Inborn Errors of Inborn Errors of MetabolismMetabolism

A Hospitalist’s ApproachA Hospitalist’s Approach

Erich C. Maul, DO, FAAPErich C. Maul, DO, FAAPAssistant Professor of PediatricsAssistant Professor of PediatricsSection of Inpatient PediatricsSection of Inpatient PediatricsKentucky Children’s HospitalKentucky Children’s Hospital

University of Kentucky College of MedicineUniversity of Kentucky College of Medicine

ObjectivesObjectives

Understand grand concepts of Understand grand concepts of metabolic diseases and inborn errors metabolic diseases and inborn errors of metabolism (IEM) in infantsof metabolism (IEM) in infants

Raise clinical suspicion for these Raise clinical suspicion for these diseasesdiseases

Form conceptual framework for initial Form conceptual framework for initial diagnosis and management of IEM in diagnosis and management of IEM in infantsinfants

Briefly discuss Newborn ScreensBriefly discuss Newborn Screens

Why this talk?Why this talk?

Metabolic disease is toughMetabolic disease is tough

However, for me…However, for me…

Copyright Roche Diagnostics GmbH, 1993, used with permission

Why this talk?Why this talk?

Metabolic disease is toughMetabolic disease is tough Often thought of later in illnessOften thought of later in illness

With catastrophic outcomesWith catastrophic outcomes There can be a simple construct that There can be a simple construct that

can help standardize the approach to can help standardize the approach to uncovering metabolic diseaseuncovering metabolic disease

IEM’s in GeneralIEM’s in General Mostly due to defect in or absence of an Mostly due to defect in or absence of an

enzyme, cofactor or transport protein enzyme, cofactor or transport protein resulting a block in a specific metabolic resulting a block in a specific metabolic pathwaypathway

Generally single gene defectsGenerally single gene defects Involve all inheritance patterns, however, most Involve all inheritance patterns, however, most

common is autosomal recessivecommon is autosomal recessive Common defects on a biochemical levelCommon defects on a biochemical level

Transport defectsTransport defects Accumulation of substrateAccumulation of substrate Deficiency of productDeficiency of product Secondary inhibitionSecondary inhibition

A

A B C

D

negative

E F

Apoenzyme + cofactor

What can go wrong?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

IEM’s in GeneralIEM’s in General Individually-very rare, Collectively-Individually-very rare, Collectively-

very commonvery common More than 500 identified IEM’sMore than 500 identified IEM’s

Include amino acidopathies, fatty acid Include amino acidopathies, fatty acid oxidation defects, organic acidemias, oxidation defects, organic acidemias, urea cycle defects, carbohydrate urea cycle defects, carbohydrate metabolism defects, peroxisomal metabolism defects, peroxisomal disorders, lysosomal disorders, disorders, lysosomal disorders, mitochondrial disordersmitochondrial disorders

Newborn Screening has been lifesavingNewborn Screening has been lifesaving Variable presentationsVariable presentations

Mild to severeMild to severe Subtle to overtSubtle to overt

IEM’s in GeneralIEM’s in General

Generally present in newborn period Generally present in newborn period or shortly thereafteror shortly thereafter Typically at end of 1Typically at end of 1stst week of life week of life This will be the focus of this talkThis will be the focus of this talk

Key to finding IEM’s is not a detailed Key to finding IEM’s is not a detailed knowledge of biochemical pathways, knowledge of biochemical pathways, but a HIGH INDEX OF SUSPICION in but a HIGH INDEX OF SUSPICION in any critically ill neonateany critically ill neonate

When should I suspect IEM?When should I suspect IEM? When the obvious confronts you…When the obvious confronts you…

POSITIVE STATE NEWBORN SCREENPOSITIVE STATE NEWBORN SCREEN Subject to false positivesSubject to false positives Require confirmatory testingRequire confirmatory testing State labs are helpful in guiding you through State labs are helpful in guiding you through

the processthe process More on this laterMore on this later

ANY SICK NEWBORNANY SICK NEWBORN However in IEM’s BP more easily However in IEM’s BP more easily

maintained, acidosis unresponsive to maintained, acidosis unresponsive to fluids and respiratory support, cultures fluids and respiratory support, cultures sterilesterile

4 Common Presentations4 Common Presentations

Encephalopathy with metabolic Encephalopathy with metabolic acidosisacidosis

Encephalopathy without metabolic Encephalopathy without metabolic acidosisacidosis

Neonatal hepatic syndromeNeonatal hepatic syndrome Non-immune fetal hydropsNon-immune fetal hydrops

Non-immune fetal hydropsNon-immune fetal hydrops

Syndrome of severe anemia, congenital Syndrome of severe anemia, congenital heart disease, and congenital infectionheart disease, and congenital infection IEM of RBC energy metabolism results severe IEM of RBC energy metabolism results severe

anemia which leads to high-output heart failureanemia which leads to high-output heart failure G6PD deficiency, pyruvate kinase deficiencyG6PD deficiency, pyruvate kinase deficiency

Lysosomal storage diseases can be born Lysosomal storage diseases can be born with severe peripheral edema, which can with severe peripheral edema, which can have variable coursehave variable course Excrete and improve; worsen and dieExcrete and improve; worsen and die Gaucher type 2, Niemann-Pick type C, GM1 Gaucher type 2, Niemann-Pick type C, GM1

gangliosidosisgangliosidosis

Neonatal Hepatic SyndromeNeonatal Hepatic Syndrome

Acute liver disease in the neonatal period Acute liver disease in the neonatal period delineated by:delineated by: JaundiceJaundice

Lasts longer than ‘run of the mill’ newborn pumpkin Lasts longer than ‘run of the mill’ newborn pumpkin periodperiod

Unconjugated primarily; later can see conjugatedUnconjugated primarily; later can see conjugated Severe hepatic dysfunctionSevere hepatic dysfunction

Jaundice, hypoglycemia, hyperammonemia, elevated Jaundice, hypoglycemia, hyperammonemia, elevated transaminases, ascites/anasarca, coagulopathytransaminases, ascites/anasarca, coagulopathy

Persistent hypoglycemia without overt Persistent hypoglycemia without overt evidence of hepatocellular dysfunctionevidence of hepatocellular dysfunction

EncephalopathyEncephalopathy Without acidosisWithout acidosis

Most commonly after Most commonly after hypoxic-ischemic insulthypoxic-ischemic insult

IEM’s like this generally IEM’s like this generally have a period of normalcy have a period of normalcy and no history of birth and no history of birth trauma, then trauma, then encephalopathyencephalopathy

6 prototypical IEM’s6 prototypical IEM’s MSUD, urea cycle defects, MSUD, urea cycle defects,

nonketotic nonketotic hyperglycinemia, hyperglycinemia, pyridoxine dependent pyridoxine dependent seizures, peroxisomal seizures, peroxisomal disorders, molybdenum disorders, molybdenum cofactor defectcofactor defect

With acidosisWith acidosis Typically well until 3-5 Typically well until 3-5

days of lifedays of life Feeding difficulties arise Feeding difficulties arise

along with tachypnea, along with tachypnea, increased work of increased work of breathing and breathing and encephalopathyencephalopathy

CXR is normal and blood CXR is normal and blood gas show metabolic gas show metabolic acidosisacidosis

Renal loss of bicarbonate Renal loss of bicarbonate is rare in term infant, but is rare in term infant, but accumulation of accumulation of unmeasured anion, unmeasured anion, ketones, or ammonium is ketones, or ammonium is commoncommon

Prototypes are organic Prototypes are organic acidurias and congenital acidurias and congenital lactic acidosislactic acidosis

Summary of PresentationsSummary of Presentations

ExtremisExtremis ““He looks septic or near death”He looks septic or near death”

EncephalopathyEncephalopathy HyperammonemiaHyperammonemia

Metabolic acidosisMetabolic acidosis KetosisKetosis

Abnormal liver enzymes/functionAbnormal liver enzymes/function HypoglycemiaHypoglycemia

Alright, I suspect it,Alright, I suspect it,now how do I work it up?now how do I work it up?

ABC’s, OABC’s, O22, IV, MONITOR, IV, MONITOR Mantra of PALSMantra of PALS

Brief history and directed physicalBrief history and directed physical Remember differential of critically ill Remember differential of critically ill

neonateneonate Eliminate intake and production of toxic Eliminate intake and production of toxic

metabolitemetabolite Accelerate removal of toxic metaboliteAccelerate removal of toxic metabolite Cautiously correct acidosisCautiously correct acidosis Investigate causeInvestigate cause

History and PhysicalHistory and Physical Period of normalcy, rapidity of onset, Period of normalcy, rapidity of onset,

consanguinity, FHx of neonatal death, odd consanguinity, FHx of neonatal death, odd odor to infant, birth hxodor to infant, birth hx

Subtle signs or symptomsSubtle signs or symptoms Feeding difficulty, odd cry, vomiting, diarrhea, Feeding difficulty, odd cry, vomiting, diarrhea,

tachypnea, dyspnea, hypotonia/hypertonia, tachypnea, dyspnea, hypotonia/hypertonia, tachycardia, mental status changestachycardia, mental status changes

Overt signs or symptomsOvert signs or symptoms Persistent hypoglycemia, acidosis, dehydration, Persistent hypoglycemia, acidosis, dehydration,

shock, apnea, seizures, abnormal mental shock, apnea, seizures, abnormal mental status, temperature instability, arrhythmia, status, temperature instability, arrhythmia, cardiomyopathy, sudden deathcardiomyopathy, sudden death

Dysmorphic features, strange odor, signs Dysmorphic features, strange odor, signs of abuse, rashes, jaundice, organomegalyof abuse, rashes, jaundice, organomegaly

Differential Diagnosis ofDifferential Diagnosis ofCritically Ill NeonateCritically Ill Neonate

Sepsis, sepsis, sepsis, sepsisSepsis, sepsis, sepsis, sepsis E. coliE. coli, , ListeriaListeria spp., spp., S. agalactiaeS. agalactiae (GBS), (GBS),

HSVHSV AbuseAbuse Congenital heart diseaseCongenital heart disease Congenital adrenal hyperplasiaCongenital adrenal hyperplasia IEMIEM

Critical InterventionsCritical Interventions

Eliminate toxinEliminate toxin NPO and eliminate proteinNPO and eliminate protein IV glucoseIV glucose

2-4mL/kg D10W-D25W; may need glucagon2-4mL/kg D10W-D25W; may need glucagon 8-10 mg/kg/min D10W; may need higher infusions8-10 mg/kg/min D10W; may need higher infusions If acidosis worsens, suspect pyruvate dehydrogenase If acidosis worsens, suspect pyruvate dehydrogenase

deficiencydeficiency Consider hemodialysis for hyperammonemia, Consider hemodialysis for hyperammonemia,

along with arginine, and Na along with arginine, and Na benzoate/phenacetate/phenylbutyratebenzoate/phenacetate/phenylbutyrate

Consider pyridoxine, biotin, B12, carnitineConsider pyridoxine, biotin, B12, carnitine

Critical InterventionsCritical Interventions

Correct acidosis, which may be difficultCorrect acidosis, which may be difficult Attempt to stop production of metaboliteAttempt to stop production of metabolite Frequent evaluation of acid-base status and Frequent evaluation of acid-base status and

gauge bicarbonate administration off thatgauge bicarbonate administration off that Since toxic metabolite is usually still being Since toxic metabolite is usually still being

produced, can be difficult to control acid-base produced, can be difficult to control acid-base statusstatus

Consider hemodialysis for severe acidosis, Consider hemodialysis for severe acidosis, especially if concurrently hyperammonemicespecially if concurrently hyperammonemic

Address additional electrolyte abnormalitiesAddress additional electrolyte abnormalities

Critical InterventionsCritical Interventions

Initial laboratory work-Initial laboratory work-upup CBC, blood cultureCBC, blood culture CMP, lactate, pyruvate, CMP, lactate, pyruvate,

ammoniaammonia ABGABG PT/PTTPT/PTT UA, urine culture, UA, urine culture,

reducing substancesreducing substances CSF studies if stableCSF studies if stable

Routine studies plus Routine studies plus lactate and amino acidslactate and amino acids

Secondary labsSecondary labs Repeat initialRepeat initial Carnitine/acylcarnitine Carnitine/acylcarnitine

profileprofile Serum amino acidsSerum amino acids Urine organic acidsUrine organic acids Urine amino acidsUrine amino acids Urine acylglycinesUrine acylglycines

Take a breathTake a breath

Now that the child is being stabilized and labs are Now that the child is being stabilized and labs are coming back, you can actively think about your coming back, you can actively think about your data and find out what is wrong with your patientdata and find out what is wrong with your patient

A consult by phone to a biochemical geneticist or A consult by phone to a biochemical geneticist or a metabolic medicine specialist is a critical a metabolic medicine specialist is a critical portion of patient careportion of patient care

A Clinical Guide to Inherited Metabolic DiseasesA Clinical Guide to Inherited Metabolic Diseases by JTR Clarke, is a great, simple text with many by JTR Clarke, is a great, simple text with many excellent algorithms to help figure out IEM’s, as is excellent algorithms to help figure out IEM’s, as is Rudolph’s PediatricsRudolph’s Pediatrics See referencesSee references

Broad GeneralizationsBroad Generalizationsaka Board Generalizationsaka Board Generalizations

Hyperammonemia without acidosisHyperammonemia without acidosis Urea cycle enzyme defect (UCED)Urea cycle enzyme defect (UCED)

Hyperammonemia with acidosis or anion gapHyperammonemia with acidosis or anion gap Organic acidemiaOrganic acidemia

With ketones=fatty acid oxidation defectWith ketones=fatty acid oxidation defect Elevated lactate=organic acidemiaElevated lactate=organic acidemia

Metabolic acidosis with normal ammoniaMetabolic acidosis with normal ammonia Organic acidemia, oxidation disorders, Organic acidemia, oxidation disorders,

carbohydrate diseasescarbohydrate diseases Normal ammonia and acid base statusNormal ammonia and acid base status

Aminoacidopathy, galactosemiaAminoacidopathy, galactosemia

IEM’s in Older ChildrenIEM’s in Older Children

Paroxysmal stupor, vomitingParoxysmal stupor, vomiting Especially during periods of fastingEspecially during periods of fasting Tend to be disorders of carbohydrate metabolism Tend to be disorders of carbohydrate metabolism

or mucopolysaccharidoses, mucolipidoses, or or mucopolysaccharidoses, mucolipidoses, or glycoproteinosesglycoproteinoses

Failure to thriveFailure to thrive Organomegaly, neuromotor delay, Organomegaly, neuromotor delay,

macrocephalymacrocephaly Dysmorphic featuresDysmorphic features Labs are the same as for infant, however Labs are the same as for infant, however

include karyotype and possible additional include karyotype and possible additional genetic studiesgenetic studies

Newborn ScreeningNewborn Screening

Basic conceptBasic concept Goal is to detect diagnostic markers of Goal is to detect diagnostic markers of

metabolic disease in metabolic disease in asymptomaticasymptomatic infants infants Disease should be frequent enough to have Disease should be frequent enough to have

a favorable cost-benefit ratioa favorable cost-benefit ratio Should screen for diseases we can do Should screen for diseases we can do

something for, i.e., therapy availablesomething for, i.e., therapy available Low false positive and false negative ratesLow false positive and false negative rates

Newborn ScreeningNewborn Screening

What started with PKU…What started with PKU… KY screens for 29 different IEM’s as of KY screens for 29 different IEM’s as of

20052005 Supplemental Newborn ScreensSupplemental Newborn Screens

>50 additional screening tests via tandem >50 additional screening tests via tandem mass spectrometrymass spectrometry

Specific screens differ by statesSpecific screens differ by states Know what your state screens for and how to Know what your state screens for and how to

follow-up abnormal screensfollow-up abnormal screens

KY Newborn ScreensKY 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)

SummarySummary

Suspect these with ill neonatesSuspect these with ill neonates Don’t get bogged down in Don’t get bogged down in

biochemistrybiochemistry ABC, O2, IV, monitorABC, O2, IV, monitor Correct metabolic problemsCorrect metabolic problems Ask for help i.e., a biochemical Ask for help i.e., a biochemical

geneticistgeneticist

ReferencesReferences Burton, BK. 1998. Inborn Errors of Metabolism in Infancy: A Burton, BK. 1998. Inborn Errors of Metabolism in Infancy: A

Guide Guide to Diagnosis. to Diagnosis. PediatricsPediatrics 102(6) e69 102(6) e69 Clarke, JTR. 2002. Clarke, JTR. 2002. A Clinical Guide to Inherited Metabolic A Clinical Guide to Inherited Metabolic

DiseasesDiseases, , 22ndnd Edition, Cambridge University Press Edition, Cambridge University Press Claudius, I., et al. 2005. The Emergency Department Claudius, I., et al. 2005. The Emergency Department

Approach to Approach to Newborn and Childhood Metabolic Crisis. Newborn and Childhood Metabolic Crisis. Emergency Medicine Emergency Medicine Clinics of North AmericaClinics of North America 23, 843-883 23, 843-883

Colletti, JE, et al. 2004. Unsuspected Neonatal Killers in Colletti, JE, et al. 2004. Unsuspected Neonatal Killers in Emergency Emergency Medicine. Medicine. Emergency Medicine Clinics of Emergency Medicine Clinics of North AmericaNorth America 22, 22, 929-60929-60

Lieh-Lei, MW. 2001. Lieh-Lei, MW. 2001. Pediatric Acute CarePediatric Acute Care, 2, 2ndnd Edition, Edition, Lippincott, Lippincott, Williams & WilkinsWilliams & Wilkins

McInnes, R.R., et al. 2003. McInnes, R.R., et al. 2003. Metabolic DisordersMetabolic Disorders. . IN:IN: Rudolph’s Rudolph’s PediatricsPediatrics, 21, 21stst edition, C.D. Rudolph, et al., edition, C.D. Rudolph, et al., eds. Pp 597-711eds. Pp 597-711

Raghuveer, TS, et al. 2006. Inborn Raghuveer, TS, et al. 2006. Inborn Errors of Metabolism in Errors of Metabolism in Infancy and Early Childhood: An Update. Infancy and Early Childhood: An Update. American American

Family Family PhysicianPhysician 73:11, 1981-90 73:11, 1981-90

QuestionsQuestions

Erich Maul, DO, FAAPErich Maul, DO, FAAP

Kentucky Children’s HospitalKentucky Children’s Hospital

800 Rose St, Rm HA-415800 Rose St, Rm HA-415

Lexington, KY 40536Lexington, KY 40536

Erich.maul@uky.eduErich.maul@uky.edu

859-257-7134859-257-7134