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Inborn Errors of Metabolism A Hospitalist’s Approach Erich C. Maul, DO, FAAP Assistant Professor of Pediatrics Section of Inpatient Pediatrics Kentucky.

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Presentation on theme: "Inborn Errors of Metabolism A Hospitalist’s Approach Erich C. Maul, DO, FAAP Assistant Professor of Pediatrics Section of Inpatient Pediatrics Kentucky."— Presentation transcript:

1 Inborn Errors of Metabolism A Hospitalist’s Approach Erich C. Maul, DO, FAAP Assistant Professor of Pediatrics Section of Inpatient Pediatrics Kentucky Children’s Hospital University of Kentucky College of Medicine

2 Objectives Understand grand concepts of metabolic diseases and inborn errors of metabolism (IEM) in infants Understand grand concepts of metabolic diseases and inborn errors of metabolism (IEM) in infants Raise clinical suspicion for these diseases Raise clinical suspicion for these diseases Form conceptual framework for initial diagnosis and management of IEM in infants Form conceptual framework for initial diagnosis and management of IEM in infants Briefly discuss Newborn Screens Briefly discuss Newborn Screens

3 Why this talk? Metabolic disease is tough Metabolic disease is tough

4 However, for me… Copyright Roche Diagnostics GmbH, 1993, used with permission

5 Why this talk? Metabolic disease is tough Metabolic disease is tough Often thought of later in illness Often thought of later in illness With catastrophic outcomes With catastrophic outcomes There can be a simple construct that can help standardize the approach to uncovering metabolic disease There can be a simple construct that can help standardize the approach to uncovering metabolic disease

6 IEM’s in General Mostly due to defect in or absence of an enzyme, cofactor or transport protein resulting a block in a specific metabolic pathway Mostly due to defect in or absence of an enzyme, cofactor or transport protein resulting a block in a specific metabolic pathway Generally single gene defects Generally single gene defects Involve all inheritance patterns, however, most common is autosomal recessive Involve all inheritance patterns, however, most common is autosomal recessive Common defects on a biochemical level Common defects on a biochemical level Transport defects Transport defects Accumulation of substrate Accumulation of substrate Deficiency of product Deficiency of product Secondary inhibition Secondary inhibition

7 A ABC D negative EF Apoenzyme + cofactor What can go wrong? Molecule A needs to enter the cell via a transport protein. If A can’t enter cell because of defective transport protein then the rest of reactions are moot (transport defect) A goes to B, then B goes to C via enzymatic reactions. If the enzyme converting B to C is defective, B can back up and divert down alternate pathways to D. Also, if the apoenzyme and cofactors that form the enzyme converting B to C are defective, B backs up and diverts down alternate paths again to D (accumulation of substrate) Let’s suppose C has negative feedback inhibition of reaction A to B. If C is not present because the enzyme to make B to C is defective, B accumulates and further shunts down alternate pathways to D. (deficiency of product) Let’s consider secondary inhibition. Let’s look at the reaction of E to F. The primary defect is in the conversion of B to C, but as B backs up and diverts down the path to D, D acts as an inhibitor on the enzyme converting E to F. Let’s consider molecule A sitting outside a cell Modified from Clarke, 2002, Cambridge University Press, used with permission

8 IEM’s in General Individually-very rare, Collectively-very common Individually-very rare, Collectively-very common More than 500 identified IEM’s More than 500 identified IEM’s Include amino acidopathies, fatty acid oxidation defects, organic acidemias, urea cycle defects, carbohydrate metabolism defects, peroxisomal disorders, lysosomal disorders, mitochondrial disorders Include amino acidopathies, fatty acid oxidation defects, organic acidemias, urea cycle defects, carbohydrate metabolism defects, peroxisomal disorders, lysosomal disorders, mitochondrial disorders Newborn Screening has been lifesaving Newborn Screening has been lifesaving Variable presentations Variable presentations Mild to severe Mild to severe Subtle to overt Subtle to overt

9 IEM’s in General Generally present in newborn period or shortly thereafter Generally present in newborn period or shortly thereafter Typically at end of 1 st week of life Typically at end of 1 st week of life This will be the focus of this talk This will be the focus of this talk Key to finding IEM’s is not a detailed knowledge of biochemical pathways, but a HIGH INDEX OF SUSPICION in any critically ill neonate Key to finding IEM’s is not a detailed knowledge of biochemical pathways, but a HIGH INDEX OF SUSPICION in any critically ill neonate

10 When should I suspect IEM? When the obvious confronts you… When the obvious confronts you… POSITIVE STATE NEWBORN SCREEN POSITIVE STATE NEWBORN SCREEN Subject to false positives Subject to false positives Require confirmatory testing Require confirmatory testing State labs are helpful in guiding you through the process State labs are helpful in guiding you through the process More on this later More on this later ANY SICK NEWBORN ANY SICK NEWBORN However in IEM’s BP more easily maintained, acidosis unresponsive to fluids and respiratory support, cultures sterile However in IEM’s BP more easily maintained, acidosis unresponsive to fluids and respiratory support, cultures sterile

11 4 Common Presentations Encephalopathy with metabolic acidosis Encephalopathy with metabolic acidosis Encephalopathy without metabolic acidosis Encephalopathy without metabolic acidosis Neonatal hepatic syndrome Neonatal hepatic syndrome Non-immune fetal hydrops Non-immune fetal hydrops

12 Non-immune fetal hydrops Syndrome of severe anemia, congenital heart disease, and congenital infection Syndrome of severe anemia, congenital heart disease, and congenital infection IEM of RBC energy metabolism results severe anemia which leads to high-output heart failure IEM of RBC energy metabolism results severe anemia which leads to high-output heart failure G6PD deficiency, pyruvate kinase deficiency G6PD deficiency, pyruvate kinase deficiency Lysosomal storage diseases can be born with severe peripheral edema, which can have variable course Lysosomal storage diseases can be born with severe peripheral edema, which can have variable course Excrete and improve; worsen and die Excrete and improve; worsen and die Gaucher type 2, Niemann-Pick type C, GM1 gangliosidosis Gaucher type 2, Niemann-Pick type C, GM1 gangliosidosis

13 Neonatal Hepatic Syndrome Acute liver disease in the neonatal period delineated by: Acute liver disease in the neonatal period delineated by: Jaundice Jaundice Lasts longer than ‘run of the mill’ newborn pumpkin period Lasts longer than ‘run of the mill’ newborn pumpkin period Unconjugated primarily; later can see conjugated Unconjugated primarily; later can see conjugated Severe hepatic dysfunction Severe hepatic dysfunction Jaundice, hypoglycemia, hyperammonemia, elevated transaminases, ascites/anasarca, coagulopathy Jaundice, hypoglycemia, hyperammonemia, elevated transaminases, ascites/anasarca, coagulopathy Persistent hypoglycemia without overt evidence of hepatocellular dysfunction Persistent hypoglycemia without overt evidence of hepatocellular dysfunction

14 Encephalopathy Without acidosis Without acidosis Most commonly after hypoxic- ischemic insult Most commonly after hypoxic- ischemic insult IEM’s like this generally have a period of normalcy and no history of birth trauma, then encephalopathy IEM’s like this generally have a period of normalcy and no history of birth trauma, then encephalopathy 6 prototypical IEM’s 6 prototypical IEM’s MSUD, urea cycle defects, nonketotic hyperglycinemia, pyridoxine dependent seizures, peroxisomal disorders, molybdenum cofactor defect MSUD, urea cycle defects, nonketotic hyperglycinemia, pyridoxine dependent seizures, peroxisomal disorders, molybdenum cofactor defect With acidosis With acidosis Typically well until 3-5 days of life Feeding difficulties arise along with tachypnea, increased work of breathing and encephalopathy CXR is normal and blood gas show metabolic acidosis Renal loss of bicarbonate is rare in term infant, but accumulation of unmeasured anion, ketones, or ammonium is common Prototypes are organic acidurias and congenital lactic acidosis

15 Summary of Presentations Extremis Extremis “He looks septic or near death” “He looks septic or near death” Encephalopathy Encephalopathy Hyperammonemia Hyperammonemia Metabolic acidosis Metabolic acidosis Ketosis Ketosis Abnormal liver enzymes/function Abnormal liver enzymes/function Hypoglycemia Hypoglycemia

16 Alright, I suspect it, now how do I work it up? ABC’s, O 2, IV, MONITOR ABC’s, O 2, IV, MONITOR Mantra of PALS Mantra of PALS Brief history and directed physical Brief history and directed physical Remember differential of critically ill neonate Remember differential of critically ill neonate Eliminate intake and production of toxic metabolite Eliminate intake and production of toxic metabolite Accelerate removal of toxic metabolite Accelerate removal of toxic metabolite Cautiously correct acidosis Cautiously correct acidosis Investigate cause Investigate cause

17 History and Physical Period of normalcy, rapidity of onset, consanguinity, FHx of neonatal death, odd odor to infant, birth hx Period of normalcy, rapidity of onset, consanguinity, FHx of neonatal death, odd odor to infant, birth hx Subtle signs or symptoms Subtle signs or symptoms Feeding difficulty, odd cry, vomiting, diarrhea, tachypnea, dyspnea, hypotonia/hypertonia, tachycardia, mental status changes Feeding difficulty, odd cry, vomiting, diarrhea, tachypnea, dyspnea, hypotonia/hypertonia, tachycardia, mental status changes Overt signs or symptoms Overt signs or symptoms Persistent hypoglycemia, acidosis, dehydration, shock, apnea, seizures, abnormal mental status, temperature instability, arrhythmia, cardiomyopathy, sudden death Persistent hypoglycemia, acidosis, dehydration, shock, apnea, seizures, abnormal mental status, temperature instability, arrhythmia, cardiomyopathy, sudden death Dysmorphic features, strange odor, signs of abuse, rashes, jaundice, organomegaly Dysmorphic features, strange odor, signs of abuse, rashes, jaundice, organomegaly

18 Differential Diagnosis of Critically Ill Neonate Sepsis, sepsis, sepsis, sepsis Sepsis, sepsis, sepsis, sepsis E. coli, Listeria spp., S. agalactiae (GBS), HSV E. coli, Listeria spp., S. agalactiae (GBS), HSV Abuse Abuse Congenital heart disease Congenital heart disease Congenital adrenal hyperplasia Congenital adrenal hyperplasia IEM IEM

19 Critical Interventions Eliminate toxin Eliminate toxin NPO and eliminate protein NPO and eliminate protein IV glucose IV glucose 2-4mL/kg D10W-D25W; may need glucagon 2-4mL/kg D10W-D25W; may need glucagon 8-10 mg/kg/min D10W; may need higher infusions 8-10 mg/kg/min D10W; may need higher infusions If acidosis worsens, suspect pyruvate dehydrogenase deficiency If acidosis worsens, suspect pyruvate dehydrogenase deficiency Consider hemodialysis for hyperammonemia, along with arginine, and Na benzoate/phenacetate/phenylbutyrate Consider hemodialysis for hyperammonemia, along with arginine, and Na benzoate/phenacetate/phenylbutyrate Consider pyridoxine, biotin, B12, carnitine Consider pyridoxine, biotin, B12, carnitine

20 Critical Interventions Correct acidosis, which may be difficult Correct acidosis, which may be difficult Attempt to stop production of metabolite Attempt to stop production of metabolite Frequent evaluation of acid-base status and gauge bicarbonate administration off that Frequent evaluation of acid-base status and gauge bicarbonate administration off that Since toxic metabolite is usually still being produced, can be difficult to control acid-base status Since toxic metabolite is usually still being produced, can be difficult to control acid-base status Consider hemodialysis for severe acidosis, especially if concurrently hyperammonemic Consider hemodialysis for severe acidosis, especially if concurrently hyperammonemic Address additional electrolyte abnormalities Address additional electrolyte abnormalities

21 Critical Interventions Initial laboratory work-up Initial laboratory work-up CBC, blood culture CBC, blood culture CMP, lactate, pyruvate, ammonia CMP, lactate, pyruvate, ammonia ABG ABG PT/PTT PT/PTT UA, urine culture, reducing substances UA, urine culture, reducing substances CSF studies if stable CSF studies if stable Routine studies plus lactate and amino acids Routine studies plus lactate and amino acids Secondary labs Secondary labs Repeat initial Carnitine/acylcarnitine profile Serum amino acids Urine organic acids Urine amino acids Urine acylglycines

22 Take a breath Now that the child is being stabilized and labs are coming back, you can actively think about your data and find out what is wrong with your patient Now that the child is being stabilized and labs are coming back, you can actively think about your data and find out what is wrong with your patient A consult by phone to a biochemical geneticist or a metabolic medicine specialist is a critical portion of patient care A consult by phone to a biochemical geneticist or a metabolic medicine specialist is a critical portion of patient care A Clinical Guide to Inherited Metabolic Diseases by JTR Clarke, is a great, simple text with many excellent algorithms to help figure out IEM’s, as is Rudolph’s Pediatrics A Clinical Guide to Inherited Metabolic Diseases by JTR Clarke, is a great, simple text with many excellent algorithms to help figure out IEM’s, as is Rudolph’s Pediatrics See references See references

23 Broad Generalizations aka Board Generalizations Hyperammonemia without acidosis Hyperammonemia without acidosis Urea cycle enzyme defect (UCED) Urea cycle enzyme defect (UCED) Hyperammonemia with acidosis or anion gap Hyperammonemia with acidosis or anion gap Organic acidemia Organic acidemia With ketones=fatty acid oxidation defect With ketones=fatty acid oxidation defect Elevated lactate=organic acidemia Elevated lactate=organic acidemia Metabolic acidosis with normal ammonia Metabolic acidosis with normal ammonia Organic acidemia, oxidation disorders, carbohydrate diseases Organic acidemia, oxidation disorders, carbohydrate diseases Normal ammonia and acid base status Normal ammonia and acid base status Aminoacidopathy, galactosemia Aminoacidopathy, galactosemia

24 IEM’s in Older Children Paroxysmal stupor, vomiting Paroxysmal stupor, vomiting Especially during periods of fasting Especially during periods of fasting Tend to be disorders of carbohydrate metabolism or mucopolysaccharidoses, mucolipidoses, or glycoproteinoses Tend to be disorders of carbohydrate metabolism or mucopolysaccharidoses, mucolipidoses, or glycoproteinoses Failure to thrive Failure to thrive Organomegaly, neuromotor delay, macrocephaly Organomegaly, neuromotor delay, macrocephaly Dysmorphic features Dysmorphic features Labs are the same as for infant, however include karyotype and possible additional genetic studies Labs are the same as for infant, however include karyotype and possible additional genetic studies

25 Newborn Screening Basic concept Basic concept Goal is to detect diagnostic markers of metabolic disease in asymptomatic infants Goal is to detect diagnostic markers of metabolic disease in asymptomatic infants Disease should be frequent enough to have a favorable cost-benefit ratio Disease should be frequent enough to have a favorable cost-benefit ratio Should screen for diseases we can do something for, i.e., therapy available Should screen for diseases we can do something for, i.e., therapy available Low false positive and false negative rates Low false positive and false negative rates

26 Newborn Screening What started with PKU… What started with PKU… KY screens for 29 different IEM’s as of 2005 KY screens for 29 different IEM’s as of 2005 Supplemental Newborn Screens Supplemental Newborn Screens >50 additional screening tests via tandem mass spectrometry >50 additional screening tests via tandem mass spectrometry Specific screens differ by states Specific screens differ by states Know what your state screens for and how to follow- up abnormal screens Know what your state screens for and how to follow- up abnormal screens

27 KY Newborn Screens Disorders of Amino Acid Metabolism: 1. Phenylketonuria (PKU) 2. Maple Syrup Urine Disease (MSUD) 3. Homocystinuria (HCY) 4. Citrullinemia (CIT) 5. Arginosuccinic acidemia (ASA) 6. Tyrosinemia type 1 (TYR 1) Disorders of Fatty Acid Oxidation 7. Medium chain acyl-CoA dehydrogenase deficiency (MCAD) 8. Very long chain acyl-CoA dehydrogenase deficiency (VLCAD) 9. Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) 10. Short-chain acyl-CoA dehydrogenase deficiency (SCAD) 11. Trifunctional protein deficiency (TFP) 12. Carnitine uptake defect (CUD) Disorders of Organic Acid Metabolism 13. Isovaleric acidemia (IVA) 14. Glutaric acidemia type 1 (GA 1) hydroxy-3-methyl glutaric aciduria (HMG) 16. Multiple carboxylase deficiency (MCD) 17. Methylmalonic acidemia (Cbl A, B) 18. Methylmalonic acidemia mutase deficiency (MUT) 19. Propionic Acidemia (PA) 20. β-ketothiolase deficiency (BKT) Methylcrotonyl-CoA carboxylase deficiency Hemoglobinopathies 22. Sickle Cell Disease 23. Hemoglobin SC Disease 24. Hemoglobin S/β-thalassemia Others 25. Galactosemia 26. Biotinidase deficiency 27. Congenital Adrenal Hyperplasia (CAH) 28. Cystic Fibrosis (CF) 29. Congenital Hypothyroidism (CH)

28 Summary Suspect these with ill neonates Suspect these with ill neonates Don’t get bogged down in biochemistry Don’t get bogged down in biochemistry ABC, O2, IV, monitor ABC, O2, IV, monitor Correct metabolic problems Correct metabolic problems Ask for help i.e., a biochemical geneticist Ask for help i.e., a biochemical geneticist

29 References Burton, BK Inborn Errors of Metabolism in Infancy: A Guide to Diagnosis. Pediatrics 102(6) e69 Burton, BK Inborn Errors of Metabolism in Infancy: A Guide to Diagnosis. Pediatrics 102(6) e69 Clarke, JTR A Clinical Guide to Inherited Metabolic Diseases, 2 nd Edition, Cambridge University Press Clarke, JTR A Clinical Guide to Inherited Metabolic Diseases, 2 nd Edition, Cambridge University Press Claudius, I., et al The Emergency Department Approach to Newborn and Childhood Metabolic Crisis. Emergency Medicine Clinics of North America 23, Claudius, I., et al The Emergency Department Approach to Newborn and Childhood Metabolic Crisis. Emergency Medicine Clinics of North America 23, Colletti, JE, et al Unsuspected Neonatal Killers in Emergency Medicine. Emergency Medicine Clinics of North America 22, Colletti, JE, et al Unsuspected Neonatal Killers in Emergency Medicine. Emergency Medicine Clinics of North America 22, Lieh-Lei, MW Pediatric Acute Care, 2 nd Edition, Lippincott, Williams & Wilkins Lieh-Lei, MW Pediatric Acute Care, 2 nd Edition, Lippincott, Williams & Wilkins McInnes, R.R., et al Metabolic Disorders. IN: Rudolph’s Pediatrics, 21 st edition, C.D. Rudolph, et al., eds. Pp McInnes, R.R., et al Metabolic Disorders. IN: Rudolph’s Pediatrics, 21 st edition, C.D. Rudolph, et al., eds. Pp Raghuveer, TS, et al Inborn Errors of Metabolism in Infancy and Early Childhood: An Update. American Family Physician 73:11, Raghuveer, TS, et al Inborn Errors of Metabolism in Infancy and Early Childhood: An Update. American Family Physician 73:11,

30 Questions Erich Maul, DO, FAAP Kentucky Children’s Hospital 800 Rose St, Rm HA-415 Lexington, KY


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