to be the most discriminating biomarkers (area > 0.92).ConclusionsAge-dependent acylcarnitine correlations may represent metabolic compensation responsive to age-related changes in GHB and GABA. Our study highlights novel biomarkers in SSADHD and expands the metabolic pathophysiology of this rare disorder of GABA metabolism.
Highlights
Previous work has identified age-related negative correlations for γ-hydroxybutyric acid (GHB) and γaminobutyric acid (GABA) in plasma of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD)
We examined the hypothesis that other biomarkers of SSADHD would manifest an age-dependent negative correlation as seen for GHB and GABA
The negative correlation for gly in patients was replicated in dried blood spots (DBS) (Fig. 2; sarc not measured in DBS)
Summary
Previous work has identified age-related negative correlations for γ-hydroxybutyric acid (GHB) and γaminobutyric acid (GABA) in plasma of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD). Using plasma and dried blood spots (DBS) collected in an ongoing natural history study, we tested the hypothesis that other biomarkers would follow a similar age-related negative correlation as seen for GHB/GABA. Succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD) is a rare disorder on the GABA metabolic pathway. SSADHD is frequently referred to as γ-hydroxybutyric aciduria. This is due to the fact that accumulated SSA, in the absence of functional SSADH activity, is converted to γ-hydroxybutyrate (GHB), the latter being a compound with diverse and still poorly understood neuromodulatory roles [13]. In addition to increased GABA and GHB, patients manifest a broad variety of additional metabolic abnormalities, which have recently been summarized [2, 11]
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