Inborn Errors of Metabolism biochemistry.pptx

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1. Inborn Errors of Metabolism & Newborn Screening Dr. Sucharita Mohanty

2. Inborn Errors of Metabolism Inborn errors of metabolism occur in 1 out of 2500 births.  50% of all inborn errors present outside of the neonatal period, and some are not diagnosed until adulthood.

3. Inborn Errors of Metabolism Inherited disorders caused by mutations in genes coding for proteins (enzyme/transporter)/cofactors that function in metabolism.  Most are inherited as autosomal recessive.  Rarely,  they are autosomal dominant and X-linked.  Environmental , epigenetic , and microbiome factors and additional genes are potential modifying etiologic factors

4. Inborn Errors of Metabolism If not treated timely some of the metabolic disorders can lead to severe life threatening condition. Sir Archibald Garrod coined the word “Inborn Errors of Metabolism” in 1909 Garrod’s tetrad Alkaptonuria Albinism Pentosuria Cystinuria

5. How to Suspect a Metabolic Disorder? In an otherwise healthy newborn if you see the followings Catastrophic Neonatal Presentation Biochemical Disturbances Liver Disease or Dysfunction Neurologic Features Cardiac Features Skin, Eye Symptoms Coarse Facies Signs of a Storage Disorder

6. Metabolic Pathophysiology Accumulation of substrate Accumulation of precursors Redirection of substrate into alternative pathways Deficiency of products Deficiency of subsequent products Secondary effects by any of the above on unrelated pathways

7. Classification of Inborn Errors of Metabolism 1. Carbohydrate Metabolism Galactosemia Lactose Intolerance Lactic Acidosis Glycogen Storage Diseases Fructose Intolerance Mucopolysaccharadoses 2. Amino Acid Metabolism Aminoacidopathies Organic acidurias Urea Cycle Defects 3. Lipid Metabolism Fatty Acid Oxidation Defects Sphingolipidoses

8. Inborn Errors of Metabolism Diseases that result in errors of metabolizing and breaking down food will often cause hypoglycemia . Patients with severe errors in carbohydrate metabolism present early (typically in the neonatal period) and catastrophically.

9. Inborn Errors of Metabolism Pathophysiology Diseases that interfere with excretion of metabolites will cause intoxication (i.e., hyperammonemia ). The patients present with lethargy and altered mental status, seizures, vomiting, and vital sign abnormalities . Diseases that interfere with fatty acid oxidation result in hypoglycemia and acidosis.

10. Inborn Errors of Metabolism Most children with inborn errors of metabolism will have an elevated lactate level, hypoglycemia , hyperammonemia , or acidosis on blood testing, or ketonuria/elevated urinary reducing substances on urine testing.  

11. Importance of Early Detection Treatment may prevent irreversible clinical consequences or death, e.g. phenylketonuria (PKU), galactosemia, and maple syrup urine disease (MSUD). In some conditions, a definite diagnosis will either prevent further ill effects or a precipitating factor can be avoided. Examples: familial hypercholesterolemia, glucose phosphate dehydrogenase (GPD) deficiency, acute porphyrias, cystinuria, hemochromatosis.

12. Inborn Errors of Metabolism Biochemical Diagnosis Diagnosis and Treatment Monitoring of IEM: Analysis of Metabolites Analysis of Enzyme Activity &/ Analysis of DNA sequence

13. Newborn Screening Newborn Screening helps in Early detection so that there can be early intervention which can either eliminate/ reduce Morbidity, mortality & disability.

14. Newborn Screening The disease to be screened must be serious fairly common have a natural history that is understood have helpful treatment & genetic counselling available The screening test must be Acceptable Reliable Valid Affordable

15. IEM for which Newborn Screening Available in India Congenital hearing loss, C ongenital hypothyroidism, C ongenital adrenal hyperplasia (CAH), G lucose-6-phosphate dehydrogenase (G6PD) deficiency C ystic fibrosis B iotinidase deficiency and a few more metabolic conditions.

16. Benefits of NBS Congenital hearing loss is an important condition and if not tackled before 6 months of age, may lead to permanent hearing and speech impairment. Congenital hypothyroidism is also a common occurrence in babies and one of the preventable causes of intellectual disability.”

17. Benefits of NBS “Congenital adrenal hyperplasia, if undetected at birth, can cause mortality, morbidity or genital abnormalities.  G6PD deficiency can cause anemia and jaundice in children 

18. Benefits of NBS Early diagnosis of cystic fibrosis through neonatal screening  prevents severe malnutrition and improves long-term growth . Early d etection and treatment of Biotinidase deficiency can prevent health problems such as hair loss, skin rash, and even seizures .If treated early, children with this condition can have healthy growth and development.