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Clinical biochemistry

Clinical biochemistry. Dr Shahida Mushtaq LECTURE 2. IEM. a single gene defect causes a clinically significant block in a metabolic pathway resulting either in accumulation of substrate behind the block or deficiency of the product.

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Clinical biochemistry

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  1. Clinical biochemistry Dr ShahidaMushtaq LECTURE 2

  2. IEM • a single gene defect causes a clinically significant block in a metabolic pathway resulting either in accumulation of substrate behind the block or deficiency of the product

  3. IEM arises from a damaged gene which leads to abnormal enzyme. • May be autosomal or sex-linked. • May be recessive or dominant in expression. • Heterozygote will have both normal and abnormal alleles. But homozygote will have two alleles the same on each chromosome.

  4. Investigations • An accumulation of the substrate before the enzyme defect*. • A decrease in the amount of the product is observed. • An increased concentration of the alternative metabolites*. • A decrease or absence of the enzyme activity.

  5. Investigations • Screening for IEM who do not have the symptoms • Investigations of the patient with symptoms of the IEM

  6. Screening of newborn • It is the process of detecting a patient with an IEM before they show overt symptoms of the disease. • Allow the treatment to begin • Counseling to be given Screening is done for high risk group which includes • All newborn infants • Family of affected children • Expectant mothers who have history of affected children. (prenatal diagnosis)

  7. Screening should be done only if: • Suitable treatment for disease • Life threatening disease • High incidence of disease • A suitable test is available • Acceptable cost. • PKU • Congenital hypothyroidism Test to identify carriers of the disease

  8. Investigations of the suspected IEM • Failure to thrive • Poor feeding • Persistent vomiting • Unexplained jaundice • Unexplained hypoglycemia • Ketosis • Lactic acidosis • Convulsions and coma • Lethargy • Hypotonia • hyperventilation

  9. Some may present later (within first few years) • Abnormal liver function tests • Mental retardation • Front line tests • Plasma • Electrolytes • Acid base balance • Blood gases • Glucose • Liver function tests • calcium

  10. Follow up tests • Plasma • Insulin • Lactic acid • Ammonia • Ketones • Urine • Amino acids • Organic acids • Sugars

  11. Prenatal diagnosis • History of affected individual • Amniocentesis (15th week of gestation -20th week) fibroblast extracted from amniotic fluid. fibroblasts are cultured and specific enzyme studies are done • Cvs (9th week completed within 10 days) • DNA analysis (cystic fibrosis) • Down syndrome • Hemoglobinopathies • Taysachsdisaease

  12. Phenylketonuria • Autosomal recessive disorder • 1 in 15,000 live births in America. • Deficiency of phenylalanine hydroxylase

  13. Phenylketoneuria (PKU) Deficiency

  14. Laboratory Diagnosis of IEM May be carried out in three stages: • Diagnosis of Broad Category: Saudubrayet al (2002)* suggested a battery of simple and routine tests for identification of the broad category of the disorders. These tests include plasma electrolytes, ABGs, blood ammonia and lactic acid etc. *Saudubray JM, Nasoogne MC, Lonlay PD, Touati G. Clinical approach to inherited metabolic disorders in neonates: an overview. SminNeonatol 2002; 7: 3-15.

  15. Laboratory Diagnosis of IEM (cont) May be carried out in three stages: b. Diagnosis of the exact disorder • It requires very sophisticated equipment e.g. HPLC, tandem mass spectrometry, GC-MS and ion exchange chromatography.

  16. Laboratory Diagnosis of IEM (Cont) May be carried out in three stages: b. Diagnosis of the exact disorder (cont) • These techniques also require elaborate infrastructure of trained manpower, proper back-up service for the instruments and regular supply of reagents.

  17. Laboratory Diagnosis of IEM May be carried out in three stages: b. Diagnosis of the exact disorder (cont) • AKU hospital has taken an initiative to establish the first-ever lab in the country for the pin-point diagnosis of some of the IEM.

  18. Laboratory Diagnosis of IEM (Cont) May be carried out in three stages: c. Determination of deficient enzyme or proteinAlthough a few laboratories in the world provide this facility, this is only of academic and research interest. Diagnosis of the genetic defect provides another promising pathway for some of these disorders.

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