CHAPTER and G6PD deficiency is 2-7.8%. Worldwide, the incidence

                                              CHAPTER1                                          INTRODUCTION 1.1  Inborn Error of MetabolismInborn Error ofMetabolism (IEM) are group of genetic disorders that affect the metabolicpathways in neonates after birth.

IEM are due to genetic mutations in the genescoding a key enzyme or cofactor involved in metabolism, thus producing anincomplete or non-functional enzyme causing a block in a metabolic pathway.These genetic disorders have clinically significant consequences and if leftundiagnosed and untreated may cause infant mortality or death in earlychildhood. A new born baby with IEM is normal however after external intake ofdietary proteins or drugs, the disorder starts to manifests and the predominantsymptoms are seen as lethargy, acidosis, ketosis, poor feeding, seizures,failure to thrive or coma(Udani & Kumta, 2005).

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Theinheritance pattern of IEMs is autosomal recessive where the defective gene ispresent in both parents and can be passed on from generation to generation. The incidence of IEMsvaries in different ethnic groups and geographical regions with higherincidences in regions with greater occurrence of consanguineous marriages. Themost common disorder observed in India are Congenital Hypothyroidism, Phenylketonuria(PKU), Biotindase Deficiency, Glucose 6 Phosphate Dehydrogenase Deficiency(G6PD), Congenital Adrenal Hyperplasia (CAH), Galactosemia (GAL), and MapleSyrup Urine Disease (MSUD)The prevalence of Inborn Error of Metabolism in Indiais one in 2497 newborns, congenitalhypothyroidism incidence is 2.

1 per 1000 and G6PD deficiency is 2-7.8%.Worldwide, the incidence of IEM is more than 1/1000(Fatima, Kumar Sonkar, Tripathi, & Singh, 2017).A metabolic approach isused to diagnose an IEM in a new born.

Biofluids and dried bloodspots are takenand investigated using technology namely Radioimmunoassay, ELISA,fluoroimmunossay, Tandem Mass Spectroscopy, and NMR. 1.2  New Born ScreeningNew Born Screening is animportant test done for a neonate for early detection and diagnosis ofmetabolic, genetic and endocrine disorders. NBS is a simple and inexpensivetest which enables early prevention and treatment of diseases and help the babyto lead a normal life and reach their full potential. It is considered as astandard practice to detect significant number of IEMs at birth in mostcountries. On the basis of available resources and prevalence of a condition,the new born screening for a condition differ from country to country. It ismandatory to universally screen about 50 disorders in most developed nationacross the world. Although universal screening is a cost intensive procedure,benefits of NBS outweigh the cost in terms of human suffering and in reducingthe mortality rate of these disorders.

Certain criteria were proposed by Wilsonand Jungner for condition to be screened by NBS(Sachidananda Kamath, 2015). These include:(i) condition should pose serious health problem; (ii) disease should notmanifest at birth or during routine examination; (iii) irreversible damagecaused if diagnosis is delayed; (iv) test should be simple and reliable andmust be readily accepted by the population; (v) mortality and morbidity must beprevented by the suggested treatment; and (vi) screening should be costeffective.The conditions forwhich new born screening has been proposed for Indian scenario are congenitalhypothyroidism, hearing loss, glucose-6-phosphate dehydrogenase (G6PD)deficiency and congenital adrenal hyperplasia. However, implication of routineNBS is almost non-existent in India and with Infant Mortality Rate of 40, ithas been recommended by WHO to introduce new born screening and geneticservices in the country. Similarly, the Indian Academy of Paediatrics stronglyadvocates the inclusion of new born screening in country’s public health policyand promise to offer logistics and technical support to the Government ofIndian for successful initiation and implementation of the program(Sachidananda Kamath, 2015).  1.3  G6PD Glucose-6-phosphatedehydrogenase is an oxidoreductase enzyme which catalyses the first step of thehexose monophosphate pathway in matured red blood cells producing ribose5-phosphate and generating NADPH. Since matured red blood cells lack the citricacid cycle, this pathway is the only NADPH-generation process in RBCs,therefore deficiency of G6PD may have serious clinical consequences.

1.3.1      Gene structure The cytogeneticlocation of the human G6PD gene is Xq28 with genomic coordinates X:154,531,389-154,547,585 (from NCBI). It is a housekeeping gene containig13exons and spans a length of18kb where the protein-coding region is divided into12 segments ranging from 12 to 236 bp, and an intron present in 5-primeuntranslated region.1.3.

2     EnzymestructureIn its active form,G6PD exist as dimer and contains a tightly bound NADP. The monomer has 515amino acid subunits with a molecular weight of 59,256 daltons. The enzymerequires NADP for aggregation of monomers into functionally active dimers.Thus, NADP is bound to the enzyme both as one of the substrates of the reactionand as a structural component. One of the phosphates of NADP is bound to the basicamino acids lysine and arginine at position 386 and 387 respectively.

The glucose-6-phosphatebinding site has been identified at position 205 occupied by amino acid lysine(Desforges & Beutler, 1991). 1.4  G6PD deficiencyG6PD deficiency is themost prevalent form of metabolic disorder affecting 400 million peopleworldwide. The G6PD locus is highlypolymorphic with over 400 allelic variants reported.

Enzyme deficiency is dueto single base mutation in the G6PD gene. G6PD is responsible for reduction ofNADP to NADPH in RBCs, therefore enzyme deficiency subjects the RBCs tooxidative stress causing haemolysis. Severity of the disorder is determined by the G6PD variants associated withspecific G6PD alleles and consecutively on the reduced enzyme levels