2-Pyrrolidinone and Succinimide As Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-Seizure Medications Impact Accurate Diagnosis
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Washington University School of Medicine Digital Commons@Becker Open Access Publications 2019 2-pyrrolidinone and succinimide as clinical screening biomarkers for GABA-transaminase deficiency: Anti-seizure medications impact accurate diagnosis Adam D. Kennedy Metabolon, Inc. Kirk L. Pappan Metabolon, Inc. Taraka Donti Baylor College of Medicine Mauricio R. Delgado University of Texas Southwestern Medical Center at Dallas Marwan Shinawi Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Kennedy, Adam D.; Pappan, Kirk L.; Donti, Taraka; Delgado, Mauricio R.; Shinawi, Marwan; Pearson, Toni S.; Lalani, Seema R.; Craigen, William E.; Sutton, V. Reid; Evans, Anne M.; Sun, Qin; Emrick, Lisa T.; and Elsea, Sarah H., ,"2-pyrrolidinone and succinimide as clinical screening biomarkers for GABA-transaminase deficiency: Anti-seizure medications impact accurate diagnosis." Frontiers in Neuroscience.13,. 394. (2019). https://digitalcommons.wustl.edu/open_access_pubs/7791 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Adam D. Kennedy, Kirk L. Pappan, Taraka Donti, Mauricio R. Delgado, Marwan Shinawi, Toni S. Pearson, Seema R. Lalani, William E. Craigen, V. Reid Sutton, Anne M. Evans, Qin Sun, Lisa T. Emrick, and Sarah H. Elsea This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/ open_access_pubs/7791 fnins-13-00394 May 6, 2019 Time: 15:13 # 1 ORIGINAL RESEARCH published: 08 May 2019 doi: 10.3389/fnins.2019.00394 2-Pyrrolidinone and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-seizure Medications Impact Accurate Diagnosis Adam D. Kennedy1†, Kirk L. Pappan1, Taraka Donti2†, Mauricio R. Delgado3, Marwan Shinawi4, Toni S. Pearson5, Seema R. Lalani2, William E. Craigen2, V. Reid Sutton2, Anne M. Evans1, Qin Sun2, Lisa T. Emrick2,6 and Sarah H. Elsea2* Edited by: 1 Metabolon, Inc., Morrisville, NC, United States, 2 Department of Molecular and Human Genetics, Baylor College Cristian Bonvicini, of Medicine, Houston, TX, United States, 3 Department of Neurology and Neurotherapeutics, Texas Scottish Rite Hospital IRCCS Centro San Giovanni di Dio for Children, The University of Texas Southwestern Medical Center, Dallas, TX, United States, 4 Department of Pediatrics, Fatebenefratelli, Italy Washington University School of Medicine St. Louis, St. Louis, MO, United States, 5 Department of Neurology, Washington Reviewed by: University School of Medicine St. Louis, St. Louis, MO, United States, 6 Department of Neurology, Baylor College Gerarda Cappuccio, of Medicine, Houston, TX, United States University of Naples Federico II, Italy Claudia Saraceno, IRCCS Centro San Giovanni di Dio Broad-scale untargeted biochemical phenotyping is a technology that supplements Fatebenefratelli, Italy widely accepted assays, such as organic acid, amino acid, and acylcarnitine analyses *Correspondence: typically utilized for the diagnosis of inborn errors of metabolism. In this study, we Sarah H. Elsea investigate the analyte changes associated with 4-aminobutyrate aminotransferase [email protected]; [email protected] (ABAT, GABA transaminase) deficiency and treatments that affect GABA metabolism. †Present address: GABA-transaminase deficiency is a rare neurodevelopmental and neurometabolic Adam D. Kennedy, disorder caused by mutations in ABAT and resulting in accumulation of GABA in the Baebies, Inc., Morrisville, NC, United States cerebrospinal fluid (CSF). For that reason, measurement of GABA in CSF is currently Taraka Donti, the primary approach to diagnosis. GABA-transaminase deficiency results in severe PerkinElmer Genetics, Pittsburgh, developmental delay with intellectual disability, seizures, and movement disorder, and is PA, United States often associated with death in childhood. Using an untargeted metabolomics platform, Specialty section: we analyzed EDTA plasma, urine, and CSF specimens from four individuals with GABA- This article was submitted to transaminase deficiency to identify biomarkers by comparing the biochemical profile Neurogenomics, a section of the journal of individual patient samples to a pediatric-centric population cohort. Metabolomic Frontiers in Neuroscience analyses of over 1,000 clinical plasma samples revealed a rich source of biochemical Received: 21 February 2019 information. Three out of four patients showed significantly elevated levels of the Accepted: 05 April 2019 Published: 08 May 2019 molecule 2-pyrrolidinone (Z-score ≥2) in plasma, and whole exome sequencing revealed Citation: variants of uncertain significance in ABAT. Additionally, these same patients also had Kennedy AD, Pappan KL, Donti T, elevated levels of succinimide in plasma, urine, and CSF and/or homocarnosine in urine Delgado MR, Shinawi M, Pearson TS, and CSF. In the analysis of clinical EDTA plasma samples, the levels of succinimide Lalani SR, Craigen WE, Sutton VR, Evans AM, Sun Q, Emrick LT and and 2-pyrrolidinone showed a high level of correlation (R = 0.73), indicating impairment Elsea SH (2019) 2-Pyrrolidinone in GABA metabolism and further supporting the association with GABA-transaminase and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase deficiency and the pathogenicity of the ABAT variants. Further analysis of metabolomic Deficiency: Anti-seizure Medications data across our patient population revealed the association of elevated levels of 2- Impact Accurate Diagnosis. pyrrolidinone with administration of vigabatrin, a commonly used anti-seizure medication Front. Neurosci. 13:394. doi: 10.3389/fnins.2019.00394 and a known inhibitor of GABA-transaminase. These data indicate that anti-seizure Frontiers in Neuroscience| www.frontiersin.org 1 May 2019| Volume 13| Article 394 fnins-13-00394 May 6, 2019 Time: 15:13 # 2 Kennedy et al. 2-Pyrrolidinone and Succinimide as Biochemical Phenotyping Markers 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. Keywords: 2-pyrrolidinone, vigabatrin, GABA, neurometabolic, inborn error of metabolism, neurotransmitter, 4- aminobutyrate aminotransferase deficiency, GABA-transaminase deficiency INTRODUCTION (Pearl et al., 2009; Dracopoulos et al., 2010; Schonstedt et al., 2015; Hussain et al., 2017). Traditional diagnostic avenues for Gamma-aminobutyric acid (GABA) transaminase deficiency GABA-transaminase deficiency include enzymatic testing of (OMIM #613163), also known as 4-ABAT deficiency is a rare ABAT, neurotransmitter profiling of CSF – including GABA, and genetic disorder that disrupts the degradation of GABA to molecular testing of ABAT for pathogenic variants. Biomarkers succinic semialdehyde (Figure 1). This IEM is due to decreased of GABA-transaminase deficiency include elevated GABA in or deficient activity of the enzyme 4-ABAT (ABAT, EC 2.6.1.19, CSF; however, CSF GABA may not be included in some OMIM #137150). GABA-transaminase deficiency is an ultra- clinically available neurotransmitters analyses, limiting the rare disease reported and characterized in only a few patients diagnostic utility. (Medina-Kauwe et al., 1998, 1999; Tsuji et al., 2010; Besse As a neurometabolic disorder, GABA-transaminase deficiency et al., 2016; Louro et al., 2016; Koenig et al., 2017; Nagappa typically presents initially with hypotonia and may present with et al., 2017). The few reports suggest it is much rarer than difficult to control seizures, including infantile spasms. Seizures other disorders of GABA metabolism, including glutamate can sometimes be moderated through dietary and/or medical decarboxylase deficiency (OMIM 603513), SSADH deficiency intervention such as ketogenic diets which can influence seizure (OMIM 271980), and homocarnosinosis (serum carnosinase activity and GABA levels (Dahlin et al., 2005; Bough, 2008; Nylen deficiency) (OMIM 236130) (Jakobs et al., 1993). et al., 2008; Yudkoff et al., 2008; Suzuki et al., 2009; Woolf et al., GABA has a relatively short half-life in plasma, is rapidly 2015; Li et al., 2017). Topiramate and vigabatrin are anti-seizure absorbed, and has both endocrine and hormonal effects (Abel and medications utilized to treat seizure disorders including infantile McCandless, 1992; Li et al., 2015; Maguire et al., 2015). GABA spasms. Vigabatrin is an irreversible inhibitor of ABAT that serves as the primary inhibitory neurotransmitter in the human causes increased levels of GABA in the brain (Gram et al., nervous system, and GABA metabolism to succinic semialdehyde 1989; Sheean et al., 1992; Petroff et al., 1999a; Kang et al., 2003; helps to regulate its levels and neurotransmitter activity. The Rogawski and Loscher, 2004). In a rat model, inhibition of ABAT accumulation of GABA, either through enzymatic inactivity of with vigabatrin resulted in decreased ABAT activity in brain, liver, ABAT or medical intervention, can result in elevated levels of and kidney and significantly increased levels of GABA in liver,