Transcript Inborn Errors of Metabolism A Hospitalist`s Approach
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
Objectives
Understand grand concepts of metabolic diseases and inborn errors of metabolism (IEM) in infants Raise clinical suspicion for these diseases Form conceptual framework for initial diagnosis and management of IEM in infants Briefly discuss Newborn Screens
Why this talk?
Metabolic disease is tough
However, for me…
Copyright Roche Diagnostics GmbH, 1993, used with permission
Why this talk?
Metabolic disease is tough Often thought of later in illness With catastrophic outcomes There can be a simple construct that can help standardize the approach to uncovering metabolic disease
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 Generally single gene defects Involve all inheritance patterns, however, most common is autosomal recessive Common defects on a biochemical level Transport defects Accumulation of substrate Deficiency of product Secondary inhibition
A
What can go wrong?
negative
A B C D
Apoenzyme + cofactor
E F
Let’s consider secondary inhibition. Let’s look at the reaction of E to F. The 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) Modified from Clarke, 2002, Cambridge University Press, used with permission
IEM’s in General
Individually-very rare, Collectively-very common 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 Newborn Screening has been lifesaving Variable presentations Mild to severe Subtle to overt
IEM’s in General
Generally present in newborn period or shortly thereafter Typically at end of 1 st week of life 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
When should I suspect IEM?
When the obvious confronts you… POSITIVE STATE NEWBORN SCREEN Subject to false positives Require confirmatory testing State labs are helpful in guiding you through the process More on this later ANY SICK NEWBORN However in IEM’s BP more easily maintained, acidosis unresponsive to fluids and respiratory support, cultures sterile
4 Common Presentations
Encephalopathy with metabolic acidosis Encephalopathy without metabolic acidosis Neonatal hepatic syndrome Non-immune fetal hydrops
Non-immune fetal hydrops
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 G6PD deficiency, pyruvate kinase deficiency Lysosomal storage diseases can be born with severe peripheral edema, which can have variable course Excrete and improve; worsen and die Gaucher type 2, Niemann-Pick type C, GM1 gangliosidosis
Neonatal Hepatic Syndrome
Acute liver disease in the neonatal period delineated by: Jaundice Lasts longer than ‘run of the mill’ newborn pumpkin period Unconjugated primarily; later can see conjugated Severe hepatic dysfunction Jaundice, hypoglycemia, hyperammonemia, elevated transaminases, ascites/anasarca, coagulopathy Persistent hypoglycemia without overt evidence of hepatocellular dysfunction
Encephalopathy
Without acidosis Most commonly after hypoxic ischemic insult IEM’s like this generally have a period of normalcy and no history of birth trauma, then encephalopathy 6 prototypical IEM’s MSUD, urea cycle defects, nonketotic hyperglycinemia, pyridoxine dependent seizures, peroxisomal disorders, molybdenum cofactor defect 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
Summary of Presentations
Extremis “He looks septic or near death” Encephalopathy Hyperammonemia Metabolic acidosis Ketosis Abnormal liver enzymes/function Hypoglycemia
Alright, I suspect it, now how do I work it up?
ABC’s, O 2 , IV, MONITOR Mantra of PALS Brief history and directed physical Remember differential of critically ill neonate Eliminate intake and production of toxic metabolite Accelerate removal of toxic metabolite Cautiously correct acidosis Investigate cause
History and Physical
Period of normalcy, rapidity of onset, consanguinity, FHx of neonatal death, odd odor to infant, birth hx Subtle signs or symptoms Feeding difficulty, odd cry, vomiting, diarrhea, tachypnea, dyspnea, hypotonia/hypertonia, tachycardia, mental status changes Overt signs or symptoms 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
Differential Diagnosis of Critically Ill Neonate
Sepsis, sepsis, sepsis, sepsis E. coli , Listeria spp., S. agalactiae Abuse Congenital heart disease Congenital adrenal hyperplasia IEM (GBS), HSV
Critical Interventions
Eliminate toxin NPO and eliminate protein IV glucose 2-4mL/kg D10W-D25W; may need glucagon 8-10 mg/kg/min D10W; may need higher infusions If acidosis worsens, suspect pyruvate dehydrogenase deficiency Consider hemodialysis for hyperammonemia, along with arginine, and Na benzoate/phenacetate/phenylbutyrate Consider pyridoxine, biotin, B12, carnitine
Critical Interventions
Correct acidosis, which may be difficult Attempt to stop production of metabolite 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 Consider hemodialysis for severe acidosis, especially if concurrently hyperammonemic Address additional electrolyte abnormalities
Critical Interventions
Initial laboratory work-up CBC, blood culture CMP, lactate, pyruvate, ammonia ABG PT/PTT UA, urine culture, reducing substances CSF studies if stable Routine studies plus lactate and amino acids Secondary labs Repeat initial Carnitine/acylcarnitine profile Serum amino acids Urine organic acids Urine amino acids Urine acylglycines
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 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 See references
Broad Generalizations
aka Board Generalizations Hyperammonemia without acidosis Urea cycle enzyme defect (UCED) Hyperammonemia with acidosis or anion gap Organic acidemia With ketones=fatty acid oxidation defect Elevated lactate=organic acidemia Metabolic acidosis with normal ammonia Organic acidemia, oxidation disorders, carbohydrate diseases Normal ammonia and acid base status Aminoacidopathy, galactosemia
IEM’s in Older Children
Paroxysmal stupor, vomiting Especially during periods of fasting Tend to be disorders of carbohydrate metabolism or mucopolysaccharidoses, mucolipidoses, or glycoproteinoses Failure to thrive Organomegaly, neuromotor delay, macrocephaly Dysmorphic features Labs are the same as for infant, however include karyotype and possible additional genetic studies
Newborn Screening
Basic concept Goal is to detect diagnostic markers of metabolic disease in asymptomatic infants 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 Low false positive and false negative rates
Newborn Screening
What started with PKU… KY screens for 29 different IEM’s as of 2005 Supplemental Newborn Screens >50 additional screening tests via tandem mass spectrometry Specific screens differ by states Know what your state screens for and how to follow up abnormal screens
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) 15. 3-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) 21. 3-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)
Summary
Suspect these with ill neonates Don’t get bogged down in biochemistry ABC, O2, IV, monitor Correct metabolic problems Ask for help i.e., a biochemical geneticist
References
Burton, BK. 1998. Inborn Errors of Metabolism in Infancy: A Guide to Diagnosis. 102(6) e69 Clarke, JTR. 2002. A Clinical Guide to Inherited Metabolic Diseases, 2 nd Edition, Cambridge University Press Claudius, I., et al. 2005. The Emergency Department Approach to Newborn and Childhood Metabolic Crisis. Clinics of North America Colletti, JE, et al. 2004. Unsuspected Neonatal Killers in Emergency Medicine. Emergency Medicine Clinics of North America 929-60 Lieh-Lei, MW. 2001. Pediatric Acute Care, 2 nd Williams & Wilkins McInnes, R.R., et al. 2003. Pediatrics, 21 st Physician Pediatrics 73:11, 1981-90 23, 843-883 Infancy and Early Childhood: An Update. Emergency Medicine Metabolic Disorders Raghuveer, TS, et al. 2006. Inborn Errors of Metabolism in 22, Edition, Lippincott, . IN: Rudolph’s edition, C.D. Rudolph, et al., eds. Pp 597-711 American Family
Questions
Erich Maul, DO, FAAP Kentucky Children’s Hospital 800 Rose St, Rm HA-415 Lexington, KY 40536 [email protected]
859-257-7134