Polymorphisms of
 ABAT
 ,
 SCN2A
 and
 ALDH5A1
 May Affect Valproic Acid Responses in the Treatment of Epilepsy in Chinese

Li, Xi; Zhang, Jun; Wu, Xiaoxiang; Yan, Han; Zhang, Yin; He, Ruohui; Tang, Yongjun; He, Yijing; Tan, Dan; Mao, Xiao‐Yuan; Yin, Ji‐Ye; Liu, Zhao‐Qian; Zhou, Hong‐Hao; Liu, Jie

doi:10.2217/pgs-2016-0093

Cited by 30 publications

(19 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Succinate can enter the tricarboxylic acid cycle for NADH and FADH 2 production. Inhibitors of ABAT include valproate (Li et al, 2016; Piplani et al, 2016), vigabatrin (Petroff et al, 1995, 1996a,b), and topiramate (Meldrum and Rogawski, 2007; Porter et al, 2012). The inhibition of ABAT activity results in the accumulation of GABA, β-alanine, homocarnosine, and 2-pyrrolidinone (Jaeken et al, 1990; Parviz et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

View full text Add to dashboard Cite

show abstract

“…ABAT rs1731017, SCN2A rs2304016, and ALDH5A1 rs1054899 are associated with VPA response in Chinese patients [279]. Female CYP2C19-PMs are more susceptible to VPA-induced weight gain in the Japanese population [280], and SNPs in the leptin receptor (LEPR) (rs1137101) and ankyrin repeat kinase domain containing 1 (ANKK1) (rs1800497) show associations with VPA-induced weight gain in the Chinese population [281]. Oral clearance (CL/F) of VPA in patients with the LEPR-A668G and G668G (rs1137101) variants is lower than in patients with the LEPR-A668A genotype [282].…”

Section: Epilepsymentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

View full text Add to dashboard Cite

Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

show abstract

“…Different type of studies on populations from Hong Kong, Malaysia and China found no significant association of polymorphisms in the SCN2A gene with AEDs responsiveness in epileptic patients (Haerian et al, 2013, Zhou et al, 2015). In contrast, Kwan et al and Li et al suggested that treatment responsiveness was significantly associated with the genetic polymorphism within SCN2A gene (Kwan et al, 2008, Li et al, 2016). A study on north Indian population indicates a differential role of SCN2A gene in epilepsy susceptibility and drug responsiveness to treatment (Lakhan et al, 2009).…”

Section: Discussionmentioning

confidence: 92%

Effects of GRM4, SCN2A and SCN3B polymorphisms on antiepileptic drugs responsiveness and epilepsy susceptibility

AL-Eitan

Al-Dalalah

Aljamal

2019

Saudi Pharmaceutical Journal

View full text Add to dashboard Cite

BackgroundPharmacotherapy of epilepsy including antiepileptic drugs (AEDs) is one of the main treatment approaches. As a biological target, sodium channels (Nav channels) and glutamate receptor genes are playing a major role in the etiology and treatment of epilepsy.ObjectiveThis study aims to investigate the genetic associations of certain genetic polymorphisms with increased risk of epilepsy susceptibility and variability in response to AEDs treatment in a Jordanian Arab population.MethodA pharmacogenetics and case-control study on 296 unrelated epileptic Jordanian patients recruited from the pediatric neurology clinic at the Queen Rania Al-Abdullah Hospital (QRAH) in Amman, Jordan and 299 healthy individuals was conducted. Children up to 15 years old which receiving AEDs for at least three months were scanned for genetic association of 7 single nucleotide polymorphisms (SNPs) within three candidate genes (SCN2A, SCN3B and GRM4) with epilepsy susceptibility.ResultsSCN2A rs2304016 (P = 0.04) and GRM4 rs2499697 (P = 0.031) were statistically significant with generalized epilepsy. Haplotype of CAACG GRM4 was genetically associated with epilepsy and partial epilepsy (P = 0.036; P = 0.024, respectively). This study also found that TGTAA genetic haplotype formed within GRM4 gene was associated with generalized epilepsy susceptibility (P = 0.006). While, no significant linkage of SCN3B rs3851100 to either disease susceptibility or drug responsiveness was found.ConclusionThis study identified no significant associations of allelic or genotypic SNPs with the susceptibility of epilepsy and medication response with an exception of rs2304016 and rs2499697 SNPs that were associated with the generalized type of epilepsy among Jordanian population. Further studies are required in different populations to confirm our results and identify genetic factors that involved in susceptibility and treatment response.

show abstract

Polymorphisms of ABAT , SCN2A and ALDH5A1 May Affect Valproic Acid Responses in the Treatment of Epilepsy in Chinese

Abstract: This study found three SNPs and one interaction among ABAT, SCN2A and ALDH5A1 were significantly associated with VPA response, which indicated that these genes may play important roles in the pharmacological mechanism of VPA.

Cited by 30 publications

References 30 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

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Effects of GRM4, SCN2A and SCN3B polymorphisms on antiepileptic drugs responsiveness and epilepsy susceptibility

Contact Info

Product

Resources

About