研究背景
癲癇是由大腦神經細胞功能異常所引起的神經系統疾病，該疾病會影響個人的健康狀況和生活質量，尤其是在耐藥性的難治型患者中更為明顯。考慮到藥物治療反應和新陳代謝會因個體差異和種族而異，因此我們需要探索針對個體化藥物的潛在標靶。本研究的首要目的是探討台灣人群基因多型性與癲癇之間的關係。其次是評估接受多種維生素補充劑對於難治型癲癇患者的臨床療效。最後，第三個目標是探討耐藥性癲癇（DRE）患者中維生素相關的基因多型性與治療效果之間的關係。

研究方法
全基因組關聯研究(GWAS)和後續分析
本次的全基因組關聯研究選用台灣人體生物資料庫的癲癇個案和其對應的非癲癇患者。我們在Golden Helix上進行樣本和基因位點(SNP)的品質控制(QC)，並使用邏輯回歸進行關聯性分析。基因型的插補使用Beagle 4.1軟體進行，並且基於千人基因組計劃(1000 Genome project)。我們後續利用基因型-組織表達研究聯盟（GTEx）第八版數據庫進行差異表達分析，並在STRING上進行基因間的關聯網分析，接著通過人類表型本體（HPO）註釋基因群相對應的表型。路徑分析基於KEGG GENOME和REACTOME數據庫。功能豐富度註釋是基於基因本體論（GO）。藥物基因相互作用數據庫（DGIdb）則主要用於搜索基因與藥物之間的相互作用。
臨床耐藥性難治型癲癇受試者
這項研究已經由國立成功大學醫院的機構審查委員會批准，所有受試者將簽署知情同意書。受試者為被診斷為難治型癲癇（年齡20歲以上）並接受多種維生素補充（B6，B9，D，E，Q10）。
臨床評估
疾病嚴重程度以癲癇發作次數和治療反應來評估。受試者會被採集空腹血樣以檢測代謝指標、色氨酸代謝產物和多種維生素的血清濃度。使用Axiom TWB 2.0 array檢測受試者的全基因組基因型，以進行後續臨床驗證以及探討維生素相關的基因多型性。

結果與討論
由台灣人體生物資料庫中，最後共有332名癲癇患者和986名對照受試者通過了品質管控標準。在進行關聯分析後，我們發現了幾個與疾病有關的基因座，例如CMTM7、DNAH11、CARS2、ADCY7等。在這些基因座的組織差異表達分析中，我們發現SH3GL2、GRIK2和SNX10在腦部相關區域中高表達，並且顯示在大腦皮層，杏仁核，海馬迴，基底神經節等中有顯著差異表達（P < 10-3）。在機轉路徑及GO豐富度的分析中以下幾個項目較為顯著，包含「神經遞質受體和突觸後信號傳遞」、「PKA激活」及「白介素信號傳導」等。後續我們在耐藥性難治型癲癇門診患者（n = 32）中驗證了上述基因座的連鎖不平衡區域中的位點，並發現了幾個潛在與癲癇相關的位點。另外，在臨床維生素補充的試驗中，我們觀察到這些患者在維生素補充前癲癇發作控制不良（癲癇發作每月次數= 6.6±15.7次），並且已平均接受了3種以上的抗癲癇藥物。在接受多重維生素補充後，患者們的平均癲癇發作頻率降低到每月1.9±3.6次，並在治療6個月後，約有75％的患者被定義為對治療有反應。經過這段時間的維生素補充，維生素B9和D的平均血中含量顯著增加，而B6、E和Q10含量則下降。最後，在與維生素攝取和代謝有關的基因變異中發現，在介入前維生素血中濃度及介入後有顯著影響，而介入後的發作頻率也有觀察到不同基因型間的差異。例如，在葉酸相關的基因SLC19A1中，rs1051266、rs12659、rs2838956、rs914232擁有相似的基因型分布，在補充維生素前可以觀察到野生型比起變異型擁有較高的葉酸濃度，補充後也觀察到其維生素濃度的變化及發作次數的變化在不同基因型間有顯著差異。在維生素D相關的基因中，rs4646537 (CYP27B1), rs2296241 (CYP24A1)等與維生素D濃度有關，也與介入後的發作次數相關。另外，過去文獻中提到與Q10濃度相關的基因中，我們發現在rs41313321 (SWI5)及rs7412 (APOE)中，不同的基因型濃度變化的趨勢相反。

結論
根據上述結果，癲癇患者罹患精神和心血管疾病的風險更高。並且我們通過GWAS結果，發現了與癲癇相關的基因座，並由基因集中豐富的表型、機轉路徑和功能為臨床發現和開發新型的潛在癲癇生物標誌物提供了可能的研究方向。此外，在維生素補充和基因變異之間對癲癇發作頻率和維生素濃度變化的相互作用揭示了個體化醫療的重要性。

INTRODUCTION
Epilepsy, a neurological disorder caused by malfunctioning nerve cell activity in the brain, affects individuals’ health status and life quality, especially in anti-epilepsy drugs (AEDs) resistant patients. Considered that pharmacotherapy response and metabolism varied in individual differences and ethnicity, the exploration of potential targeting markers for personalized medicine were needed. The first objective of the current study was to investigate the association between genetic polymorphisms and epilepsy in Taiwanese population. The secondary objective was to evaluate the clinical effectiveness in AED-resistance patients receiving multivitamins supplementation. Finally, the third objective was to explore the associations between vitamin related polymorphisms and the treatment outcomes in drug-resistant epilepsy (DRE) patients.

MATERIALS AND METHODS
Genome-wide association study (GWAS) and post-GWAS
GWAS was performed on epilepsy and non-epilepsy individuals from Taiwan Biobank. Quality control (QC) and logistic association analysis were performed on Golden Helix. Genotype imputation was based on the 1000 genome project using Beagle 4.1. The gene-set differential expression was operated utilizing Genotype-Tissue Expression project (GTEx) v8 database. The network analysis was performed on STRING and the phenotypes were annotated by the Human Phenotype Ontology (HPO). Pathway analyses were based on KEGG GENOME and REACTOME database. The functional enrichment annotation and network analysis were based on Gene Ontology (GO). The Drug Gene Interaction database (DGIdb) were mainly used for searching interaction between genes and drugs.
AED-resistance Subjects
This study was approved by the institutional review boards at the National Cheng Kung University Hospital. All subjects will sign the informed consent. Patients (aged  20 years) who are diagnosed refractory epilepsy were enrolled and received multi-vitamins (B6, B9, D, E, Q10).
Measurements
Disease severity were assessed by seizure frequency and treatment response rate. Fasting blood samples were collected to detect metabolic indices (include lipid profiles and sugar profiles), tryptophan metabolites and multi-vitamins concentration. After genotyping the whole genome profiles using Axiom TWB 2.0 array, we further performed clinical validation on GWAS results and determined the vitamin-related genetic polymorphisms.
RESULTS AND DISCUSSION
332 epilepsy and 986 control subjects passed the quality criteria. After the association test, we found several genetic loci, such as CMTM7, DNAH11, CARS2, ADCY7, etc. In the tissue expression analysis for those top loci, we found SH3GL2, GRIK2, and SNX10 highly expressed in brain-related regions, and shown significant differential expressed (P < 10-3) in brain cortex, amygdala, hippocampus, basal ganglia, etc. Further pathway and GO term enrichment analysis highlighted in “Neurotransmitter receptors and postsynaptic signal transmission”, “PKA activation”, “Interleukin signaling”, etc. Then, we validated regions in the top loci’s linkage disequilibrium blocks with drug-resistant epilepsy outpatients (n = 32) and found several targeted SNPs. At first, these drug-resistant patients were averagely received more than 3 kinds of AEDs and observed to have bad seizure control (seizure number = 6.6±15.7 per month). However, after receiving multi-vitamins supplementation, their average seizure frequency reduced to 1.9±3.6 per month, and about 75% of patients were defined as responder after 6-month treatment. What’s more, vitamin levels had significant increase in B9 and D, and decreased in B6, E and Q10. Finally, the investigation on genetic variants related to vitamin uptake and metabolism found significant results on both baseline vitamin level and after intervention. For example, among the folate-related genes SLC19A1, rs1051266, rs12659, rs2838956, and rs914232 have similar genotype distributions. The wild type group in these four SNPs had a higher folate concentration than the mutant type before vitamin supplementation, and we also observed the difference between changes in vitamin concentration and seizure frequency after receiving vitamins. Among the genes related to vitamin D, rs4646537 (CYP27B1), rs2296241 (CYP24A1), etc. were related to the concentration of vitamin D, as well as the seizure frequency after intervention. Additionally, in genes related to Q10 which were mentioned in the past literature, we found that the trend of Q10 concentration during the six months were different by genotypes in rs41313321 (SWI5) and rs7412 (APOE).

CONCLUSION
Our findings indicated the higher risk of mental and cardiovascular disease in epilepsy. Through the GWAS results, loci associated with epilepsy was found, and the corresponding phenotypes, pathways and functions enriched in the gene set gave possible insights to explain clinical findings, and to develop novel potential biomarker in epilepsy. Additionally, the interaction effects found between vitamin supplements and genetic variants on changes of seizure frequency and vitamin levels revealed the importance of personalized medicine.

Abuelezz, S. A., Hendawy, N., et al. (2017). Targeting oxidative stress, cytokines and serotonin interactions via indoleamine 2, 3 dioxygenase by coenzyme Q10: role in suppressing depressive like behavior in rats. Journal of Neuroimmune Pharmacology, 12(2), 277-291.
Acosta, M. J., Fonseca, L. V., et al. (2016). Coenzyme Q biosynthesis in health and disease. Biochimica et Biophysica Acta (BBA)-Bioenergetics, 1857(8), 1079-1085.
Adjei, A. A., Salavaggione, O. E., et al. (2010). Correlation between polymorphisms of the reduced folate carrier gene (SLC19A1) and survival after pemetrexed-based therapy in non-small cell lung cancer: a North Central Cancer Treatment Group-based exploratory study. Journal of Thoracic Oncology, 5(9), 1346-1353.
Agus, A., Planchais, J., et al. (2018). Gut microbiota regulation of tryptophan metabolism in health and disease. Cell host & microbe, 23(6), 716-724.
Alcázar-Fabra, M., Trevisson, E., et al. (2018). Clinical syndromes associated with Coenzyme Q10 deficiency. Essays in Biochemistry, 62(3), 377-398.
Alcocer-Gómez, E., Sánchez-Alcázar, J. A., et al. (2014). Coenzyme q10 regulates serotonin levels and depressive symptoms in fibromyalgia patients: results of a small clinical trial. Journal of clinical psychopharmacology, 34(2), 277-278.
Alliance of Genome Resources Portal: unified model organism research platform. (2020). Nucleic acids research, 48(D1), D650-D658.
Arciero, E., Biagini, S. A., et al. (2015). Genes regulated by Vitamin D in bone cells are positively selected in East Asians. PloS one, 10(12), e0146072.
Athanasiu, L., Giddaluru, S., et al. (2017). A genetic association study of CSMD1 and CSMD2 with cognitive function. Brain, behavior, and immunity, 61, 209-216.
Azade, M., Sazegar, H., et al. (2017). The Effects of Vitamin D on Kynurenine Level in Children With Attention Deficit Hyperactivity Disorder: An Epidemiological Study. International Journal of Epidemiologic Research, 4(4), 255-259.
Baird, M. F., Graham, S. M., et al. (2012). Creatine-kinase-and exercise-related muscle damage implications for muscle performance and recovery. Journal of nutrition and metabolism, 2012.
Bakir-Gungor, B., Baykan, B., et al. (2013). Identifying SNP targeted pathways in partial epilepsies with genome-wide association study data. Epilepsy Research, 105(1-2), 92-102.
Bank, G., Kagan, D., et al. (2011). Coenzyme Q10: clinical update and bioavailability. Journal of evidence-based complementary & alternative medicine, 16(2), 129-137.
Barros, D., Xavier, S., et al. (2007). Effects of the vitamin E in catalase activities in hippocampus after status epilepticus induced by pilocarpine in Wistar rats. Neuroscience letters, 416(3), 227-230.
Beal, M. F. (2004). Therapeutic effects of coenzyme Q10 in neurodegenerative diseases. In Methods in enzymology (Vol. 382, pp. 473-487): Elsevier.
Beckett, E. L., Duesing, K., et al. (2016). Relationship between methylation status of vitamin D-related genes, vitamin D levels, and methyl-donor biochemistry. Journal of Nutrition & Intermediary Metabolism, 6, 8-15.
Beghi, E., & Giussani, G. (2018). Aging and the Epidemiology of Epilepsy. Neuroepidemiology, 51(3-4), 216-223.
Beghi, E., Giussani, G., et al. (2019). Global, regional, and national burden of epilepsy, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology, 18(4), 357-375.
Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal statistical society: series B (Methodological), 57(1), 289-300.
Berg, A. T. (2006). Defining intractable epilepsy. Advances in neurology, 97, 5-10.
Bergman, R. N., Stefanovski, D., et al. (2011). A better index of body adiposity. Obesity, 19(5), 1083-1089.
Bloch-Damti, A., & Bashan, N. (2005). Proposed mechanisms for the induction of insulin resistance by oxidative stress. Antioxidants & redox signaling, 7(11-12), 1553-1567.
Botez, M., Botez, T., et al. (1993). Thiamine and folate treatment of chronic epileptic patients: a controlled study with the Wechsler IQ scale. Epilepsy Research, 16(2), 157-163.
Bothamley, G. (2001). Drug treatment for tuberculosis during pregnancy. Drug safety, 24(7), 553-565.
Bouchard, C., & Ordovas, J. M. (2012). Recent advances in nutrigenetics and nutrigenomics: Academic Press.
Brodie, M. J., Mintzer, S., et al. (2013). Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia, 54(1), 11-27.
Browning, B. L., & Browning, S. R. (2016). Genotype imputation with millions of reference samples. The American Journal of Human Genetics, 98(1), 116-126.
Browning, S. R., & Browning, B. L. (2007). Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. The American Journal of Human Genetics, 81(5), 1084-1097.
Bueno, O., Molloy, A. M., et al. (2016). Common polymorphisms that affect folate transport or metabolism modify the effect of the MTHFR 677C> T polymorphism on folate status. The Journal of Nutrition, 146(1), 1-8.
Burtis, C. A., Ashwood, E. R., et al. (2012). Tietz textbook of clinical chemistry and molecular diagnostics-e-book: Elsevier Health Sciences.
Camfield, P. R., & Camfield, C. S. (1996). Antiepileptic drug therapy: when is epilepsy truly intractable? Epilepsia, 37, S60-S65.
Cardenas-Rodriguez, N., Huerta-Gertrudis, B., et al. (2013). Role of oxidative stress in refractory epilepsy: evidence in patients and experimental models. International journal of molecular sciences, 14(1), 1455-1476.
Cervenka, I., Agudelo, L. Z., et al. (2017). Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science, 357(6349).
Chang, H. H., Sung, P.-S., et al. (2020). An Open Pilot Study of the Effect and Tolerability of Add-On Multivitamin Therapy in Patients with Intractable Focal Epilepsy. Nutrients, 12(8), 2359.
Chen, Z., Brodie, M. J., et al. (2018). Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA neurology, 75(3), 279-286.
Chiang, K.-L., Kuo, F.-C., et al. (2018). Association of epilepsy and asthma: a population-based retrospective cohort study. PeerJ, 6, e4792.
Christensen, M. H., Fadnes, D. J., et al. (2018). Inflammatory markers, the tryptophan-kynurenine pathway, and vitamin B status after bariatric surgery. PloS one, 13(2), e0192169.
Christiansen, C., Rødbro, P., et al. (1974). “Anticonvulsant action” of vitamin D in epileptic patients? A controlled pilot study. Br Med J, 2(5913), 258-259.
Chuang, S.-C., Fanidi, A., et al. (2014). Circulating biomarkers of tryptophan and the kynurenine pathway and lung cancer risk. Cancer Epidemiology and Prevention Biomarkers, 23(3), 461-468.
Consortium, E., Consortium, E., et al. (2012). Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16. 1, 2q22. 3 and 17q21. 32. Human molecular genetics, 21(24), 5359-5372.
Consortium, G. O. (2004). The Gene Ontology (GO) database and informatics resource. Nucleic acids research, 32(suppl_1), D258-D261.
Consortium, G. P. (2015). A global reference for human genetic variation. Nature, 526(7571), 68.
Consortium, T. I. L. A. E. (2014). Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. The Lancet. Neurology, 13(9), 893.
Consortium, T. I. L. A. E. (2018). Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nature communications, 9.
Corrigan, A., Walker, J., et al. (2014). Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations. The pharmacogenomics journal, 14(5), 411-417.
Cotto, K. C., Wagner, A. H., et al. (2017). DGIdb 3.0: a redesign and expansion of the drug–gene interaction database. Nucleic acids research, 46(D1), D1068-D1073.
Coughlin, C. R., Scharer, G. H., et al. (2015). Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. Journal of medical genetics, 52(8), 532-540.
Crawhall, J., Tolis, G., et al. (1976). Elevation of serum creatine kinase in severe hypokalemic hyperaldosteronism. Clinical Biochemistry, 9, 237-240.
Croft, D., Mundo, A. F., et al. (2013). The Reactome pathway knowledgebase. Nucleic acids research, 42(D1), D472-D477.
D'Andrea-Meira, I., Krüger, L. T., et al. (2019). Ketogenic diet and epilepsy: what we know so far. Frontiers in neuroscience, 13, 5.
Dalic, L., & Cook, M. J. (2016). Managing drug-resistant epilepsy: challenges and solutions. Neuropsychiatric disease and treatment, 12, 2605.
Davis, I., & Liu, A. (2015). What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics? In: Taylor & Francis.
Davis, J. (2017). My Health Legacy.
Dawson-Hughes, B., Heaney, R. P., et al. (2005). Estimates of optimal vitamin D status. In: Springer.
de Albuquerque Oliveira, A., Linhares, M. I., et al. (2016). Antioxidant properties of antiepileptic drugs levetiracetam and clonazepam in mice brain after in vitro-induced oxidative stress. African Journal of Pharmacy and Pharmacology, 10(14), 278-288.
de Benoist, B. (2008). Conclusions of a WHO Technical Consultation on folate and vitamin B12 deficiencies. Food and nutrition bulletin, 29(2_suppl1), S238-S244.
de Leeuw, C. A., Mooij, J. M., et al. (2015). MAGMA: generalized gene-set analysis of GWAS data. PLoS computational biology, 11(4), e1004219.
Degenhardt, F., Niklowitz, P., et al. (2016). Genome-wide association study of serum coenzyme Q10 levels identifies susceptibility loci linked to neuronal diseases. Human molecular genetics, 25(13), 2881-2891.
Del Pozo-Cruz, J., Rodríguez-Bies, E., et al. (2014). Physical activity affects plasma coenzyme Q 10 levels differently in young and old humans. Biogerontology, 15(2), 199-211.
Dennis, G., Sherman, B. T., et al. (2003). DAVID: database for annotation, visualization, and integrated discovery. Genome biology, 4(9), R60.
Deopa, B., Parakh, M., et al. (2018). Effect of folic acid supplementation on seizure control in epileptic children receiving long term antiepileptic therapy. The Indian Journal of Pediatrics, 85(7), 493-497.
Desrumaux, C. M., Mansuy, M., et al. (2018). Brain vitamin E deficiency during development is associated with increased glutamate levels and anxiety in adult mice. Frontiers in Behavioral Neuroscience, 12, 310.
Devinsky, O., Marsh, E., et al. (2016). Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. The Lancet Neurology, 15(3), 270-278.
Dhamija, R., Eckert, S., et al. (2013). Ketogenic diet. Canadian journal of neurological sciences, 40(2), 158-167.
DiPalma, J. R., & Ritchie, D. M. (1977). Vitamin toxicity. Annual review of pharmacology and toxicology, 17(1), 133-148.
Doimo, M., Desbats, M. A., et al. (2014). Genetics of coenzyme q10 deficiency. Molecular syndromology, 5(3-4), 156-162.
Dolina, S. A. (2016). Epilepsy as a Pyridoxine-Dependent Condition: Quantitative Urinary Biomarkers of Epilepsy. Family Disorders of Pyridoxine Metabolism. EPILEPTOLOGY, 105.
Duke, A. M., & Steele, D. S. (1999). Effects of creatine phosphate on Ca2+ regulation by the sarcoplasmic reticulum in mechanically skinned rat skeletal muscle fibres. The Journal of Physiology, 517(2), 447-458.
Dwyer, J. T., Picciano, M. F., et al. (2008). Progress in developing analytical and label-based dietary supplement databases at the NIH Office of Dietary Supplements. Journal of Food Composition and Analysis, 21, S83-S93.
Elfawy, H. A., & Das, B. (2018). Crosstalk between mitochondrial dysfunction, oxidative stress, and age related neurodegenerative disease: Etiologies and therapeutic strategies. Life sciences.
Eric HW Kossoff, M. (2019). Ketogenic dietary therapies for the treatment of epilepsy. Retrieved from https://www.uptodate.com/contents/ketogenic-dietary-therapies-for-the-treatment-of-epilepsy
Eyles, D. W., Burne, T. H., et al. (2013). Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Frontiers in neuroendocrinology, 34(1), 47-64.
Fan, H.-z., Zhang, R., et al. (2019). CYP24A1 genetic variants in the vitamin D metabolic pathway are involved in the outcomes of hepatitis C virus infection among high-risk Chinese population. International Journal of Infectious Diseases, 84, 80-88.
Farrokh, S., Tahsili-Fahadan, P., et al. (2018). Antiepileptic drugs in critically ill patients. Critical Care, 22(1), 153.
Figueiredo, J. C., Levine, A. J., et al. (2010). Genes involved with folate uptake and distribution and their association with colorectal cancer risk. Cancer Causes & Control, 21(4), 597-608.
Fischer, A., Schmelzer, C., et al. (2011). Association between genetic variants in the coenzyme Q 10 metabolism and coenzyme Q 10 status in humans. BMC research notes, 4(1), 245.
Fisher, R. S., Acevedo, C., et al. (2014). ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 55(4), 475-482.
Fisher, R. S., Boas, W. V. E., et al. (2005). Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia, 46(4), 470-472.
Folbergrová, J., & Kunz, W. S. (2012). Mitochondrial dysfunction in epilepsy. Mitochondrion, 12(1), 35-40.
Franco, V., French, J. A., et al. (2016). Challenges in the clinical development of new antiepileptic drugs. Pharmacological research, 103, 95-104.
Frank, M., & Finsterer, J. (2012). Creatine kinase elevation, lactacidemia, and metabolic myopathy in adult patients with diabetes mellitus. Endocrine Practice, 18(3), 387-393.
Ge, A., Gonzalez, E., et al. (2017). Seizure triggers in epilepsy patients: a national perspective (S37. 002). In: AAN Enterprises.
Ge, S. X., Jung, D., et al. (2020). ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics, 36(8), 2628-2629.
Geronzi, U., Lotti, F., et al. (2018). Oxidative stress in epilepsy. Expert review of neurotherapeutics, 18(5), 427-434.
Gholipour, T., Ghasemi, M., et al. (2010). Seizure susceptibility alteration through 5-HT3 receptor: modulation by nitric oxide. Seizure, 19(1), 17-22.
Ghose, K. (1983). L-Tryptophan in hyperactive child syndrome associated with epilepsy: a controlled study. Neuropsychobiology, 10(2-3), 111-114.
Gorlick, R., Cole, P., et al. (1999). Mechanisms of methotrexate resistance in acute leukemia. Decreased transport and polyglutamylation. Adv.Exp.Med.Biol., 457, 543-550.
Gostner, J. M., Kurz, K., et al. (2020). The significance of tryptophan metabolism and vitamin B-6 status in cardiovascular disease. In: Oxford University Press.
Gutch, M., Kumar, S., et al. (2015). Assessment of insulin sensitivity/resistance. Indian journal of endocrinology and metabolism, 19(1), 160.
Hallmann, K., Zsurka, G., et al. (2014). A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy. Neurology, 83(23), 2183-2187.
Hansson, O., & Hagberg, B. (1968). Effect of pyridoxine treatment in children with epilepsy. Acta Societatis Botanicorum Poloniae, 73, 35-43.
Harrow, J., Frankish, A., et al. (2012). GENCODE: the reference human genome annotation for The ENCODE Project. Genome research, 22(9), 1760-1774.
Heeley, A., Piesowicz, A. T., et al. (1968). The biochemical and clinical effect of pyridoxine in children with brain disorders. Clinical science, 35, 381-389.
Hellwig, S., Mamalis, P., et al. (2012). Psychiatric comorbidity in patients with pharmacoresistant focal epilepsy and psychiatric outcome after epilepsy surgery. Epilepsy & Behavior, 23(3), 272-279.
Herzog, A. G., MacEachern, D. B., et al. (2017). Folic acid use by women with epilepsy: Findings of the Epilepsy Birth Control Registry. Epilepsy & Behavior, 72, 156-160.
Heyes, M. P., Saito, K., et al. (1994). Kynurenine pathway metabolites in cerebrospinal fluid and serum in complex partial seizures. Epilepsia, 35(2), 251-257.
Hibler, E. A., Klimentidis, Y. C., et al. (2015). CYP24A1 and CYP27B1 polymorphisms, concentrations of vitamin D metabolites, and odds of colorectal adenoma recurrence. Nutrition and cancer, 67(7), 1131-1141.
Holló, A., Clemens, Z., et al. (2012). Correction of vitamin D deficiency improves seizure control in epilepsy: a pilot study. Epilepsy & Behavior, 24(1), 131-133.
Hom, A., Weaver, R., et al. (1991). Efficacy of D-alpha tocopherol acetate as adjunctive antiepileptic agent in patients with refractory epilepsy and profound developmental disability. A prospective, randomized, double-blind, placebo-controlled trial. Epilepsia, 32(suppl 3), 63.
Hubbard, T., Barker, D., et al. (2002). The Ensembl genome database project. Nucleic acids research, 30(1), 38-41.
Hughes, P., Bower, B., et al. (1966). Metabolism of tryptophan in childhood epilepsy. Archives of Disease in Childhood, 41(220), 642.
Jaeger, B., Abeling, N., et al. (2016). Pyridoxine responsive epilepsy caused by a novel homozygous PNPO mutation. Molecular genetics and metabolism reports, 6, 60-63.
Jiang, P., Zhu, W.-Y., et al. (2015). Association between vitamin D receptor gene polymorphisms with childhood temporal lobe epilepsy. International journal of environmental research and public health, 12(11), 13913-13922.
Jiao, F.-Y., Gao, D.-Y., et al. (1997). Randomized, controlled trial of high-dose intravenous pyridoxine in the treatment of recurrent seizures in children. Pediatric neurology, 17(1), 54-57.
Jones, P., Lucock, M., et al. (2018). The vitamin D–folate hypothesis as an evolutionary model for skin pigmentation: an update and integration of current ideas. Nutrients, 10(5), 554.
Kalueff, A. V., Minasyan, A., et al. (2006). Increased severity of chemically induced seizures in mice with partially deleted Vitamin D receptor gene. Neuroscience letters, 394(1), 69-73.
Kalueff, A. V., Minasyan, A., et al. (2005). Anticonvulsant effects of 1, 25-dihydroxyvitamin D in chemically induced seizures in mice. Brain research bulletin, 67(1-2), 156-160.
Kanehisa, M. (2002). The KEGG database. Paper presented at the Novartis Foundation Symposium.
Kanner, A. M. (2016). Management of psychiatric and neurological comorbidities in epilepsy. Nature Reviews Neurology, 12(2), 106.
Kanner, A. M., Ashman, E., et al. (2018a). Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy. Epilepsy currents, 18(4), 260-268.
Kanner, A. M., Ashman, E., et al. (2018b). Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy. Epilepsy currents, 18(4), 269-278.
Kasperavičiūtė, D., Catarino, C. B., et al. (2010). Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study. brain, 133(7), 2136-2147.
Keane, K. N., Cruzat, V. F., et al. (2017). Molecular actions of vitamin D in reproductive cell biology. Reproduction, 153(1), R29-R42.
Keezer, M. R., Sisodiya, S. M., et al. (2016). Comorbidities of epilepsy: current concepts and future perspectives. The Lancet Neurology, 15(1), 106-115.
Keni, R. R., Jose, M., et al. (2020). Anti-epileptic drug and folic acid usage during pregnancy, seizure and malformation outcomes: Changes over two decades in the Kerala Registry of Epilepsy and Pregnancy. Epilepsy Research, 159, 106250.
Kim, J.-E., Choi, H.-C., et al. (2019). Perampanel affects up-stream regulatory signaling pathways of GluA1 Phosphorylation in normal and epileptic rats. Frontiers in cellular neuroscience, 13, 80.
Kobylarek, D., Iwanowski, P., et al. (2019). Advances in the potential biomarkers of epilepsy. Frontiers in neurology, 10.
Korczyn, A. D., Schachter, S. C., et al. (2013). Epilepsy, cognition, and neuropsychiatry (Epilepsy, Brain, and Mind, part 2). Epilepsy & Behavior, 28(2), 283-302.
Korte, A., & Farlow, A. (2013). The advantages and limitations of trait analysis with GWAS: a review. Plant methods, 9(1), 29.
Krause, K., Bonjour, J., et al. (1988). Effect of long-term treatment with antiepileptic drugs on the vitamin status. Drug-nutrient interactions, 5(4), 317-343.
Kwan, P., Arzimanoglou, A., et al. (2010). Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia, 51(6), 1069-1077.
Kwan, P., & Brodie, M. J. (2010). Definition of refractory epilepsy: defining the indefinable? The Lancet Neurology, 9(1), 27-29.
La Cruz, V. P.-D., Carrillo-Mora, P., et al. (2012). Quinolinic acid, an endogenous molecule combining excitotoxicity, oxidative stress and other toxic mechanisms. International Journal of Tryptophan Research, 5, IJTR. S8158.
Lam, B. C. C., Koh, G. C. H., et al. (2015). Comparison of body mass index (BMI), body adiposity index (BAI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) as predictors of cardiovascular disease risk factors in an adult population in Singapore. PloS one, 10(4), e0122985.
Landrum, M. J., Lee, J. M., et al. (2016). ClinVar: public archive of interpretations of clinically relevant variants. Nucleic acids research, 44(D1), D862-D868.
Lee, D.-G., Lee, Y., et al. (2015). Seizures related to vitamin B6 deficiency in adults. Journal of epilepsy research, 5(1), 23.
Lee, L., Kang, S. A., et al. (2001). Effect of supplementation of vitamin E and vitamin C on brain acetylcholinesterase activity and neurotransmitter levels in rats treated with scopolamine, an inducer of dementia. Journal of nutritional science and vitaminology, 47(5), 323-328.
Li, H., Bullock, K., et al. (2019). Metabolomic adaptations and correlates of survival to immune checkpoint blockade. Nature communications, 10(1), 1-6.
Li, M.-X., Gui, H.-S., et al. (2011). GATES: a rapid and powerful gene-based association test using extended Simes procedure. The American Journal of Human Genetics, 88(3), 283-293.
Li, X., Shao, C., et al. (2018). Lessons learned from the blockade of immune checkpoints in cancer immunotherapy. Journal of hematology & oncology, 11(1), 1-26.
Lin, E., Hwang, Y., et al. (2006). A case study of the utility of the HapMap database for pharmacogenomic haplotype analysis in the Taiwanese population. Mol Diagn Ther, 10(6), 367-370.
Lin, Y.-S., Ho, Y., et al. (2013). Development of a Taiwan version of the eight-item Morisky Medication Adherence Scale and factors influencing patients' comprehension. Journal of Experimental & Clinical Medicine, 5(2), 77-80.
Linnebank, M., Moskau, S., et al. (2012). Antiepileptic drugs and vitamin B6 plasma levels in adult patients. Epilepsy Research, 101(1-2), 182-184.
Livingston, S., Hsu, J. M., et al. (1955). Ineffectiveness of pyridoxine (vitamin B6) in the treatment of epilepsy. Pediatrics, 16(2), 250-251.
Lonsdale, J., Thomas, J., et al. (2013). The genotype-tissue expression (GTEx) project. Nature genetics, 45(6), 580.
Lorigados Pedre, L., Morales Chacón, L. M., et al. (2018). Follow-up of peripheral IL-1β and IL-6 and relation with apoptotic death in drug-resistant temporal lobe epilepsy patients submitted to surgery. Behavioral Sciences, 8(2), 21.
Lu, S., Niu, X., et al. (2013). A pemetrexed-based genetic study of Chinese Han patients with advanced non-small cell lung cancer (NSCLC). In: American Society of Clinical Oncology.
Luykx, J. J., Bakker, S. C., et al. (2014). Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid. Molecular Psychiatry, 19(2), 228-234.
Müller, K. I., & Bekkelund, S. I. (2011). Epilepsy in a patient with ataxia caused by vitamin E deficiency. Case Reports, 2011, bcr0120113728.
Mackay, G., Forrest, C., et al. (2006). Tryptophan metabolism and oxidative stress in patients with chronic brain injury. European journal of neurology, 13(1), 30-42.
Maglott, D., Ostell, J., et al. (2010). Entrez Gene: gene-centered information at NCBI. Nucleic acids research, 39(suppl_1), D52-D57.
Mahmuda, N. A., Yokoyama, S., et al. (2016). A study of single nucleotide polymorphisms of the SLC19A1/RFC1 gene in subjects with autism spectrum disorder. International journal of molecular sciences, 17(5), 772.
Malhotra, A. K. (2010). The pharmacogenetics of depression: enter the GWAS. In: Am Psychiatric Assoc.
Małkiewicz, M. A., Szarmach, A., et al. (2019). Blood-brain barrier permeability and physical exercise. Journal of neuroinflammation, 16(1), 1-16.
Mancini, A., Festa, R., et al. (2011). Hormonal influence on coenzyme Q10 levels in blood plasma. International journal of molecular sciences, 12(12), 9216-9225.
Mancuso, M., Coppede, F., et al. (2006). Mitochondrial dysfunction, oxidative stress and neurodegeneration. Journal of Alzheimer's Disease, 10(1), 59-73.
Mancuso, M., Orsucci, D., et al. (2010). Coenzyme Q10 in neuromuscular and neurodegenerative disorders. Current drug targets, 11(1), 111-121.
Manolis, T. A., Manolis, A. A., et al. (2019). Sudden unexpected death in epilepsy: The neuro-cardio-respiratory connection. Seizure, 64, 65-73.
Mao, X., Xing, X., et al. (2016). Folic acid and vitamins D and B12 correlate with homocysteine in Chinese patients with type-2 diabetes mellitus, hypertension, or cardiovascular disease. Medicine, 95(6).
Marcoff, L., & Thompson, P. D. (2007). The role of coenzyme Q10 in statin-associated myopathy: a systematic review. Journal of the American College of Cardiology, 49(23), 2231-2237.
Marsh, S., Kwok, P., et al. (2002). SNP databases and pharmacogenetics: great start, but a long way to go. Hum Mutat, 20(3), 174-179.
Mastrangelo, M. (2018). Actual insights into treatable inborn errors of metabolism causing epilepsy. Journal of pediatric neurosciences, 13(1), 13.
Matthews, D., Hosker, J., et al. (1985). Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28(7), 412-419.
McPherson, R. A. (2017). Henry's Clinical Diagnosis and Management by Laboratory Methods: First South Asia Edition_e-Book: Elsevier India.
Mefford, H. C., Muhle, H., et al. (2010). Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS genetics, 6(5).
Mehvari, J., Motlagh, F. G., et al. (2016). Effects of Vitamin E on seizure frequency, electroencephalogram findings, and oxidative stress status of refractory epileptic patients. Advanced biomedical research, 5.
Menik, L., & Palangasinghe, S. (2006). Comparison of insulin resistance by indirect methods-HOMA, QUICKI and McAuley-with fasting insulin in patients with type 2 diabetes in Galle, Sri Lanka: A pilot study. Online Journal of Health and Allied Sciences, 5(1).
Mering, C. v., Huynen, M., et al. (2003). STRING: a database of predicted functional associations between proteins. Nucleic acids research, 31(1), 258-261.
Mezawa, M., Takemoto, M., et al. (2012). The reduced form of coenzyme Q10 improves glycemic control in patients with type 2 diabetes: an open label pilot study. Biofactors, 38(6), 416-421.
MG Meems, L., Van der Harst, P., et al. (2011). Vitamin D biology in heart failure: molecular mechanisms and systematic review. Current drug targets, 12(1), 29-41.
Miles, M. V., Morrison, J. A., et al. (2004). Coenzyme Q10 changes are associated with metabolic syndrome. Clinica Chimica Acta, 344(1-2), 173-179.
Mills, P. B., Camuzeaux, S. S., et al. (2014). Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. brain, 137(5), 1350-1360.
Mills, P. B., Footitt, E. J., et al. (2010). Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). brain, 133(7), 2148-2159.
Mills, P. B., Surtees, R. A., et al. (2005). Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox (am) ine 5′-phosphate oxidase. Human molecular genetics, 14(8), 1077-1086.
Mintzer, S., Skidmore, C. T., et al. (2012). B-vitamin deficiency in patients treated with antiepileptic drugs. Epilepsy & Behavior, 24(3), 341-344.
Moavero, R., Santarone, M. E., et al. (2017). Cognitive and behavioral effects of new antiepileptic drugs in pediatric epilepsy. Brain and Development, 39(6), 464-469.
Morisky, D. E., Green, L. W., et al. (1986). Concurrent and predictive validity of a self-reported measure of medication adherence. Medical care, 67-74.
Morrell, M. J. (2002). Folic acid and epilepsy. Epilepsy currents, 2(2), 31-34.
Moshé, S. L., Perucca, E., et al. (2015). Epilepsy: new advances. The Lancet, 385(9971), 884-898.
Murata, S., Castillo, M. F. R., et al. (2019). Effects of inflammation modulation on tryptophan and kynurenine pathway regulation in treatment resistant bipolar depression. Neurology, Psychiatry and Brain Research, 33, 65-72.
Nachum‐Biala, Y., & Troen, A. M. (2012). B‐vitamins for neuroprotection: Narrowing the evidence gap. Biofactors, 38(2), 145-150.
Najafi, M. R., Bazooyar, B., et al. (2017). The Investigation of Insulin Resistance in Two Groups of Epileptic Patients Treated with Sodium Valproate and Carbamazepine. Advanced biomedical research, 6.
Napolitano, F., Carrella, D., et al. (2017). gene2drug: a computational tool for pathway-based rational drug repositioning. Bioinformatics, 34(9), 1498-1505.
Narasimha Rai, K., Kumari, N. S., et al. (2013). The evaluation of micronutrients and oxidative stress and their relationship with the lipid profile in healthy adults. Journal of clinical and diagnostic research: JCDR, 7(7), 1314.
Nass, R. D., Sassen, R., et al. (2017). The role of postictal laboratory blood analyses in the diagnosis and prognosis of seizures. Seizure, 47, 51-65.
Naughton, M., Mulrooney, J. B., et al. (2000). A review of the role of serotonin receptors in psychiatric disorders. Human Psychopharmacology: Clinical and Experimental, 15(6), 397-415.
Nayak, B. N., & Buttar, H. S. (2016). Evaluation of the antioxidant properties of tryptophan and its metabolites in in vitro assay. Journal of Complementary and Integrative Medicine, 13(2), 129-136.
Niebyl, J. R., & Goodwin, T. M. (2002). Overview of nausea and vomiting of pregnancy with an emphasis on vitamins and ginger. American journal of obstetrics and gynecology, 186(5), S253-S255.
Nigar, S., Pottoo, F. H., et al. (2016). Molecular insights into the role of inflammation and oxidative stress in epilepsy. J Adv Med Pharm Sci, 10, 1-9.
Nojiri, H., Shimizu, T., et al. (2006). Oxidative stress causes heart failure with impaired mitochondrial respiration. Journal of Biological Chemistry, 281(44), 33789-33801.
Null, G., Pennesi, L., et al. (2017). Nutrition and lifestyle intervention on mood and neurological disorders. Journal of evidence-based complementary & alternative medicine, 22(1), 68-74.
Ogata, H., Goto, S., et al. (1999). KEGG: Kyoto encyclopedia of genes and genomes. Nucleic acids research, 27(1), 29-34.
Ogunmekan, A., & Hwang, P. (1989). A Randomized, Double‐Blind, Placebo‐Controlled, Clinical Trial of D‐α‐Tocopheryl Acetate (Vitamin E), as Add‐On Therapy, for Epilepsy in Children. Epilepsia, 30(1), 84-89.
Oh, Y. S., & Jun, H.-S. (2018). Effects of glucagon-like peptide-1 on oxidative stress and Nrf2 signaling. International journal of molecular sciences, 19(1), 26.
Oliveira, A., Almeida, J., et al. (2007). Effects of levetiracetam in lipid peroxidation level, nitrite–nitrate formation and antioxidant enzymatic activity in mice brain after pilocarpine-induced seizures. Cellular and molecular neurobiology, 27(3), 395-406.
Onouchi, Y., Gunji, T., et al. (2008). ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nature genetics, 40(1), 35-42.
Panchal, K., & Tiwari, A. K. (2018). Mitochondrial dynamics, a key executioner in neurodegenerative diseases. Mitochondrion.
Patsalos, P. N. (2018). The epilepsy prescriber's guide to antiepileptic drugs: Cambridge University Press.
Paudel, Y. N., Shaikh, M., et al. (2018). HMGB1: a common biomarker and potential target for TBI, neuroinflammation, epilepsy, and cognitive dysfunction. Frontiers in neuroscience, 12, 628.
Paudel, Y. N., Shaikh, M. F., et al. (2018). Role of inflammation in epilepsy and neurobehavioral comorbidities: Implication for therapy. European journal of pharmacology, 837, 145-155.
Pearson-Smith, J., & Patel, M. (2017). Metabolic dysfunction and oxidative stress in epilepsy. International journal of molecular sciences, 18(11), 2365.
Pedraz-Petrozzi, B., Elyamany, O., et al. (2020). Effects of inflammation on the kynurenine pathway in schizophrenia—a systematic review. Journal of neuroinflammation, 17(1), 1-17.
Pena, I. A., Roussel, Y., et al. (2017). Pyridoxine-dependent epilepsy in zebrafish caused by Aldh7a1 deficiency. Genetics, 207(4), 1501-1518.
Peng, Y.-H., Wu, B.-R., et al. (2015). Adult asthma increases dementia risk: a nationwide cohort study. J Epidemiol Community Health, 69(2), 123-128.
Peters, J. (1991). Tryptophan nutrition and metabolism: an overview. In Kynurenine and serotonin pathways (pp. 345-358): Springer.
Petramfar, P., Yaghoobi, E., et al. (2009). Serum creatine phosphokinase is helpful in distinguishing generalized tonic–clonic seizures from psychogenic nonepileptic seizures and vasovagal syncope. Epilepsy & Behavior, 15(3), 330-332.
Plecko, B., Paul, K., et al. (2007). Biochemical and molecular characterization of 18 patients with pyridoxine‐dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene. Human mutation, 28(1), 19-26.
Plecko, B., & Stöckler, S. (2009). Vitamin B 6 Dependent Seizures. Canadian journal of neurological sciences, 36.
Porras, T. E., & Lluch, F. M. (1993). Folic acid and vitamin B12 in children under long-term anticonvulsant therapy. Anales espanoles de pediatria, 38(2), 113.
Pruitt, K. D., Tatusova, T., et al. (2007). NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic acids research, 35(suppl_1), D61-D65.
Purcell, S., Neale, B., et al. (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. The American Journal of Human Genetics, 81(3), 559-575.
Quirk, S., & Agrawal, D. K. (2014). Immunobiology of IL-37: mechanism of action and clinical perspectives. Expert review of clinical immunology, 10(12), 1703-1709.
Raju, G., Behari, M., et al. (1994). Randomized, Double‐Blind, Placebo‐Controlled, Clinical Trial of D‐α‐Tocopherol (Vitamin E) as Add‐on Therapy in Uncontrolled Epilepsy. Epilepsia, 35(2), 368-372.
Roberts, R. J. (2001). PubMed Central: The GenBank of the published literature. In: National Acad Sciences.
Roganovic, M., Pantovic, S., et al. (2019). Role of the oxidative stress in the pathogenesis of epilepsy. brain, 1, 3.
Ross, D., & Siegel, D. (2017). Functions of NQO1 in cellular protection and CoQ10 metabolism and its potential role as a redox sensitive molecular switch. Frontiers in physiology, 8, 595.
Ruiz-Martínez, J., Azcona, L. J., et al. (2017). Whole-exome sequencing associates novel CSMD1 gene mutations with familial Parkinson disease. Neurology Genetics, 3(5).
Salpekar, J. (2016). Mood disorders in epilepsy. Focus, 14(4), 465-472.
Salviati, L., Trevisson, E., et al. (2017). Primary coenzyme Q10 deficiency. In GeneReviews®[Internet]: University of Washington, Seattle.
Samsom, J. N., & Wong, A. H. (2015). Schizophrenia and depression co-morbidity: what we have learned from animal models. Frontiers in psychiatry, 6, 13.
Santulli, L., Coppola, A., et al. (2016). The challenges of treating epilepsy with 25 antiepileptic drugs. Pharmacological research, 107, 211-219.
Sardesai, V. (2011). Introduction to clinical nutrition: CRC Press.
Schlattner, U., Tokarska-Schlattner, M., et al. (2006). Mitochondrial creatine kinase in human health and disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1762(2), 164-180.
Schmidt, D., & Schachter, S. C. (2014). Drug treatment of epilepsy in adults. Bmj, 348, g254.
Schoeler, N. E., Leu, C., et al. (2018). Genome‐wide association study: Exploring the genetic basis for responsiveness to ketogenic dietary therapies for drug‐resistant epilepsy. Epilepsia, 59(8), 1557-1566.
Schroecksnadel, K., Fischer, B., et al. (2007). Antioxidants suppress Th1-type immune response in vitro. Drug Metabolism Letters, 1(3), 166-171.
Schwarcz, R., Brush, G. S., et al. (1984). Seizure activity and lesions after intrahippocampal quinolinic acid injection. Experimental neurology, 84(1), 1-17.
Shaikh, A. S., Guo, X., et al. (2018). The impact of antiepileptic drugs on vitamin levels in epileptic patients. Current Pharmaceutical Biotechnology, 19(8), 674-681.
Shannon, P., Markiel, A., et al. (2003). Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome research, 13(11), 2498-2504.
Sherzai, A. Z., Tagliati, M., et al. (2016). Micronutrients and risk of Parkinson’s disease: a systematic review. Gerontology and geriatric medicine, 2, 2333721416644286.
Simko, V., Iuliano, F., et al. (2017). Hypoxia induces cancer-associated cAMP/PKA signalling through HIF-mediated transcriptional control of adenylyl cyclases VI and VII. Scientific Reports, 7(1), 1-11.
Singh, R., Niaz, M., et al. (1999). Effect of hydrosoluble coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with coronary artery disease. Journal of human hypertension, 13(3), 203.
Speed, D., Hoggart, C., et al. (2014). A genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy. Human molecular genetics, 23(1), 247-258.
Spriet, L. L., Perry, C. G., et al. (2008). Legal pre-event nutritional supplements to assist energy metabolism. Essays in Biochemistry, 44, 27-44.
Stasiołek, M., Romanowicz, H., et al. (2016). Association between C3435T polymorphism of MDR1 gene and the incidence of drug-resistant epilepsy in the population of Polish children. Behavioral and Brain Functions, 12(1), 21.
Statnick, M. A., Dailey, J. W., et al. (1996). Abnormalities in brain serotonin concentration, high‐affinity uptake, and tryptophan hydroxylase activity in severe‐seizure genetically epilepsy‐prone rats. Epilepsia, 37(4), 311-321.
Steele, P. E., Tang, P. H., et al. (2004). Clinical laboratory monitoring of coenzyme Q10 use in neurologic and muscular diseases. Pathology Patterns Reviews, 121(suppl_1), S113-S120.
Suwarba, I. G. N. M., Novayanti, N. P. Y., et al. (2019). Correlation Between Pyridoxal 5’-Phospate Level And Valproic Acid In Epilepsy Children. Molecular and Cellular Biomedical Sciences, 3(1), 42-47.
Svalheim, S., Sveberg, L., et al. (2015). Interactions between antiepileptic drugs and hormones. Seizure, 28, 12-17.
Szklarczyk, D., Franceschini, A., et al. (2014). STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic acids research, 43(D1), D447-D452.
Téllez‐Zenteno, J. F., Hernández‐Ronquillo, L., et al. (2014). A validation of the new definition of drug‐resistant epilepsy by the I nternational L eague Against E pilepsy. Epilepsia, 55(6), 829-834.
Takemura, Y., Kobayashi, H., et al. (1999). Variable expression of the folylpolyglutamate synthetase gene at the level of mRNA transcription in human leukemia cell lines sensitive, or made resistant, to various antifolate drugs. Anticancer Drugs, 10(7), 677-683.
Tang, F., Hartz, A., et al. (2017). Drug-resistant epilepsy: multiple hypotheses, few answers. Frontiers in neurology, 8, 301.
Teran, E., Vivero, S., et al. (2005). Coenzyme Q10 is increased in placenta and cord blood during preeclampsia. Biofactors, 25(1‐4), 153-158.
Thijs, R. D., Surges, R., et al. (2019). Epilepsy in adults. The Lancet.
Tombini, M., Palermo, A., et al. (2018). Calcium metabolism serum markers in adult patients with epilepsy and the effect of vitamin D supplementation on seizure control. Seizure, 58, 75-81.
Ugur, K., Aydogan, Y., et al. (2019). A high creatine kinase concentration might be a sign of McArdle disease in patient with type 1 diabetes. Biochemistry insights, 12, 1178626419861407.
Uher, R., Perroud, N., et al. (2010). Genome-wide pharmacogenetics of antidepressant response in the GENDEP project. American Journal of Psychiatry, 167(5), 555-564.
Urban, P. P., Wellach, I., et al. (2010). Subacute axonal neuropathy in Parkinson's disease with cobalamin and vitamin B6 deficiency under duodopa therapy. Movement disorders, 25(11), 1748-1752.
Valadbeigi, P., Behpour, N., et al. (2018). Effect of acute and chronic coenzyme Q10 supplementation on creatine kinase after exhaustive aerobic activity. International Journal of Biomedicine and Public Health, 1(1), 17-22.
Verrier, R. L., Pang, T. D., et al. (2020). The Epileptic Heart: concept and clinical evidence. Epilepsy & Behavior, 105, 106946.
Verrier, R. L., & Schachter, S. C. (2018). Is heart disease in chronic epilepsy a consequence of seizures or a fellow traveler? Epilepsy & Behavior, 86, 211-213.
Visioli, F., & Burgos-Ramos, E. (2016). Selected micronutrients in cognitive decline prevention and therapy. Molecular neurobiology, 53(6), 4083-4093.
Walker, L., Mirza, N., et al. (2015). Personalized medicine approaches in epilepsy. Journal of internal medicine, 277(2), 218-234.
Wang, J., Liu, Y., et al. (2017). Identification of key genes and pathways in Parkinson's disease through integrated analysis. Molecular medicine reports, 16(4), 3769-3776.
Wang, P., Zhang, H., et al. (2015). Association of the CYP24A1-rs2296241 polymorphism of the vitamin D catabolism enzyme with hormone-related cancer risk: a meta-analysis. OncoTargets and therapy, 8, 1175.
Warde-Farley, D., Donaldson, S. L., et al. (2010). The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic acids research, 38(suppl_2), W214-W220.
Warnick, G. R., Knopp, R. H., et al. (1990). Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints. Clinical chemistry, 36(1), 15-19.
Watanabe, K., Taskesen, E., et al. (2017). Functional mapping and annotation of genetic associations with FUMA. Nature communications, 8(1), 1-11.
Wen, Y., Wu, K., et al. (2019). Inhibitory effects of glucagon-like peptide-1 receptor on epilepsy. Biochemical and biophysical research communications, 511(1), 79-86.
WHO. (2011). Waist circumference and waist-hip ratio: report of a WHO expert consultation, Geneva, 8-11 December 2008.
WHO. (2019). World Health Organization_Epilepsy. Retrieved from https://www.who.int/news-room/fact-sheets/detail/epilepsy
Wilke, R. A., Simpson, R. U., et al. (2009). Genetic variation in CYP27B1 is associated with congestive heart failure in patients with hypertension. Pharmacogenomics, 10(11), 1789-1797.
Williams, T. J., & Cervenka, M. C. (2017). The role for ketogenic diets in epilepsy and status epilepticus in adults. Clinical Neurophysiology Practice, 2, 154-160.
Wu, R.-Y., Kong, P.-F., et al. (2019). Regorafenib promotes antitumor immunity via inhibiting PD-L1 and IDO1 expression in melanoma. Clinical Cancer Research, 25(14), 4530-4541.
Wu, X., Cheng, J., et al. (2016). Vitamin D-related gene polymorphisms, plasma 25-hydroxy-vitamin D, cigarette smoke and non-small cell lung cancer (NSCLC) risk. International journal of molecular sciences, 17(10), 1597.
Xiong, S., Wang, Y., et al. (2019). Interaction among GRIK2 gene on epilepsy susceptibility in Chinese children. Acta Neurologica Scandinavica, 139(6), 540-545.
Xu, K., Liu, G., et al. (2018). The tryptophan pathway targeting antioxidant capacity in the placenta. Oxidative Medicine and Cellular Longevity, 2018.
Yao, G., Chung, C.-W., et al. (2002). Development and verification of validity and reliability of the WHOQOL-BREF Taiwan version. Journal of the Formosan Medical Association, 101(5), 342-351.
Ye, L., Morse, L. R., et al. (2015). Osteopetrorickets due to Snx10 deficiency in mice results from both failed osteoclast activity and loss of gastric acid-dependent calcium absorption. PLoS Genet, 11(3), e1005057.
Yeh, J. K., & Brown, R. R. (1977). Effects of vitamin B-6 deficiency and tryptophan loading on urinary excretion of tryptophan metabolites in mammals. The Journal of Nutrition, 107(2), 261-271.
Yi, C., Huang, C., et al. (2020). Association study between CYP24A1 gene polymorphisms and cancer risk. Pathology-Research and Practice, 216(1), 152735.
Yip, T., O'doherty, C., et al. (2014). SCN1A variations and response to multiple antiepileptic drugs. The pharmacogenomics journal, 14(4), 385-389.
Yuen, A. W., Bell, G. S., et al. (2010). Effects of AEDs on biomarkers in people with epilepsy: CRP, HbA1c and eGFR. Epilepsy Research, 91(2-3), 187-192.
Żarnowska, I., Wróbel-Dudzińska, D., et al. (2019). Changes in tryptophan and kynurenine pathway metabolites in the blood of children treated with ketogenic diet for refractory epilepsy. Seizure, 69, 265-272.
Zerbino, D. R., Achuthan, P., et al. (2018). Ensembl 2018. Nucleic acids research, 46(D1), D754-D761.
Zhang, X., Men, T., et al. (2018). Genetic risk factors for post-transplantation diabetes mellitus in Chinese Han renal allograft recipients treated with tacrolimus. Transplant Immunology, 49, 39-42.
Zhang, Y., Fang, J., et al. (2018). The role of the GLP-1/GLP-1R signaling pathway in regulating seizure susceptibility in rats. Brain research bulletin, 142, 47-53.
Zhao, H., Lin, Y., et al. (2018). 5-HT3 Receptors: a potential therapeutic target for epilepsy. Current neuropharmacology, 16(1), 29-36.
Zingg, J.-M. (2018). Water-Soluble Vitamin E—Tocopheryl Phosphate. In Advances in Food and Nutrition Research (Vol. 83, pp. 311-363): Elsevier.
Zoratti, M., & Szabò, I. (1995). The mitochondrial permeability transition. Biochimica et Biophysica Acta (BBA)-Reviews on Biomembranes, 1241(2), 139-176.
尚捷醫事檢驗所. Retrieved from http://www.accuspeedy.com.tw/index
衛生福利部統計處. 107年度全民健康保險醫療統計年報. Retrieved from https://dep.mohw.gov.tw/DOS/lp-4648-113.html