Metabolomics Profile in ABAT Deficiency Pre- and Post-treatment

Koenig, Mary Kay; Bonnen, Penelope E.

doi:10.1007/8904_2018_94

Cited by 3 publications

(5 citation statements)

References 21 publications

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“…While treatments which elevate 2-pyrrolidinone levels through GABA-transaminase inhibition can interfere with the use of 2-pyrrolidinone as a biomarker for screening GABA-transaminase deficiency, the treatment of patients with these drugs can be discerned from the patient medical history, and many of these medications can also be detected in clinical metabolomic analysis of plasma. As mentioned in a preliminary case study citing clinical data and interpretations from our clinical diagnostic platform (Koenig and Bonnen, 2018), monitoring 2-pyrrolidinone and levels by metabolomic profiling in patients with GABA-transaminase deficiency may inform the efficacy of therapeutic intervention. Here, we show that the integrated use of metabolomic and genomic testing provides an informed approach to diagnose GABA-transaminase deficiency and distinguish it from other sources of GABA/2-pyrrolidinone elevations, that may be otherwise confounding in targeted GABA analyses.…”

Section: Discussionmentioning

confidence: 99%

2-Pyrrolidinone and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-seizure Medications Impact Accurate Diagnosis

et al. 2019

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Broad-scale untargeted biochemical phenotyping is a technology that supplements widely accepted assays, such as organic acid, amino acid, and acylcarnitine analyses typically utilized for the diagnosis of inborn errors of metabolism. In this study, we investigate the analyte changes associated with 4-aminobutyrate aminotransferase (ABAT, GABA transaminase) deficiency and treatments that affect GABA metabolism. GABA-transaminase deficiency is a rare neurodevelopmental and neurometabolic disorder caused by mutations in ABAT and resulting in accumulation of GABA in the cerebrospinal fluid (CSF). For that reason, measurement of GABA in CSF is currently the primary approach to diagnosis. GABA-transaminase deficiency results in severe developmental delay with intellectual disability, seizures, and movement disorder, and is often associated with death in childhood. Using an untargeted metabolomics platform, we analyzed EDTA plasma, urine, and CSF specimens from four individuals with GABA-transaminase deficiency to identify biomarkers by comparing the biochemical profile of individual patient samples to a pediatric-centric population cohort. Metabolomic analyses of over 1,000 clinical plasma samples revealed a rich source of biochemical information. Three out of four patients showed significantly elevated levels of the molecule 2-pyrrolidinone ( Z -score ≥ 2) in plasma, and whole exome sequencing revealed variants of uncertain significance in ABAT . Additionally, these same patients also had elevated levels of succinimide or its ring-opened form, succinamic acid, in plasma, urine, and CSF and/or homocarnosine in urine and CSF. In the analysis of clinical EDTA plasma samples, the levels of succinamic acid and 2-pyrrolidinone showed a high level of correlation ( R = 0.72), indicating impairment in GABA metabolism and further supporting the association with GABA-transaminase deficiency and the pathogenicity of the ABAT variants. Further analysis of metabolomic data across our patient population revealed the association of elevated levels of 2-pyrrolidinone with administration of vigabatrin, a commonly used anti-seizure medication and a known inhibitor of GABA-transaminase. These data indicate that anti-seizure medications may alter the biochemical and metabolomic data, potentially impacting the interpretation and diagnosis for the patient. Further, these data demonstrate the power of combining broad scale genotyping and phenotyping technologies to diagnose inherited neurometabolic disorders and support the use of metabolic phenotyping of plasma to screen for GABA-transaminase deficiency.

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Section: Discussionmentioning

confidence: 99%

2-Pyrrolidinone and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-seizure Medications Impact Accurate Diagnosis

et al. 2019

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“…This results in accumulation of GHB, in addition to GABA and succinic semialdehyde (SSA). Under physiological conditions, GABA can undergo lactonization to form the internal γ-lactam, 2-pyrrolidone (2-pyr [ 12 ];). Structural similarities of 2-pyr with the imidazole/pyrrolidine structures of crn, pro and his may associate with alterations in EA, sarc, gly, guac, crn, figlu and pro.…”

Section: Discussionmentioning

confidence: 99%

“…Our studies confirm that, in addition to disruptions of the GGG cycle, the GABA shunt, and oxidative phosphorylation, SSADHD appears to significantly alter β-oxidation, urea and creatine cycles, the sarcosine pathway, as well as multiple amino acid pathways [ 2 , 5 , 14 ]. GABA can cyclize to 2-pyrrolidone, its internal γ-lactam, a recently described biomarker for GABA-transaminase deficiency [ 12 ]. We postulate that 2-pyrrolidone (2-pyr) may provide the link between some of the novel biomarkers identified in the current study, including crn, pro, and figlu (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Kirby

Walters

Shi

et al. 2020

Orphanet J Rare Dis

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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.

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“…The diagnosis of GABA-T deficiency has potential therapeutic implications because GABAergic medications are potentially harmful and treatment with flumazenil has been shown to improve neurologic function. 1,7 In addition to GABA levels and 1 H MRS, 5 2-pyrrolidinone is a surrogate biomarker for GABA-T deficiency and can be detected in plasma and CSF. 7 Our patients show that GABA-T deficiency can cause paroxysmal dyskinesia with epilepsy and should be added to the differential diagnosis of this syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…1,7 In addition to GABA levels and 1 H MRS, 5 2-pyrrolidinone is a surrogate biomarker for GABA-T deficiency and can be detected in plasma and CSF. 7 Our patients show that GABA-T deficiency can cause paroxysmal dyskinesia with epilepsy and should be added to the differential diagnosis of this syndrome.…”

Section: Discussionmentioning

confidence: 99%

Paroxysmal dyskinesias with drowsiness and thalamic lesions in GABA transaminase deficiency

et al. 2019

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The proband (patient 1), a 25-year-old woman, was the product of normal pregnancy and delivery. Her parents were first cousins from Lebanon. She sat at 6 months and crawled at 12 months. At age 3, she was noted to have developmental delay, hypotonia, and ataxia. The following year, she had a febrile illness and suspected absence seizure. EEG showed 4-5 Hz spike and slow wave complexes and she was treated with sodium valproate. At age 6, seizure frequency increased but improved with the addition of ethosuximide. Brain MRI at age 10 revealed increased T2 signal in both thalami and upper brainstem (figure). Serum and urinary amino acids, white blood cell lysosomal enzymes, serum lactate and pyruvate, liver function, and ammonia were normal. CSF neurotransmitters, glucose, and lactate were normal, although GABA was not measured. Her condition then remained static with occasional absence seizures. At age 22, she developed paroxysmal episodes of chorea in the neck, arms, and trunk associated with drowsiness, triggered by fever or hot weather (video 1). These occurred 4-5 times a year, lasting from 1 to 10 minutes. In all episodes, she remained responsive to verbal stimuli. Prolonged interictal video EEGs showed intermittent 4-6 Hz generalized epileptiform discharges, although no motor events were recorded.

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Metabolomics Profile in ABAT Deficiency Pre- and Post-treatment

Cited by 3 publications

References 21 publications

2-Pyrrolidinone and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-seizure Medications Impact Accurate Diagnosis

2-Pyrrolidinone and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-seizure Medications Impact Accurate Diagnosis

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

Paroxysmal dyskinesias with drowsiness and thalamic lesions in GABA transaminase deficiency

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