Novel biomarkers and age-related metabolite correlations in plasma and dried blood spots from patients with succinic semialdehyde dehydrogenase deficiency

Abstract

Background Previous 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. Results Metabolites 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). Conclusions Age-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.

Acylcarnitines: Nomenclature, Biomarkers, Therapeutic Potential, Drug Targets, and Clinical Trials

“…The ACS family includes multiple short-chain (ACSS), medium-chain (ACSM), and long-chain (ACSL) members. It should be noted that the specific loss of long-chain ACS (acyl-CoA synthetase long-chain family member 1; ACSL1, EC:6.2.1.3) activity in mouse liver tissues results in a decrease in long-chain acylcarnitines and an increase in medium-chain acylcarnitine content due to the upregulation of peroxisomal fatty acid oxidation (Li et al, (Roe et al, 1990;Kimura et al, 2004;Miinalainen et al, 2009) Decreased Familial Mediterranean fever (Kiykim et al, 2016); schizophrenia (Cao et al, 2020 (Wood et al, 2001;Shigematsu et al, 2003;Tajima et al, 2008;Laforet et al, 2009;Hisahara et al, 2015;Lepori et al, 2018); trifunctional protein (mitochondrial longchain ketoacyl-CoA thiolase) deficiency (Das et al, 2006); mitochondrial dysfunction in diabetes patients (Abu Bakar and Sarmidi, 2017); nonalcoholic fatty liver disease (Chen et al, 2016) (Gempel et al, 2001;Minkler et al, 2005;Brucknerova et al, 2008;Illsinger et al, 2008;Tajima et al, 2017); cardiovascular mortality in incident dialysis patients (Kalim et al, 2013); schizophrenia (Cao et al, 2020); succinic semialdehyde dehydrogenase deficiency (Kirby et al, 2020); neonatal macrosomia (Wright and Baker, 2020); liver cirrhosis (Miyaaki et al, 2020); carnitine/ acylcarnitine translocase deficiency (Iacobazzi et al, 2004); ischemia/ reperfusion (Shah et al, 2012;Rizza et al, 2014); increased all-cause mortality and hospitalization in heart failure patients (Ahmad et al, 2016) Octadecadienylcarnitine (C18:2) Blood Increased Parkinson's disease (Chang et al, 2018); chronic heart failure (Ahmad et al, 2016;Hunter et al, 2016); carnitine/acylcarnitine translocase deficiency...…”

Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder

“…Evidence also shows that as individuals with SSADHD age, their overall clinical severity worsens, as well as the severity of their epilepsy and psychiatric behaviors [ 21 ]. Moreover, it was demonstrated that GABA and other indices of cerebral inhibition decrease with age in SSADHD [ 67 , 68 ]. This study’s biomarker-clinical severity relationship analyses showed that lower levels of age-adjusted plasma GABA and GHB significantly correlate with lower scores of the total CSS (reflecting an overall worst severity) and its psychiatric domain.…”

Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency

“…Only later, when they gain enough functionality and still manifest ASD symptoms, are these reported as ASD‐related and they are sent for formal ASD testing. It is also possible that their ASD symptoms fully manifest and exceed the capacity of social demand only as they age, resulting from the increasing excitation:inhibition trajectory driven by declining GABA and GHB levels with age 25 (vide infra).…”