Emergency Management of Inborn Errors of Metabolism

1. Emergency Management of Inborn Errors of Metabolism Christian Schaaf, MD, PhD Department of Molecular and Human Genetics

2. History 1902 – Archibald Garrod describes alkaptonuria Over 300 diseases described to date Alkaptonuria – a deficiency of homogentisate 1,2-dioxygenase. See OCHRONOSIS, a bluish-black discoloration in connective tissue. Alkaptonuria – a deficiency of homogentisate 1,2-dioxygenase. See OCHRONOSIS, a bluish-black discoloration in connective tissue.

3. Mechanisms of Disease

4. Examples

5. Phenylketonuria (PKU) Deficiency of phenylalanine hydroxylase enzyme results in accumulation of phenylalanine causing intellectual disability

6. MCAD Deficiency Impaired ß–oxidation of fatty acids at times of fasting ? Ketone production Hypoglycemia Medium chain Acyl-CoA Dehydrogenase deficiency. Results in HYPOKETOTIC hypolgycemia Medium chain Acyl-CoA Dehydrogenase deficiency. Results in HYPOKETOTIC hypolgycemia

7. Homocystinuria Homocystinuria means increased excretion of homocysteine in the urine. This can be caused by various enzyme or cofactor deficiencies. Homocystinuria means increased excretion of homocysteine in the urine. This can be caused by various enzyme or cofactor deficiencies.

8. Clinical Presentation of Acute Metabolic Disorders Lethargy Poor feeding Vomiting Shock Acidosis Hyperammonemia Sepsis (real or perceived) Clinical presentation of metabolic disordersClinical presentation of metabolic disorders

9. More Presenting Symptoms of Metabolic Disorders Developmental Delay/ID – with or without regression “Cerebral Palsy” Recurrent episodes of vomiting/dehydration SIDS/near SIDS Seizures Focal neurologic signs/symptoms

10. Myopathy/cardiomyopathy Hepatomegaly/splenomegaly Acute decompensation after giving birth Dysmorphic features Etc.

11. Laboratory Evaluation of Metabolic Disorders Draw labs when acutely ill Electrolytes & ABG Glucose & UA for ketones Plasma ammonia Lactate Plasma amino acid analysis Urine organic acid analysis Plasma acylcarnitine profile

12. Plasma Ammonia UCDs typically 300-1000 mmol/l – associated with respiratory alkalosis Organic acidemias typically < 300 mmol/l – associated with a metabolic acidosis Liver disease Normal level when not acutely ill does not exclude these disorders

13. Electrolytes & ABG Acidosis associated with organic acidemias (not with urea cycle disorders!) Typically have an elevated anion gap May have elevated lactate Respiratory alkalosis seen with urea cycle disorders (hyperammonemia causes hyperpnea)

14. Glucose & Urine Ketones Hypoglycemia seen in: Fatty acid oxidation disorders (e.g. MCAD) No or inappropriately low ketones Glycogen storage diseases (von Gierke) ? Lactate, uric acid & triglycerides Disorders of fructose metabolism Elevated ketones

16. High Lactate Mitochondrial/ox-phos disorders GSD Ia Organic acidemias Disorders of fructose metabolism Anything that causes poor perfusion (cardiomyopathy, sepsis, etc.)

17. Plasma Amino Acid Analysis Quantitative analysis by HPLC Normally present in blood at relatively constant levels Look at patterns Correlate with clinical situation Diagnosis of urea cycle disorders, Maple syrup urine disease and other amino acid disorders

18. Urine Organic Acid Analysis Qualitative analysis by GC/MS Completely filtered by glomerulus Levels fluctuate in blood Diagnosis of organic acidemias and some fatty acid oxidation disorders

19. Acylcarnitine Profile Measures fatty acids conjugated to carnitine (C2-C18) by MS/MS Patterns/interpretation important Diagnosis of fatty acid oxidation disorders (e.g. MCAD) and some organic acidemias

20. The Downward Spiral

21. Questions What sort of diet promotes anabolism (high/low calorie)?

22. Questions What sort of diet promotes anabolism - high calorie Is there a commonly used, therapeutic hormone that promotes anabolism (i.e. storage of glycogen and fat and inhibits lipolysis, glycogenolysis and protein breakdown)?

23. Questions What sort of diet promotes anabolism - high calorie Is there a commonly used, therapeutic hormone that promotes anabolism (i.e. storage of glycogen and fat and inhibits lipolysis, glycogenolysis and protein breakdown)? Insulin!

24. Basic Principles of Acute Management Decrease intake of precursors to defective process of metabolism Make the patient anabolic -calories & insulin Fluid resuscitation Drugs, amino acids, vitamins to optimize defective enzyme/process Remove toxic metabolites - dialysis

25. Case 1 26 month old Caucasian girl Played hard 1 day PTA; awoke screaming in the night Difficult to awaken Taken to local doctors office Cold, clammy and diaphoretic Glucose 20

26. History & Physical Exam Birth history and development normal Family history unremarkable PE Weight & length 25-50% OFC 75-90% No HSM Neuro exam normal

27. Emergency Treatment Glucose at 8-10 mg/kg/min IVF Labs? D-glucose = dextrose Labs: e’lytes, lactate, pH – PAA, UOA, ACPD-glucose = dextrose Labs: e’lytes, lactate, pH – PAA, UOA, ACP

28. Lab Results Na+ 137; K+ 4.1; Cl- 108; HCO3- 16 pH 7.37 Urine 2+ ketones PAA – normal UOA – hexanoylglycine (C6) & suberylglycine (C8) Acylcarnitine profile - Anion gap – 13 (normal 8-12) For a BG of 20, urine ketones of only 2+ are inappropriately low. Anion gap – 13 (normal 8-12) For a BG of 20, urine ketones of only 2+ are inappropriately low.

29. Diagnosis: MCAD defDiagnosis: MCAD def

30. Diagnosis?

31. MCAD Deficiency

32. Chronic Treatment Eat frequently (no fasting) When ill, encourage sugared liquids Carnitine supplementation Carnitine 100 mg/kg/dayCarnitine 100 mg/kg/day

33. Case 2 2 day old FT male Home at 24 hours Mother noted decreasing oral intake and increasing lethargy FH – of European, Asian, Mexican and Syrian descent; 3 healthy sibs

34. Physical Exam PE Weight, length and OFC 75% Lethargic; deep breathing; no HSM; o/w normal Labs pH 7.08; pCO2 17 Na+ 150; K+ 4.9; Cl- 107; HCO3- 5 (gap 38) NH4 492 mmol/l (normal 0-60mmol/l) Lactate 2.2 (0.4-2.0)

35. Summary of Labs Metabolic acidosis with increased anion gap Hyperammonemia Differential Diagnosis? Urea cycle defect – but acidosis Organic aciduria – MMA, IVA, Proprionic AcUrea cycle defect – but acidosis Organic aciduria – MMA, IVA, Proprionic Ac

36. Emergency Treatment Make anabolic IV dextrose @ 8-10 mg/kg/min Insulin drip 0.05-0.1 U/kg/hr IVF & bicarb to correct acidosis No enteral intake or TPN until diagnosis IV Carnitine 100 – 200 mg/kg/d Labs? PAA, UOA, ACPPAA, UOA, ACP

37. More Labs PAA Glycine 558 µM (104-344 µM) Several values low

38. Acylcarnitine Profile

39. UOA

40. Diagnosis?

41. Propionic Acidemia

42. NAGS – N-acetyl-glutamate-synthetaseNAGS – N-acetyl-glutamate-synthetase

43. Chronic Treatment Formula & foods low in precursors (Valine, Isoleucine, Methionine & Threonine) Carnitine

44. Case 3 4 day old Hispanic boy 36 6/7 week gestation; uncomplicated pregnancy; D/C from LBJ DOL #3 Found to be lethargic EMS called and took to TCH ED Labs done Transferred to NICU for sepsis mgt

45. Physical Exam & Labs FH – unremarkable PE – comatose & hyperpneic otherwise unremarkable Na+ 139; K+ 4.1; Cl- 108; HCO3- 20 pH 7.54 Lactate 3 NH4 881 mmol/L (normal 0-60 mmol/L) – done 6 hours later in NICU – not done in ED Differential Diagnosis? Highly suspicious of a urea cycle disorderHighly suspicious of a urea cycle disorder

47. Emergency Treatment Make anabolic IV dextrose @ 8-10 mg/kg/min Insulin drip 0.05 - 0.1 U/kg/hr No enteral intake or TPN until diagnosis Hemodialysis to remove ammonia IV phenylacetate, benzoate & arginine Labs?

55. Chronic Treatment Low protein diet & special formula (Cyclinex) Citrulline supplementation Phenylbutyrate Follow measures of AA/protein nutrition Liver transplant

56. References

57. Thank you!