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

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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



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Transport defects
Accumulation of substrate
Deficiency of product
Secondary inhibition
What can go wrong?
A
negative
A
B
C
D
E
Apoenzyme + cofactor
F
consider
secondary
inhibition.
at the reaction of E to F. The
Let’sLet’s
consider
molecule
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outside
aLet’s
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then
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IfIfthe
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the cell via
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Aupenzyme
primary
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is
in
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but
as
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and
Let’s suppose
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feedback
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of reaction
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B.
converting
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defective,
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and
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can’t
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Also,
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B accumulates
anddefective,
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(deficiency
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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


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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

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Mild to severe
Subtle to overt
IEM’s in General

Generally present in newborn period or
shortly thereafter

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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
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
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However in IEM’s BP more easily maintained,
acidosis unresponsive to fluids and respiratory
support, cultures sterile
4 Common Presentations
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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
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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

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Excrete and improve; worsen and die
Gaucher type 2, Niemann-Pick type C, GM1
gangliosidosis
Neonatal Hepatic Syndrome
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Acute liver disease in the neonatal period
delineated by:

Jaundice
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Severe hepatic dysfunction
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Lasts longer than ‘run of the mill’ newborn pumpkin period
Unconjugated primarily; later can see conjugated
Jaundice, hypoglycemia, hyperammonemia, elevated
transaminases, ascites/anasarca, coagulopathy
Persistent hypoglycemia without overt evidence of
hepatocellular dysfunction
Encephalopathy
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Without acidosis
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Most commonly after hypoxicischemic insult
IEM’s like this generally have a
period of normalcy and no
history of birth trauma, then
encephalopathy
6 prototypical IEM’s
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MSUD, urea cycle defects,
nonketotic hyperglycinemia,
pyridoxine dependent seizures,
peroxisomal disorders,
molybdenum cofactor defect

With acidosis
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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
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Extremis
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Encephalopathy
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Hyperammonemia
Metabolic acidosis
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“He looks septic or near death”
Ketosis
Abnormal liver enzymes/function
Hypoglycemia
Alright, I suspect it,
now how do I work it up?
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ABC’s, O2, IV, MONITOR
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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
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Period of normalcy, rapidity of onset,
consanguinity, FHx of neonatal death, odd odor
to infant, birth hx
Subtle signs or symptoms
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Overt signs or symptoms
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Feeding difficulty, odd cry, vomiting, diarrhea,
tachypnea, dyspnea, hypotonia/hypertonia,
tachycardia, mental status changes
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
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Sepsis, sepsis, sepsis, sepsis
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E. coli, Listeria spp., S. agalactiae (GBS), HSV
Abuse
Congenital heart disease
Congenital adrenal hyperplasia
IEM
Critical Interventions
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Eliminate toxin
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NPO and eliminate protein
IV glucose
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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
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Address additional electrolyte abnormalities
Critical Interventions
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Initial laboratory work-up
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CBC, blood culture
CMP, lactate, pyruvate,
ammonia
ABG
PT/PTT
UA, urine culture, reducing
substances
CSF studies if stable
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Routine studies plus
lactate and amino acids
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Secondary labs
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Repeat initial
Carnitine/acylcarnitine
profile
Serum amino acids
Urine organic acids
Urine amino acids
Urine acylglycines
Take a breath
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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
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Hyperammonemia without acidosis
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Urea cycle enzyme defect (UCED)
Hyperammonemia with acidosis or anion gap
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Organic acidemia
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Metabolic acidosis with normal ammonia
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With ketones=fatty acid oxidation defect
Elevated lactate=organic acidemia
Organic acidemia, oxidation disorders, carbohydrate
diseases
Normal ammonia and acid base status
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Aminoacidopathy, galactosemia
IEM’s in Older Children
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Paroxysmal stupor, vomiting
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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
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Basic concept
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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
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What started with PKU…
KY screens for 29 different IEM’s as of 2005
Supplemental Newborn Screens
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>50 additional screening tests via tandem mass
spectrometry
Specific screens differ by states

Know what your state screens for and how to followup abnormal screens
KY Newborn Screens
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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
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

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
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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
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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
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