Approach to Inborn Errors of Metabolism

1. Approach to Inborn Errors of Metabolism Dr Yaser A. Mohammad

2. Why did you choose this topic ?

3. 2 Cases • 2 yrs old boy KCO Ethylmalonic Aciduria. • Presenting with bronchopneumonia & Metabolic crisis. • Drowsy, acidotic breathing, tachycardic , BP & SPo2 maintained with O2. • BGA PH: 7.15 CO2: 2 HCO3: 12 BE: -15 RBS : 8 Lactate: 6.5 Ammonia : 40

4. 5 yrs old boy KCO Arginosuccinic Aciduria. • Presenting sleepy & vomiting after taking an overdose of his antiepileptics(phenobarbitone & Keppra) & missing 2-3 doses of his metabolic medicine. • Drowsy GCS 11-12 , HR 70, BP & SPo2 maintained in R.A. • BGA PH 7.43 PC02: 5 HCO3: 23 BE : -1.5 K : 1.9 RBS : 8 Ammonia 246

5. Outline • Brief description of types of IEM that have an acute presentation. • Approach to metabolic emergencies. • Diagnostic clues • Quiz

6. Organic Acid Disorders - Results from enzyme deficiencies in the pathway of Amino acids degradation. • Presentation with acidosis, hypoglycaemia lactic acidosis & hyperammonaemia. Ketosis may also occur. • Analysis of the urine for Organic Acids is the mainsty of the Dx. • E.g. Methylmalonic, Ethylmalonic & propionic Acidaemia. • Rx low protein diet, avoid catabolic state; high carbs feeds during illness & carnitine.

7. Urea Cycle Defect • Defect in the metabolism of Ammonia in the Urea Cycle, so high Ammonia. • Presentation : poor feeding, lethargy, convulsion, coma & Resp. alkalosis. • Difficult to Dx due to lack of biochemical abnormality apart of hyperammonaemia. • Treated as sepsis initially. • Dx with raised Plasma Amino Acids. • E.g. Ornithine transcarbomylase, Arginosuccinicaciduria. • Rx low protein diet, Na benzoate, phenylbutyrate & arginine. Avoid catabolic state.

8. Fatty acid oxidation defect • FA oxidised in skeletal muscle, heart & liver. • 4 enzymes inolved (Chain Acyl-CoA Dehydrogenase). • SCAD, MCAD, LCAD & VLCAD. • Presentation: Non-ketotichypoglycaemia, lethargy, siezures, myoglubiuria, mucsle weakness & cardiomyopathy. • Dx: Reye like illness ( hypoglycaemia, raised ALT & AST , no ketosis). Hyperammonaemia. • Dx: Acylcarnitine profile by tandem mass spectrometry. Urine O.A & skin fibroblasts enzyme assay. • Rx prevention of fasting stress & carnitine.

9. Mitochondrial DO • Have their own DNA & are derived from the ovum, so all mtDNA DO are mternally inherited. • Presentation: weakness, abnormal tone, opthalmoplegia, seizures, cadiomyopathy, liver failure. Lactic acidosis with normal glucose. • Dx enzyme analysis of fibroblast, muscle or liver biopsy. • E.g MELAS ( Mitochondrial Encephalopathy, Lactic acidosis & Stroke like episodes). MERRF ( Myoclonic Epilepsy with ragged red fibres)

10. Carbohydrate metabolism DO • Galactosaemia; GAL-1-PUT. Accumulatiomof GAL-1 phosphate damages liver , brain & kidney • Presentation: vomiting, hypoglycaemia, irritibilitysiezures, jaundice, hepatomegaly & cataracts.E.coli sepsis. • Dx enzyme assay in RBC. Urine: non-glucose reducing substance. • Rx Lactose & galactose free diet.

11. Carbohydrate metabolism DO • Glycogen Storage disease • Threre are several enzyme deficiencies that leads to glycogen accumulation. • Primarly affect liver, muscle or both. • Presentation : hypoglycaemia, hepatomegaly, lactic acidosis, weakness & cardiomyopathy. • Dx : enzyme assay of blood, liver or muscle biopsy. • Rx : avoidance of fasting, continuous overnight feeds & uncooked corn starch.

12. How IEM present? • Non-specific symptoms • Attributed to infection or sepsis • Routine blood tests could be normal • Suspect when lack of improvement with standard therapy. • Neontal screening.

13. Metabolic crisis • Metabolic crisis occur when there is build up of toxic metabolites. Triggers factors that increase catabolism: • Infection • Fasting • trauma • Surgery • Increase consumption of protein.

14. Clinical presentation • An acute presentation with multisystem involvement is strongly suggestive of an IEM. It can include: - Vomiting and anorexia or failure to feed. - Lethargy that can progress to coma. - Seizures, particularly intractable. - Rapid, deep breathing that can progress to apnea. - Hypothermia (related to illness, not specific to a particular metabolic pathway).

15. In one review of 53 patients who presented to an emergency department and were subsequently diagnosed with an IEM:- • 85 % had neurologic signs or symptoms. • 58 % had gastrointestinal signs or symptoms. • 51 % had both neurologic and gastrointestinal signs and/or symptoms.

16. investigations • Glucose • ABG • CBC, U &E, LFT • Urine: color, odor, dipstick & ketones • Ammonia • Lactate

17. Diagnostic clues

18. Diagnostic clues

19. Diagnostic clues

20. Immediate Mx • Fluid resuscitation • Treatment of hypogycaemia • Ventilation support • HCO3 for correction of acidosis ( rapid correction have adverse effect on CNS). • Empiric IV antibiotic • Stop oral feeding pending Dx. • Avoid catabolism by administration of IV D10% with electrolyte. 8-10mg/kg/min.

21. Provision of co-factors: • Pyridoxine: 100mg iv for uncontrolled seizures. • Cobalmine: (Vit B 12 1mg im) metabolic acidosis & suspected organic acidaemia. • Carnitine: (100 mg/kg per day in three divided doses either orally or IV) may be useful in patients with organic acidemias, fatty acid oxidation disordersorcarnitinedefeciency. • Biotin: 10 mg for neonate with recurrent seizures

22. Quiz

25. Summary • Optimal outcome of IEM depends on early recognition, diagnosis, treatment of metabolic decompensation. • Symptoms are non-specific • Initial investigation could give a clue to diagnosis pending more detailed ones. • management of metabolic decompensation must be initiated promptly to avoid long term sequele.

26. References • Inborn Errors of Metabolism overview & specific disorders by Paul Levy. Pediatrics in review vol 30. No. 4 April 2009. • Inborn errors of metabolism : metabolic emergencies. Uptodate, pediatrics. Reid Sutton.