Approach to Inborn error of metabolism.pptx

How to approach a newborn with suspected iem.

1. Dr.ABHILASH SAHOO JR2 PAEDIATRICS APPROACH TO INBORN ERROR OF METABOLISM

2. BACKGROUND TO UNDERSTAND THE GRAVITY

3. CLASSIFICATION OF PRESENTATION Encephalopathy without metabolic acidosis: Ureacycle defects, nonketotic hyperglycinemia, defects inbranched chain aminoacids like maple syrup urine disease(MSUD), peroxisomal disorders, molybdenumcofactor deficiency, and pyridoxine dependent seizures. Encephalopathy with metabolic acidosis: Organic acidemias, congenital lactic acidosis, dicarboxylicaciduria.

4. . Hepatic involvement with or without hepatocellular dysfunction : Aminoacidopathies like tyrosinemia, fatty acid oxidation defects, mitochondrial defects, disorders of carbohydrate metabolism like glycogen storage disorders, hereditary fructose intolerance, galactosemia Cardiac manifestations Glycogen storage disease type II, Fatty acid oxidation defects

5. 3 STEPS Suspect Evaluate Manage Emergency

6. WHEN SHOULD WE SUSPECT?

7. Rapid deterioration of general condition and/ or reduced consciousness, particularly when preceded by vomiting, fever, fasting Nonspecific, unexplained findings of sepsis, poor feeding, drowsiness, lethargy, hypotonia, failure to thrive, abnormal breathing,seizures and jaundice in the presence of normal sepsis screen. Rapidly progressive encephalo pathy of unknown etiology& Family history of neonatal death (“sepsis” or“SIDS”) or parental consanguinity treatment for patients with an inborn error of& Intractable hiccupsmetabolism (IEM) are prevention of further& Apnea or respiratory distress Sepsis, particularly with E. coli Dysmorphic features (in very few IEMs) Metabolic acidosis, Hyperammonemia, Peculiar.odor*[*musty—phenylketonuria; cabbage like—tyrosinemia; maple syrup—maple syrup urine disease.; sweaty feet—isovaleric academia, glutaricacidemia type II; cat urine—3-methylcrotonyl CoAphases:carboxylase and multiple carboxylase deficiencies]

8. Evaluation and Emergency Hypoto nia and seizures. Disorders of glucose, protein and fat fat breakdown (intermediary metabolism) in the neonatal period, asymptomatic,second day of life, although hyperammonemia due to transient hyperammonemia of newborn may present on day 1 of life. A quick history including family history (previous sib death due to sepsis, SIDS, or unexplained disorders like progressive neurological disease, multiple miscar riages,history suggestive of HELLP syndrome etc. PICU

9. Patient present s to picu with re current vomiting, lethargy progressing to coma without any focal neurological signs. They may also have had episodic problems associated with minor illnesses or may just have failure to thrive and developmental delay. nonspecific findings like lethargy, coma,

10. likeapnea or hyperpnea, seizures, hypotonia etc. vomiting,Presence of facial dysmorphism, cataract, reti nopathy, structural brain anomalies, hypertrophic or dilated cardiomyopathy, hepatomegaly, multicystic dysplastic kidneys, myopathy and peculiar odour & Rapidly progressive encephalopathy of unknownodor can give clue towards a specific diagnosis. accumulation of harmful substances, correction

11. of metabolic abnormalities, and elimination of toxic metabolites. Even the apparently stable patient with mild symptoms may deteriorate With appropriate therapy, patients may com pletely recover without sequelae. rapidly with progression to death within hours

12. SCREENING The initial screening investigations can be done in two phases.

13. (B) Initial Screening : CBC: Neutropenia in some organic acidemia Electrolyte/ABG: metabolic acidosis and anion gap Glucose: To rule out hypoglycaemia. CRP, CPK, LFT, RFT Ammonia: Rapidly flowing fasting blood arterial or venous, ice packed,done within 1 h Neonate> 200 micromol/L, Then> 100micromol/L. Uric acid: Low in molybdenumfactor deficiency

14. Lactate, Pyr uvate : Elevated in IEM Normal Lactate/Pyruvate ratio <25( use arterial sample) SPECIFIC TESTS: Plasma aminoacids specific Urinary ketones : unusual even in sick neonates Ferric Chloride for ketoacids(positive in phenylketonuria, tyrosinemia, maple syrup urine disease, tyrosinemia, histidinemia, alkaptonuria) Cyanide Nitroprusside test disulphide (positive in cystinutia and homocystinuria)

15. Urine organic acids : 10-20 ml of urine at -20*C in air tight container obtain during illness only TMS: dried blood spot for TMS, EDTA sample for DNA analysis, freeze 1-2 ml of plasma If Lumbar Punctured, then CSF should be frozen immediately

16. GENERAL TREATMENT PROTOCOL

17. Eliminate Protein, fat, galactose, fructose. AVOID RINGER’S LACTATE C ALORIE : High carbs D10% in 0.2% NaCl at 1.5 * maintainance. Add KCl after urine output Start 60Kcal/kg/ day (120 ml/kg/day) maxm 150 Kcal/ kg/day. PROTEIN : Restrictions for maximum 3 days. If patient is undiagnosed but improving, add essential amino acids @0.5 g protein/ kg/24h maxm 1g/kg/24h until final diagnosis. If Fatty acid oxidation defects ruled out add IV lipids.

18. SPECIFIC THERAPY

19. EXCRETION OF TOXIC METABOLITE: by alternate pathway, add Carnitinine in organic acidemia s, Sodium benzoate and phenylacetate in hyperammonemia In encephalopathy due to urea cycle defect, add Sodium Benzoate, load 250 mg/kg (5.5 g/m ) or Sodium Phenylacetate, load 250 mg/kg (5.5 g/m) as priming doses 20 ml/kg of 10% glucose over 1-2 hr only by CENTRAL LINE. Maintainance:Benzoate & Phenylacetate 250-500mg/kg/24h,

20. Hyperammonemia without acidosis: Infuse 200-600 mg/kg 10% arginine HCL IV stat over 60 min then 1.5 ml/kg QID. Dose decreased to 200 mg/kg in CPS or OTC deficiency. Maintainance : 200-600 mg/kg/24 h as 1% solutions NEVER COMBINE L- CARNITINE WITH BENZOATE and PHENYLACETATE. ALL IV Doses of 3 reagent is same as oral doses.

21. INDICATIONS OF DIALYSIS If Ammonia rises 4 times the normal limit Comatose Ventilatior-dependent Evidence of Cerebral edema Severly acidotic neonates irrespective of Ammonia levels Alternative of dialysis : Double volume exchange transfusion till dialyser available Optimum Dialysis duration: 2-3 days

22. B Correction of HAGMA : Infuse HCO3- only when <10 mmol/L i. e sodabicarb 0.25 mEq/ kg/ h max 2mEq/kg/h , correct only half of deficit. C CORRECT HYPOGLYCEMIA: 10% glucose with electrolytes (110–150 ml/kg/d)—8–12 mg/kg/min IV at 1–1.5 times maintenance to maintain serum glucose level at 120–170 mg/dL

23. .Avoid hypotonic fluid load due to the risk of cerebral e dema, particularly if hyperammonemia is present. If necessary, treat hyperglycemia with insulin (0.2 – 0.3 U/kg/h).

24. D) RESIDUAL ENZYME ACTIVITY If Binding constant of defective enzyme is altered : consider empiric vitamin therapy until the disorder is diagnosed

25. L-carnitine at 100–200 mg/kg tid given po/ng 25–50 mg/kg IV over 2–3 min or as infusion,followed by 25–50 mg/kg/d (maximum 3 g/d) may be administered empirically in life-threatening carnitine deficiency.

26. E. Treat shock, electrolyte imbalance, infection and coagulopathies

27. F.Nonacidotic, Nonhyperammonemic Seizures Pyridoxine 100–200 mg IV trial. If,response (pyridoxine responsive seizures), If responded give 10–100 mg of pyridoxine po qd. It should be given to neonates with seizures unresponsive to conventional anticonvulsants 2. Riboflavin 200–300 mg tid po qd (glutaric acidemia type I). 3. High dose benzodiazepines, sodium benzoate in.(nonketotic hyperglycinemia).

28. If undiagnosed yet Send specific test like acylcarnitine Review clinical signs and history Monitor glucose, electrolyte, lactate, acid- base status

29. Definitive test

30. carnitine, acylcarnitines (TMS), Urine organic acids by Gas Chromatography mass Spectroscopy (GCMS),very long chain fatty acids, lysosomal enzymes, etc or DNA testing is required. It may be necessary gor ,biopsy tissues such as liver or muscle. Genetic Counseling

31. Post Mortem S pecimen Clean and Efficient Energy Sys : (a) S AVE : Serum and plasma (centrifuge about 10 ml) Dried blood spot on filter paper card used for TMS0 Freeze 20–30 ml of urine at −20 °C EDTA blood (3-5 ml) for future DNA analysis Skin biopsy for fibroblast culture

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