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 Hello, I’m Erich Maul and I wanted to talk to you today about IEM’s. (CLICK)

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 What I want to discuss today is broad concepts for metabolic disease, not getting bogged down in biochemical detail, but give you a simple construct for this topic. I also want to raise the index of suspicion for these diseases and briefly discuss newborn screens here in KY

Why this talk? Metabolic disease is tough Why should we talk about this, well, metabolic disease is a tough subject. It’s lots of biochemistry and I’m sure I am not the only one who got bogged down at times with biochemistry

However, for me… However, for me biochem can be a very complex roadmap and when I get drowned in biochem I feel like floundering. 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 Another problem is that we as physicians think about metabolic disease later in the illness process. Sometimes, this delay can have catastrophic outcomes such as bad neurodevelopmental outcomes or even death. If we raise our index of suspicion and develop a simple tool to use when we think about IEM’s, then hopefully we catch these issues before bad outcomes occur.

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 IEM’s are defined on the slide for you. They are basically enzyme defects-the enzyme is wither absent, or defective, resulting in a backup of metabolites or absence of certain products. Since these are enzyme defects, they tend to be single gene defects inherited via an autosomal recessive pattern. All forms of inheritance are seen in IEM’s, but for practical purposes, enzyme defects are autosomal recessive. There are 4 basic mechanisms by which IEM’s occur, they are transport defects, accumulation of substrate by various mechanisms, deficiency of product and secondary inhibition Let’s take a look at a diagram of what can go wrong along these pathways that can cause metabolic disease so hopefully they are easy to understand (CLICK)

What can go wrong? A A B C D E F negative A B C D Apoenzyme + cofactor E F Let’s consider molecule A sitting outside a cell (CLICK), 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) (CLICK) 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) (CLICK, CLICK) 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) (CLICK, CLICK) 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 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 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) 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) 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 Individually, IEM’s are rare, in the orders of 1 per 10-100,000 or higher, but collectively, IEM’s happen about 1 in every few thousand births More than 500 IEM’ have been identified, thus adding to the stigma of confusion and overwhelming nature of metabolic medicine. With the advent of quadripole tandem mass spectrometry, the number of disease we can detect early by newborn screen will probably increase. We’ll talk more about newborn screens later. Another stigma associated with metabolic disease is that the presentations are very variable, some children have only minor signs and symptoms which are progressive over the course of days to weeks to months, while others present seriously ill and trying to die.

IEM’s in General Generally present in newborn period or shortly thereafter Typically at end of 1st 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 Typically, though, IEM’s present in the neonatal period, usually at the end of the first week of life. There are some IEM’s that present later in childhood, but they are either a much more insidious presentation, or the child has not had exposure to the offending agent. Any example of this is hereditary fructose intolerance. Children <1 y/o have very little exposure to fructose. Once juices or other sources of fructose are added into the child’s diet, a build-up of fructose-1-phosphate occurs; this compound is toxic to the child and can result in severe disease and death. The key to uncovering an IEM is not to understand detailed biochemistry, but to remember simple things which will stabilize the child until you have time to think about the problem. If you don’t include IEM in your differential, don’t be surprised by a bad outcome somewhere in the future.

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 The question shouldn’t when should I think about IEM’s it should be the reverse, when shouldn’t I think about them. With any critically ill child, ask yourself if it could be and inborn error? Many times it is easy to dismiss, but if you don’t think about it, you will miss it. Occasionally, you will get the 4:30 PM call from the state lab about a positive newborn screen, on a Friday, as you are admitting a kid, before you need to catch a flight for vacation to Disney World.

4 Common Presentations Encephalopathy with metabolic acidosis Encephalopathy without metabolic acidosis Neonatal hepatic syndrome Non-immune fetal hydrops There are 4 basic clinical presentations of metabolic disease. They are encephalopathy with or without metabolic acidosis, hepatic synrome, and nonimmune fetal hydrops. Let’s look at those in a little more detail

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 As you can see, hydrops is jphenotypically ust like the immune mediated hydrops we see with Rh disease…if you ever see Rh disease. However, the hydrops is caused by defects in RBC metabolism or lysosomal problems. It’s pretty rare and not every kid with G6PD deficiency get this condition in utero. They need the predisposing stressor to have this happen Kids with lysosomal problems and excrete all the excess fluid and improve or can worsen and die; this is very difficult to predict.

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 Liver disease can be a common presentation of IEM in newborns. It can be as simple as hyperbili, but it just last longer than normal. My partner and I in Mt Home AFB has a child with jaundice for 3 weeks, normal NBS and wound up having hypothyroidism. Go figure. Along with the jaundice, they can have liver dysfunction as well as hypoglycemia

Encephalopathy Without acidosis With 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 Encephalopathy in infants can be difficult to tease out. The signs early on are subtle, such as feeding difficulties, strange cry, poor tone, irritability, or seizures. The only thing acidosis or no acidosis does for you is helps you predict what defect the child may have. Enceph without MA can happen after an ischemic insult, but if you had a bad birth, I think we would know about it and it should be happening minutes to hours after birth. Kids with nonacidosis IEMs that become encephalopathic generally have a period of normalcy, followed by a period of getting progressively sicker. 6 prototypical diseases that fit this category are listed in the left-hand column. The presetnation is simila rin infant who have metabolic acidosis, but there are afew extra things to think about. First off is why are they acidotic? It could be due to renal losses, but in term infants, they don’t have “stupid kidneys” and dumpo tons of bicarb into their urine. This is possible, but quite rare. The acidosis is generally due to unmeasured anion, ketones, and to some extent ammonium ion. By far, unmeasured anion is the most common since most of these kids have an anion gap 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, O2, 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 Now that I have pounded index of suspicion into your head, you encounter a child whom you suspect has an IEM, what to do now? First off, everything you needed to know you learned in kindergarten. Start with ABC’s, put them on oxygen, get and IV and place monitor leads. Every sick child needs this! You should get a brief, directed history and exam, think about a differential, eliminate intake and stop production of the toxic metabolite, facilitate removal of the toxins, correct the acidosis and find out the cause. Notice that finding the cause is last. So many times in dealing with sick infants, the thought of IEM stirs the mind to think about what I need to do to treat this child’s metabolic defect specifically and proper care goes right out the window. Take care of the immediate problems, then figure out the specific 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 Some of the history deals with the usual questions we would ask about any sick kid. However some questions that specifically target IEM’s include sudden death of an infant, odd odor to infant, hx of birth trauma, parental consanguinity (remember most of these defects are autosomal recessive and consanguinity can select for recessive genes). Dysmorphic features should be looked for, but they are rare in most of these diseases. If they are present, they may be very helpful. Many of the signs and symptoms listed above can be seen in 100’s of diseases, but there can be clues that they are from a metabolic disease. The hypoglycemia is severe and persistent and can be difficult to treat. The acidosis is severe and not controlled by conventional cardiovascular support. In addition, you can dump significant amounts of bicarb in these infants and the acidosis doesn’t budge. One last thing about odors; in textbooks, you will read about sweaty foot odor or burnt sugar, fishy odor, etc. Many of these are not found in infants early on. Don’t rely on their presence to make a disgnosis. If present they are helpful, but if absent it doesn’t mean much, they still can have MSUD without the smell of burnt sugar in their urine.

Differential Diagnosis of Critically Ill Neonate Sepsis, sepsis, sepsis, sepsis E. coli, Listeria spp., S. agalactiae (GBS), HSV Abuse Congenital heart disease Congenital adrenal hyperplasia IEM In my DDx of the critically ill neonate, I keep it simple Sepsis, sepsis, sepsis, sepsis for the 4 common causes of neonatal sepsis Abuse-yes young neonates can be abused Congenital heart disease-specifically ductal dependent lesions: obstructive lesions like AS, CoA, interrupted Ao arch, cyanotic lesions, tri atresia, HLHS, just to name a few CAH-although essentially an IEM itself, many consider it a different beast and different set of problems

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 Elimination of the offending toxin begins by eliminating intake, especially protein, until you figure out what is going on. We can replace the most simple metabolic substrate, glucose, by IV infusion. A bolus dose is given first to rapidly correct the hypoglycemia, followed by maintenance infusion. Sometimes very large glucose infusion rates are needed and central access may be required to get high glucose concentrations with minimal amounts of fluid Hemodialysis should be performed for hyperammonemia along with obtaining IV arginine and Na benz/phen/phen Cofactor replacement should be given as well; these include pyridoxine, B12, biotin and 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 Correction of the metabolic acidosis begins with preempting the production of toxic metabolite. Frequent monitoring of the acid base status is required, as is multiple doses of bicarb. Since the child is usually severely acidotic, additional electrolyte abnormalities may arise, esp with potasium. Just like in DKA, as the pH decreases, potassium moves out of the cells to maintain electrical nutrality. When pH begins to normalize, potassium shifts back into the cell and hypokalemia may develop.

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 Additional laboratory studies are essential to the evaluation of metabolic disorders. You don’t need very fancy test, many of the ones listed above are routine on the floor or the ER, just with a few additions. Your initial round of labs should include… After stabilization, more definitive studies can be done. These are included in the secondary labs. Think about obtaining these as early as possible, when it is clinically safe to do so, since some of the characteristic patterns that define IEM’s in organic and amino acid patterns can change with withdrawl of protein.

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 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) 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)

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. Pediatrics 102(6) e69 Clarke, JTR. 2002. A Clinical Guide to Inherited Metabolic Diseases, 2nd Edition, Cambridge University Press Claudius, I., et al. 2005. The Emergency Department Approach to Newborn and Childhood Metabolic Crisis. Emergency Medicine Clinics of North America 23, 843-883 Colletti, JE, et al. 2004. Unsuspected Neonatal Killers in Emergency Medicine. Emergency Medicine Clinics of North America 22, 929-60 Lieh-Lei, MW. 2001. Pediatric Acute Care, 2nd Edition, Lippincott, Williams & Wilkins McInnes, R.R., et al. 2003. Metabolic Disorders. IN: Rudolph’s Pediatrics, 21st edition, C.D. Rudolph, et al., eds. Pp 597-711 Raghuveer, TS, et al. 2006. Inborn Errors of Metabolism in Infancy and Early Childhood: An Update. American Family Physician 73:11, 1981-90

Kentucky Children’s Hospital Questions Erich Maul, DO, FAAP Kentucky Children’s Hospital 800 Rose St, Rm HA-415 Lexington, KY 40536 Erich.maul@uky.edu 859-257-7134