Journal presentation INBORN ERRORS..pptx

Notes

1. Inborn errors of metabolism (IEM) DR DIPTY SINGH JNMC BELAGAVI

2. Inborn errors of metabolism (IEM) G enetically determined biochemical disorders affecting an individual’s ability to convert nutrients or to use them or energy production. They are caused by the impaired function of ( 1) Enzymes ( 2) Transporters ( 3) Co-factors It results in accumulation of abnormal metabolites (substrates) proximal to the metabolic block or by lack of necessary products .

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4. . Newborn period or in infancy . Some diseases , or milder variants of classic metabolic disorders, may not be detected until adulthood . Despite the long asymptomatic period, their consequences are still devastating and may result in death . Therefore , it is critical to identify and treat these diseases before irreversible damage occurs .

5. Inheritance Pattern of Metabolic Disorders

6. Journal presentation

7. REVIEW ARTICLE Inborn Errors of Metabolism—Approach to Diagnosis and Management in Neonates Indian Journal of Pediatrics   volume 88 , pages679–689 ( 2021) Umamaheswari Balakrishnan 1 Department of Neonatology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu 600116, India PMID : 34097229

8. Keywords Inborn errors of metabolism . Inherited metabolic disorders . Neonates . Diet . IEM

9. Abstract Inborn errors of metabolism (IEM), otherwise known as inherited metabolic disorders (IMD). IEM challenge to diagnosis, because neonates present with nonspecific signs. Knowledge on clinical presentation may be life saving, especially for conditions that are treatable.

10. CRITIQUING So, Title - clear, concise and informative Abstract cover structured abstract and also contain purpose , methodology , findings , principal. Keywords - covering all aspects of the study. Authors information like designation, affiliation , and address is well written.

11. Introduction Inborn errors of metabolism (IEM) or inherited metabolic disorders (IMD) are due to block in the chemical pathways due to enzyme, cofactor, or transporter deficiency. Incidence of IEM vary widely and can be as high as 1 in 800. Presently more than 700 conditions have been described. .

12. Continue.. This article describes the classification of IEM into three groups, namely group 1 - Intoxication disorders group 2 - Energy defects group 3 - Storage disorders

13. Balakrishnan U. Inborn Errors of Metabolism-Approach to Diagnosis and Management in Neonates. Indian J Pediatr . 2021 Jul;88(7):679-689. doi : 10.1007/s12098-021-03759-9. Epub 2021 Jun 7. PMID: 34097229.

14. Misconceptions IEM considered in those also with negative family history . Breast-feeding is not contraindicated in majority of IEM. IEM mimics sepsis , so evaluation of IEM is warrented , especially if there is no risk factor for sepsis.

15. A pproach History - Undiagnosed neonatal deaths or childhood illness. Three generation pedigree charting helps the clinician to get details of extended family members and consanguinity.

16. Clinical presentation- Neurological Deterioration Predominantly Encephalopathy ( poor feeding , lethargy , sensorium detoriates and coma) Neurological deterioration predominantly seizures (increased fetal movement , seizures unresponsive to routine anticonvulsants) Hypotonia Hepatic failure Hypoglycaemia Cardiomyopathy Arrhythmia

17. Other presentation Microcephaly at birth Congenital cataract Lens dislocation

18. Balakrishnan U. Inborn Errors of Metabolism-Approach to Diagnosis and Management in Neonates. Indian J Pediatr . 2021 Jul;88(7):679-689. doi : 10.1007/s12098-021-03759-9. Epub 2021 Jun 7. PMID: 34097229.

19. I nvestigations G lucose, ABG, Lactate, Ammonia, Ketone (urine) Blood urea nitrogen (BUN), Creatinine, Liver function test (LFT), Electrolytes and coagulation profile, Creatinine phosphokinase (CPK), Complete blood count, uric acid, Urine nonglucose reducing substance Tandem mass spectrometry (TMS) Gas chromatography and Mass spectrometry (GCMS) are summarized in this article.

20. CRITIQUING This review article cover the approach and management of IEM confined to neonates. objective of the article is relatable. Literature review done properly. Need for the study identified.

21. Diagnostic testing A .Single test - multiple diagnosis testing a. Plasma amino acid assay by high performance liquid chromatography (HPLC) b. Urine organic acid assay by gas chromatography and mass spectrometry (GCMS) c. Acyl carnitine and amino acid profile by tandem mass spectrometry (TMS)

22. . B . Single test - single diagnosis testing Biotinidase enzyme assay Galactosemia profile: Total galactose levels, galactose 1 phosphate levels, and GALT enzyme assay

23. Diagnostic testing Specialized Testing - CSF is indicated in refractory seizures. Molecular Diagnosis- First generation sequencing (Sanger sequencing) or next generation sequencing (whole exome or whole genome sequencing) can be utilized. It is essential for genetic counseling and prenatal diagnosis in the future pregnancy. MRI with MRS

24. Balakrishnan U. Inborn Errors of Metabolism-Approach to Diagnosis and Management in Neonates. Indian J Pediatr . 2021 Jul;88(7):679-689. doi : 10.1007/s12098-021-03759-9. Epub 2021 Jun 7. PMID: 34097229.

25. Balakrishnan U. Inborn Errors of Metabolism-Approach to Diagnosis and Management in Neonates. Indian J Pediatr . 2021 Jul;88(7):679-689. doi : 10.1007/s12098-021-03759-9. Epub 2021 Jun 7. PMID: 34097229.

26. Management Emergency management is life saving. Components of emergency treatment include supportive and specific therapy

27. Supportive Therapy Majority of IEM presenting in neonatal period would require mechanical ventilation. Care should be taken to correct electrolyte abnormality, dehydration, and temperature instability. Sepsis can coexist with IEM and mandates septic workup with antibiotics.

28. Specific therapy Balakrishnan U. Inborn Errors of Metabolism-Approach to Diagnosis and Management in Neonates. Indian J Pediatr . 2021 Jul;88(7):679-689. doi : 10.1007/s12098-021-03759-9. Epub 2021 Jun 7. PMID: 34097229.

29. Dietary Management of Neonate at Risk of IEM If the previous sibling had suspected intermediary metabolic disorder in the neonatal period, then the neonate should be started on intravenous dextrose infusion followed by expressed breast milk. Appropriate biochemical testing should be done in 24–48 h of life. If the results are within normal limits, they can be switched over to breast-feeding

30. Future Therapy Therapies including Gene therapy, Gene editing, Cell transplantation, and Cell programming have huge potential in the treatment of IEM

31. Outcome IEM presenting in neonatal period can lead to death and permanent disability. Universal NBS could be a way forward to prevent disabilities. Even in a country where extended NBS is being practiced, IEM remains as one of the causes for treatable intellectual disability.

32. Balakrishnan U. Inborn Errors of Metabolism-Approach to Diagnosis and Management in Neonates. Indian J Pediatr . 2021 Jul;88(7):679-689. doi : 10.1007/s12098-021-03759-9. Epub 2021 Jun 7. PMID: 34097229.

33. Balakrishnan U. Inborn Errors of Metabolism-Approach to Diagnosis and Management in Neonates. Indian J Pediatr . 2021 Jul;88(7):679-689. doi : 10.1007/s12098-021-03759-9. Epub 2021 Jun 7. PMID: 34097229.

34. Conclusion IEM are individually rare, but collectively common. High index of suspicion is essential for the diagnosis. Algorithmic approach helps to clinch the diagnosis. It is important to identify as majority of group 1 disorders are treatable. Estimation of ammonia and baseline investigation in any sick neonate increases the detection rate. Molecular diagnosis is essential for genetic counseling and prenatal diagnosis of future pregnancy. The four main principles of management, namely substrate reduction, providing deficient metabolite, disposal of toxic metabolites, and increasing the enzyme activity can be applied to majority of treatable IEM.

35. References Garrod A. The incidence of alkaptonuria : a study in chemical individuality . Lancet. 1902;160:1616–20. 2. Sanderson S, Green A, Preece MA, Burton H. The incidence of inherited metabolic disorders in the West Midlands, UK. Arch Dis Child. 2006;91:896–9. 3. Illsinger S, Das AM. Impact of selected inborn errors of metabolism on prenatal and neonatal development. IUBMB Life. 2010;62:403– 13. 4. van Karnebeek CDM, Stockler S. Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab . 2012;105:368–81. 5. Saudubray J-M, Garcia- Cazorla À. Inborn errors of metabolism overview: pathophysiology, manifestations, evaluation, and management . Pediatr Clin N Am. 2018;65:179–208. 6. Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics . 1998;102:E69. 7. MacDonald A, Depondt E, Evans S, et al. Breast feeding in IMD. J Inherit Metab Dis. 2006;29:299–303. 8. Saudubray J-M, Sedel F, Walter JH. Clinical approach to treatable inborn metabolic diseases: an introduction. J Inherit Metab Dis. 2006;29:261–74. 9. Morton DH, Strauss KA, Robinson DL, Puffenberger EG, Kelley RI. Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics . 2002;109(6):999–1008. 10. Baumgartner MR, Hörster F, Dionisi -Vici C, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia . Orphanet J Rare Dis. 2014;9:130. 11. Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. 12. Enns GM. Inborn errors of metabolism masquerading as hypoxicischemic encephalopathy. Neoreviews . 2005;6:e549–58.

36. Critiquing research article Author followed “IMRAD” structure ? YES I – Introduction M-Methods R-Results D-Discussion Results presented in the form of tables. All medication used in study are identified . References are in vancouver style , number of references is large, all are verified against original documents.

37. . Thank you