Printer Friendly

Inborn error of metabolism screening in neonates.


Inborn errors of metabolism (IEM) form a large class of genetic disorders which occur as a result of gene defects. The majority of them are due to defects of single genes coding for enzymes. [1-3] Newborn screening of inborn error of metabolism refers to the coordinated and comprehensive way of detecting disorders which includes knowledge, awareness, screening, follow-up of abnormal test results, confirmatory testing, diagnosis, treatment and evaluation of periodic outcome, and efficiency, for example, early detection of phenylketonuria and various other disorders helps in significant decrease in morbidity and helps in prevention from mental retardation. [4-7] Screening refers to the various biochemical and clinical tests done on asymptomatic neonates for the sake of decrease in morbidity and mortality rates and improving the efficiency outcome of better and healthy living of neonates. The identification of IEM as a disorder in neonates was described in the early 20th century. First of all, the disease known as alkaptonuria was discovered by Archibald Garrod, in 1908 [8,9] followed by a research in 1917 regarding the advice of less intake of the milk by the galactosemic infants, but the treatment of various disorders of IEM changed in the 1950s with phenylketonuria. [10]

Successful treatment outcome depends on early and rapid diagnosis and early therapeutic implementation in IEM disorders of neonates. Neonate suffering from IEM disorder is suspected as a result of acute clinical symptoms. [11] Sometimes, non-specific clues also exist, like previous unexplained death of neonate in few families showing the risk of IEM disorders in the baby. These disorders are detected through newborn screening programme though in India awareness of the program and lethal consequences of IEM disorders are not paid proper attention which may be due to lack of knowledge about the disease spectrum among the population and lack of funds to meet the screening expenses.


Errors in amino acid metabolism conclude some correlations between biochemical and pathological conditions, for example, alkaptonuria, an inherited metabolic disorder is caused by the absence of enzyme homogentisate oxidase due to which accumulation of homogentisate occurs and is excreted in urine, which turns dark black on standing due to oxidation. [12-14] In maple syrup urine disease (MSUD), the oxidative decarboxylation of a-keto acids derived from valine, leucine, and isoleucine gets blocked, leading to mental and physical retardation. Phenylketonuria, another disorder of IEM, is caused by an absence of the deficiency of phenylalanine hydroxylase, leading to accumulation of phenylalanine as it cannot be converted into tyrosine. Following is the list of various IEM disorders of protein, fat, carbohydrate, nucleic acid, and hemoglobin metabolism [Table 1]. [4]


It is nearly 60 years gone for newborn screening for IEM. In course of this long span of time, our country faced many challenges with regard to its startup, including awareness among masses and its implementation in the form of pilot projects for few of the metabolic disorders. Various studies have been done in India at different times which concluded the importance of screening of IEM in neonates. In India, the prevalence of IEM is quite high. Distinct religions, communities, ethnic groups, etc., are responsible for wide variation and prevalence of IEM in these groups. [15] Hence, there is a need to do research in variation of IEM among different groups and look forward for the risk or aggravating factors of IEM in particular groups. [16,17] Many foreign countries recommend newborn screening mandatory because as per their guidelines delay in detection of few of these disorders such as metabolic errors, endocrinological disorders, and hearing loss will all lead to significant morbidity and mortality. [18,19] Andhra Pradesh is the fifth largest state of India with infant mortality rate of 66. [20] A study was done in Andhra Pradesh regarding IEM and a database was generated for 43 IEM observed in newborns. [21] Furthermore, in India, the incidence of congenital hypothyroidism (CH) is 2.1 [22] and the rate of glucose 6 phosphate deficiency is 2-7.8%. [23] In a study which was undergone over a period of 4 years in West Bengal using gas chromatography in the urine and tandem mass spectrometry for the detection of aminoacidurias concluded 15% newborns positive of IEM, [24] but their final confirmation needs either enzymatic analysis or genetic studies. A study done on 98,256 newborn showed the prevalence of homocysteinemia, hyperglycemia, MSUD, phenylketonuria, hypothyroidism, and G6PD deficiency. Another expanded study started in 2000 in Hyderabad for amino acid disorders, CH, congenital adrenal hyperplasia (CAH), G6PD deficiency, biotinidase deficiency, galactosemia, and cystic fibrosis, revealed high prevalence of CH followed by CAH and G6PD deficiency. [25] The prevalence was noticed 1 in every 1000. A Newborn Screening Pilot project concluded disorders such as homocysteinemia, hyperglycemia, MSUD, phenylketonuria, hypothyroidism, and glucose-6-phosphate dehydrogenase deficiency were found to be the common errors in the neonates. [26] Another pilot study in Hyderabad revealed high prevalence of disorders such as congenital adrenal hyperplasia, G-6-PD deficiency, and aminoacidopathies as the cause of IEM. [27]


IEM are the most important cause of the neonatal illness and many of these disorders are treatable if diagnosed in early phase; therefore, there is a need of IEM screening in newborns. [11,28] In other various countries, IEM screening has expanded quite well. A pilot study was done by Shawky et al., [29] in 2015, which included around 40 neonates with various reasons of abnormal behavior such as poor suckling, poor crying, and convulsions and was suspected to have IEM and concluded that around 32.5% of selected neonates for the case study were diagnosed with IEM who have sepsislike symptoms. Another study was done by Shawky et al. [30] in which the screening of mentally retarded children was done by paper chromatography and various other tests such as ferric chloride test and nitroprusside test resulting in 11.3% of neonates with confirmed diagnosis of IEM. In Brazil, a study was conducted on 101 hypoglycemic neonates having metabolic acidosis, jaundice, diarrhea, vomiting, hepatomegaly or splenomegaly, cataract, apnea, and convulsions. Around 63.3% of 101 were diagnosed as IEM. [31] In China, a study was conducted by Huang et al. [32] on 11,060 neonates, of which only 62 were diagnosed as IEM. The symptomatic neonates were presented with metabolic acidosis, jaundice, hepatosplenomegaly, recurrent vomiting, hypoglycemia, convulsions, and unconsciousness. In German study, [33] 106 neonates were diagnosed as IEM out of 250,000 neonates. In Taiwan, the newborn screening at the national level revealed phenylalanine metabolism defect as the most common defect of IEM followed by MSUD. [34-36] IEM screening should be done for the betterment of any country's health and wealth, but it is still lacking due to various hurdles coming in its way like financial constraints as it is quite expensive, so every individual person or country cannot afford it and also there is a lack of education and awareness among the citizens of one's country regarding the importance of IEM or its role in the well-being of the child in near future.


Individually rare kind of disorders, IEM manifest due to partial and full enzymatic defects leads to the accumulation of toxic metabolites in the body. To manage its morbid and mortal effects, early and timely diagnosis and management is essential. The newborn screening program one of the important ways to provide early and pre-symptomatic diagnosis. The approach is proved to be a boon for innocent infants suffering from IEM disorders who can live a normal life if properly managed.


The authors thankfully acknowledge the management of Santosh Medical College and Hospital, for supporting the work.


[1.] Sharma P, Kumar P, Sharma R, Dhot PS. Inborn errors of metabolism screening and scope of GC-MS. Asian J Pharm Clin 2015;8:34-6.

[2.] Inborn Errors of Metabolism. Available from: [Last accessed on 2018 Nov 12].

[3.] Yudkoff M. Inborn Errors of Metabolism. Available from: [Last accessed on 2018 Nov 12].

[4.] Sharma P, Kumar P, Dhot PS, Sharma R. Prevalence of IEM in neonates. J Clinc Diagn Res 2018;12:BC07-13.

[5.] Das SK. Inborn errors of metabolism: Challenges and management. Indian J Clin Biochem 2013;28:311-3.

[6.] Ozben T. Expanded newborn screening and confirmatory follow-up testing for inborn errors of metabolism detected by tandem mass spectrometry. Clin Chem Lab Med 2013;51:157-76.

[7.] Yang CJ, Wei N, Li M, Xie K, Li JQ, Huang CG, et al. Diagnosis and therapeutic monitoring of inborn errors of metabolism in 100,077 newborns from Jining city in China. BMC Pediatr 2018;18:110.

[8.] Galton D, Garrod AE. The founding father of biochemical genetics. In: Pioneers of Medicine without a Noble Prize. London: Imperial College Press; 2014. p. 1-21.

[9.] KNOX WE. Sir Archibald Garrod's inborn errors of metabolism. II. Alkaptonuria. Am J Hum Genet 1958;10:95-124.

[10.] Timothy BJ, Omar HA, Merrick J. Adults with Childhood Illnesses. Considerations for Practice. Berlin, Boston: De Gruyter; 2011. Available from: [Last accessed on 2018 Nov 13].

[11.] Chakrapani A, Cleary MA, Wraith JE. Detection of inborn errors of metabolism in the newborn. Arch Dis Child Fetal Neonatal Ed 2001;84:F205-10.

[12.] Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th ed. New York: W H Freeman; 2002. Section 23.6, Inborn Errors of Metabolism Can Disrupt Amino Acid Degradation. Available from: [Last accessed on 2018 Nov 14].

[13.] Mistry JB, Bukhari M, Taylor AM. Alkaptonuria. Rare Dis 2013;1:e27475.

[14.] Alkaptonuria, US National Library of Medicine, Medicine Plus. Available from: [Last accessed on 2018 Nov 14].

[15.] Shetty KT. Metabolomics: Impact on diagnosis and monitoring of 'inborn'/'acquired' metabolic disorders. Indian J Clin Biochem 2007;22:3-5.

[16.] Indian Genome Variation Consortium. Genetic landscape of the people of India: A canvas for disease gene exploration. J Genet 2008;87:3-20.

[17.] Morris AAM. Neonatal screening for Inborn Errors of Metabolism. Indian Pediatr 2000;37:1303.

[18.] Rose NC, Dolan SM. Newborn screening and the obstetrician. Obstet Gynecol 2012;120:908-17.

[19.] Health Quality Ontario. Neonatal screening of inborn errors of metabolism using tandem mass spectrometry: An evidence-based analysis. Ont Health Technol Assess Ser 2003;3:1-36.

[20.] Available from: [Last accessed on Nov 2018 14].

[21.] Latheef SA. A database for inborn errors of metabolism in the Indian state of Andhra Pradesh. Bioinformation 2010;4:276-7.

[22.] Sanghvi U, Diwarkar KK. Universal screening programme for congenital hypothyroidism. Indian Pediatr 2008;45:331-2.

[23.] Padilla CD, Therrell BL. Newborn screening in the Asia pacific region. J Inherit Metab Dis 2007;30:490-506.

[24.] Lodh M, Kerketta A. Inborn errors of metabolism in a tertiary care hospital of eastern India. Indian Pediatr 2013;50:1155-6.

[25.] Kapoor S, Kabra M. Newborn screening in India: Current perspectives. Indian Pediatr 2010;47:219-24.

[26.] Rao NA, Devi AR, Savithri HS, Rao SV, Bittles AH. Neonatal screening for amino acidaemias in Karnataka, South India. Clin Genet 1988;34:60-3.

[27.] Rama Devi AR, Naushad SM. Newborn screening in India. Indian J Pediatr 2004;71:157-60.

[28.] Mak CM, Lee HC, Chan AY, Lam CW. Inborn errors of metabolism and expanded newborn screening: Review and update. Crit Rev Clin Lab Sci 2013;50:142-62.

[29.] Shawky RM, Abd-Elkhalek HS, Elakhdar SE. Selective screening in neonates suspected to have inborn errors of metabolism. Egypt J Med Hum Genet 2015;16:165-71.

[30.] Shawky RM, El-Din Riad MS, Osman HM, Bahaa NM. Screening for some inborn errors of amino acid metabolism which impair mental function. Egypt J Med Hum Genet 2001;2:71-91.

[31.] Chiaratti de Oliveira A, dos Santos AM, Martins AM, D'Almeida V. Screening for inborn errors of metabolism among newborns with metabolic disturbance and/or neurological manifestations without determined cause. Sao Paulo Med J 2001;119:160-4.

[32.] Huang X, Yang L, Tong F, Yang R, Zhao Z. Screening for inborn errors of metabolism in high-risk children: A 3-year pilot study in Zhejiang Province, China. BMC Pediatr 2012;12:18.

[33.] Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF, et al. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: Results, outcome, and implications. Pediatrics 2003;111:1399-406.

[34.] Frazier DM, Millington DS, McCandless SE, Koeberl DD, Weavil SD, Chiang SH, et al. The tendem mass spectrometry newborn screening experience in North Carolina: 1997-2005. J Inherit Metab Dis 2006;29:76-85.

[35.] Nongalleima K, Ajungla T, Singh CB. GCMS based metabolic profiling of essential oil of Citrus macroptera Montruz, leaves and peel, assessment of in vitro antioxidant and anti-inflammatory activity. Int J Pharm Pharm Sci 2017;9:107-14.

[36.] Zerrouki K, Djebli N, Ozkan EE, Ozsoy N, Gul O, Mat A. Hypericum perforatum improve memory and learning in Alzheimer's model: Experimental study in Mice. Int J Pharm Pharm Sci 2016;8:49-57.

Preeti Sharma (1), Shivani Gupta (2), Pradeep Kumar (1), Rachna Sharma (3), Mahapatra T K (1), Gaurav Gupta (4)

(1) Department of Biochemistry, Santosh Medical College and Hospital, Ghaziabad, Uttar Pradesh, India, (2) MBBS Student, TSM Medical College and Hospital, Lucknow, Uttar Pradesh, India, (3) Department of Biochemistry, TSM Medical College and Hospital, Lucknow, Uttar Pradesh, India, (4) Department of Biochemistry, Government Medical College, Badaun, Uttar Pradesh, India

Correspondence to: Preeti Sharma, E-mail:

Received: December 14, 2018; Accepted: January 08, 2019

Source of Support: Nil, Conflict of Interest: None declared.

DOI: 10.5455/njppp.2019.9.1237608012019
Table 1: Various IEM disorders

IEM disorders

S. No.         Hemoglobinopathies
  1            Beta-thalassemia
  2            Sickle cell anemia (HB SS)
  3            Sickle cell disease (Hb S/C)
  4            Variant hemoglobinopathies (C, D, H, Bart band),
               including HbE
  5            Congenital hypothyroidism

  6            Congenital adrenal hyperplasia
  7            Cystic fibrosis
  8            G6PD deficiency
 40            Iminoglycinuria
 41            2-Ketoadipic aciduria
 42            Sacchropenuria
 43            Hydroxylysinuria
 44            Cystathionuria
 45            Hyperprolinemia
 46            Hyperprolinemia type II
 47            Hyperhydroxyprolinemia
 48            5-Oxoprolinuria
 50            Hypersarcosinemia
 51            Imidazole aminoaciduria
 52            Formiminoglutamic aciduria
 85            Lactose intolerance
Fatty acid oxidation disorders
 86            SCAD
 87            MCAD
 88            LCAD
 89            VLCAD
 90            Short/medium-chain 3-hydroxy-CoA dehydrogenase deficiency
 91            Long-chain 3-hydroxy-CoA dehydrogenase deficiency
 92            Mitochondrial trifunctional protein deficiency
 93            Carnitine transport defect
 94            Multiple CoA dehydrogenase deficiency
 95            Medium-chain ketoacyl-CoA dehydrogenase deficiency
Test done on urine samples
Amino acid disorders
  9            Phenyl ketonuria
 10            Defect in biopterin cofactor biosynthesis
 11            Defects in biopterin cofactor regeneration
 12            GTPCH deficiency
 13            Dihydropteridine reductase deficiency
 14            Benign H-PHE
 15            Tyrosinemia type I
 16            Tyrosinemia type II
 17            Tyrosinemia type III
 18            Transient tyrosinemia in infancy
 19            Tyrosinemia caused by liver dysfunctions
 20            MSUD
 21            Carbamoyl phosphate synthetase-1 deficiency
 22            OTC deficiency
 23            Citrullinemia
 24            Citrullinemia type II
 25            Argininosuccinic aciduria
 26            Argininemia
 27            Hypermethioninemia
 28            Homocystinuria
 29            Alkaptonuria
 30            Tryptophanuria with dwarform
 31            Xanthurenic aciduria
 32            Valinemia
 33            Hyperleucinemia
 34            Dihydroptoyl dehydrogenase deficiency
 35            3-Hydroxylbutyryl-CoA deacylase deficiency
 36            Histidinuria
 37            Hartnup disease
 38            Lysinuric protein intolerance
 39            Familial renal iminoglycinuria
 53            Serum carnosinase deficiency
 54            Glutathionuria
 55            Hyperpipecolatemia
 56            3-Aminobutyric aciduria
 57            Histidinemia
Organic acid disorders
 58            Propionic academia
 59            Multiple carboxylase deficiency
 60            Methylmalonic acidemia
 61            Methylmalonyl-CoA mutase deficiency
 62            Methylmalonic aciduria
 63            Malonic acidemia
 64            Biobutyryl-CoA dehydrogenase deficiency
 65            Methylbutyryl-CoA dehydrogenase deficiency
 66            Methylmalonic semialdehyde dehydrogenase deficiency
 67            B-Ketothiolase deficiency
 68            Isovaleric acidemia
 69            3-Methylcrotonyl-CoA carboxylase deficiency
 70            3-Methylglutaconic aciduria
 71            3-Hydroxy-3-methylglutaric aciduria
 72            Glutaric aciduria type-II
 73            Glutaric aciduria type-l
 74            Mevalonic acidemia
 75            3-Methyl-3-hydroxybutyric aciduria
 76            4-Hydroxybutyric aciduria Carbohydrate disorders
 77            Galactosemia
 78            Galactokinase deficiency
 79            Galactose epimerase deficiency
 80            Transient galactosemia
 81            Fructosuria
 82            D-glyceric aciduria
 83            Fructose-1, 6-diphosphatase deficiency
 84            Endogenous sucrosuria
Peroxisomal disorders
 96            Zellweger syndrome
 97            Neonatal adrenoleukodystrophy
 98            Infantile Refsum's disease
 99            Zellweger-like syndrome
100            Primary hyperoxaluria
Disorders of purine pyrimidine metabolism
101            Adenosine deaminase deficiency
102            Lesch--Nyhan syndrome
103            Partial deficiency of hypoxanthine adenine
104            Adenine phosphoribosyltransferase deficiency
105            Xanthinuria
106            Orotic aciduria
107            Thymine-uraciluria
108            Dihydropyrimidinase deficiency
109            Hyperuric acidemia
Lactic acidemia, hyperpyruvic acidemia
110            Pyruvate dehydrogenase deficiency
111            Pyruvate dehydrogenase phosphatase deficiency
112            Pyruvate carboxylase deficiency
113            Pyruvate decarboxylase deficiency
114            Leigh syndrome
               Other IEM
115            Biotinidase deficiency
116            Canavan deficiency
117            Fumarate hydrolase deficiency
118            HHH syndrome
               Miscellaneous genetic condition
119            Neuroblastoma

MSUD: Maple syrup urine disease, H-PHE: Hyperphenylalaninemia, SCAD:
Short-chain CoA dehydrogenase deficiency, MCAD: Medium-chain CoA
dehydrogenase efficiency, LCAD: Long-chain CoA dehydrogenase deficiency,
VLCAD: Very long-chain CoA dehydrogenase deficiency, HHH:
Hyperornithinemia-hyperammonemia-hyperhomocitrullinemia, GTPCH: GTP
cyclohydrolase, OTC: Ornithine transcarbamylase, IEM: Inborn errors of
COPYRIGHT 2019 Dipika Charan
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2019 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Sharma, Preeti; Gupta, Shivani; Kumar, Pradeep; Sharma, Rachna; Mahapatra, T K; Gupta, Gaurav
Publication:National Journal of Physiology, Pharmacy and Pharmacology
Date:Mar 1, 2019
Previous Article:Cefoperazone + sulbactam versus cefotaxime + sulbactam combination therapy for the treatment of complicated urinary tract infections in hospitalized...
Next Article:Prevalence of overweight and obesity among school-going children of Satara district, Maharashtra.

Terms of use | Privacy policy | Copyright © 2019 Farlex, Inc. | Feedback | For webmasters