Unformatted text preview: Approach to Inborn Errors
Andrew M. Ellefson MD
Cpt, USA, MC
Pgy-2 NCC Pediatrics Goals for this lecture:
Discuss acute/emergency management of IEMs.
Review broad categories of IEMs.
Focus on Board favorite zebras.
Complete the Board prep. Objectives in most
recent 2006 edition. Integrate the “Laughing your way through Boards”
tips. Have fun with this usually stressful topic.
Have What we WON’T DO:
What Memorize metabolic pathways. Mention, think of, or utter the enzyme αMention,
complex. Laugh at, throw bagels or coffee at, or
otherwise mock Drew.
otherwise Discuss the adverse sequelae of the Eagle’s
previous decision to recruit T.O.
previous IEM Board/Prep Goals:
– Urea Cycle defects
S+S of CHO disorders
S+S of Galactosemia
S+S of hyperinsulinism
Glycogen Storage Dz
Gaucher + Lipid Storage Dz
S+S of Tay-Sachs
S+S of Fatty Acid and
Carnitine metabolism Inheritance patterns
Indication for genetics
Eval of hypoglycemia
Eval of acidosis
Vitamin Rx for enzyme
Natural Hx of PKU
Plan/diet for PKU
Manage Glycogen storage
diseases- Type 1
diseases- IEM- Index of Suspicion:
IEM Rapid deterioration in an otherwise well infant. Septic appearing infant or abnl sepsis such as
E.coli. Failure to thrive.
Failure Regression in milestones.
Regression Recurrent emesis or feeding difficulty, alterations
in respirations, abnl urine/body smell, changing
MS/lethargy, jaundice, sz, intractable hiccups. Can masquerade like pyloric stenosis. Dietary aversion- proteins, carbs.
Dietary Basic Principles:
Basic Although individually rare, altogether they
are 1:800-5000 incidence.
are Broadly Defined: An inherent deficiency in a
key metabolic pathway resulting in
– Cellular Intoxication
– Energy deprivation
– Mixture of the two History and Antecedent Events:
History Catabolic state induction
(sepsis,fasting,dehydration) Protein intake Change or addition of PO proteins, carbs,
etc… in formula
etc… **Gotta ask- Consanguinity FHx of SIDS Assessment:
Assessment Detailed H+P
– Describe sz
– Fevers -Milestones
-NAT questions **Dysmorphology does not
r/o IEMs** Physical Exam:
Level of alertness
– Abdo- HS megaly
– Neuro- DTRs, tone, etc
– Skin- bruise, pigment,
color Emergency Management:
Emergency Can be life threatening
event requiring rapid
management. ABC’s ABG-acidosis
BMP, Ca and LFTs
CBC, Blood Cx if uncertain
UA-ketones, urine reducing
substances, hold for OA/AAs
Newborn scrn results
LP- r/o Meningitis, but send lactate
LPSTAT, AAs, hold tubes for future
Drug tox screen if indicated.
**Hold spun blood or urine sample
in fridge for later if possbile.
– **ABG, Lactate are iced STAT
– ** NH4 should be free flowing,
arterial Emergency Management:
Emergency Correct hypotension. NPO, reverse
catabolism with D5catabolism
D10 1-1.5 x maint. Correct hypoglycemia. Correct metabolic
acidosis. Dialysis, lactulose if
– (nl is <35µmol/L) Search for and treat
Infection, dehydration. Low threshold for
Sepsis w/u + ABx if
uncertain. Pyridoxine for neonatal
sz. if AED no-response
sz. Ativan, Versed, AEDs
for status epilepticus.
for Some quick supplements:
Some Carnitine for elimination of Organic Acid
through creation of carnitine esters.
through Sodium Benzoate, Phenylacetate for
Hyperammonemia elimination. Stable Patient, Now what?
Stable You could memorize some of
these: The Daunting Differential List:
Newborn Inborn Errors of Metab:
– Organic Acidemias
Fatty Acid Oxidation def
Urea Cycle Defects
Non-ketotic Hyperglycinemia Molybdenum Cofactor
Deficiency – Sulfite Oxidase Deficiency Metal Storage Disorders:
– Krabbe disease Mitochondrial Disorders Glycogen Storage
Disorders Hyperinsulinism Carbohydrate Disorders Lysosomal Disorders – Mucopolysaccharidoses (Xlinked Hunter’s, Hurler’s)
– Gaucher disease
– Tay-Sachs Disease Peroxisomal Disorders
– Zellwegger’s (CerebroHepato-renal)
Adrenoleukodystrophy Patient is stabilized. Now what:
Broad DDx for IEMs scares people.
You can group into KEY features.
Can focus on initial labs = Hyperammonia,
hypoglycemia, metabolic acidosis.
hypoglycemia, metabolic Can focus on Prominent neurologic features.
Can Can focus on Dysmorphic features.
Can If these don’t exactly fit, resort back to categories
of IEMs and Neurodegenerative Disorders. Quick References:
Hyperglycine *Urea Cycle
defects *Fatty Acid
*OAemia *OAemia *OAemia *OAemia *Glycogen Strg
Metabolism Transient Hyperammonemia of
Newborn: Markedly high NH4 in an infant less than 24
HOL, or first 1-2 DOL before protein intake
occurs. Often in context of large, premature infant with
symptomatic pulmonary disease.
symptomatic Very sick infant.
Very sick Unknown precipitant, unknown etiology (possible
slow delayed urea cycle initiation), with potential
for severe sequelae (20-30% death, 30-40% abnl
devo) if not treated. Does not recur after being treated.
Does Organic Acidemias:
*Acidotic with high Gap
*Urine Ketones high
*High to nl Ammonia
Often present first 2-7 days of life after dietary
protein Drunk appearance in infant.
Drunk *May have low WBC and Plts.
*May Check serum AAs/OAs, Urine AAs/OAs, CSF
OAs/AAs. Organic Acidemias cont:
Organic **Multiple Carboxylase Deficiency**
Defect in Biotin Utilization
Defect Biotin is vital cofactor in many pathways, defect results in: Severe deterioration, dermatitis, alopecia, immune
deficiency- candidal skin infections. High NH4, acidemic, ketotic like the others.
High Dx by enzyme assay.
Dx Rx with Biotin 10mg/kg/d PO
**Rocky will get this if he consumes too much Avidin, aka,
raw eggs. Amino Acidurias:
Amino Maple Syrup Urine Disease
– Sweet smell of body fluid esp Urine.
Classically develops in 1st week of Life.
Poor feeding, emesis, lethargy and coma.
Periods of Hypertonicity.
Possible Metabolic Acidosis, hyperammonemia
**Obtain serum/urine AAs/OAs**
Treatment requires rapid removal of Branched chain
AAs, often through dialysis. Amino Acidurias:
Amino Fresh Urine Uric acid and Sulfite Dipstick if
neurologic abnormalities are present, low
uric acid is suggestive for molybdenum
cofactor deficiency and Sulfite Oxidase
Deficiency Don’t forget PKU. Basic on newborn scrn,
but only does good if results followed up. For the Boards:
For *Sweaty feet smell*
– Isovaleric Acidemia, think ISOTONER shoes smell
think ISOTONER What defect may present with Pulmonary
Embolus? Homocystinuria- and thereafter may ask which
supplement to initiate?
supplement Pyridoxine- due to residual enzyme activity. Other names to know:
– Methylmalonic Acidemia- Rx with large dose vitamin
– Propionic Acidemia- RX with Biotin.
Biotin. Urea Cycle Defects:
Urea All but one of the disorders is autosomal recessive.
Symptom free period and then emesis->lethargy-->>COMA
– High Ammonia, low BUN
Possible Lactic acidosis
*Absence of ketonuria*
Nl to mild low Glucose **Treat high ammonia, infuse glucose, send plasma
AAs/OAs, urine orotic acid, and plasma citrulline.
AAs/OAs, Infusion of 6ml/kg 10% Arginine HCl over 90 min may help.
Infusion Milder forms may show episodic emesis, confusion, ataxia,
and combativeness after high protein meals.
high For the Boards:
For Most common Urea cycle defect and also
only Ornithine Transcarbamylase Deficiency Fatty Acid Oxidation Defects:
Fatty **Autosomal recessive inheritance**
Examples are MCAD, LCAD, VLCAD
Defect in acyl-CoA Dehydrogenase, a mitochondrial duty,
and important in fasting state.
Acute attack of life-threatening coma with Hypoglycemia
Absence of urine ketones, and reducing substances, nl
+/- mild acidosis, or hyperammonemia, elevated LFTs, abnl
Dx with serum Acylcarnitine Profile or fibroblast enzyme
assay For the Boards:
For Fetal Defect in LCHAD may result in
Prenatal course complicated by :
Prenatal Maternal HELLP syndrome Non-ketotic Hyperglycinemia:
Non-ketotic Unique entity in that Glucose, NH4, pH are all
normal. 4 types with varying ages of onset, however,
classic form is Neonatal with onset in 1st week of
life Will present just like the other devastating IEMs.
Lethargy, emesis, hypotonia, seizures, etc…
Lethargy, Uncontrolled hiccups. Dx with no urine ketones, and Elevated Glycine.
Dx No effective Rx. Will require diet restriction.
No Long term is a devastating disease. Carbohydrate related Disorders:
Galactosemia: First 1-2 wks of Life: Presents with hypoglycemia, jaundice,
emesis. Secondary to intolerance of Galactose. Will be in baby’s first
meals of breast milk or lactose containing formulas. Also index of suspicion for GramNeg or E.coli sepsis.
Dx assisted by Non-glucose reducing substances in urine.
Non-glucose reducing substances urine
Confirmation by Galactose-1-PO uridyl transferase activity in RBCs.
Adverse sequelae include Cataracts, MR, persistent liver
disease. For the Boards:
For Which is worse?
– Essential Fructosuria
– Inherited Fructose Intolerance Inherited Fructose Intolerance
– Occurs after ingestion of Fructose (sucrose= glucose +
– Severe and life threatening intoxication of
– Presents with emesis, seizures and profound illness
after ingestion of fructose.
– May also present similar to Galactosemia.
– Life long avoidance of fructose.
Life Glycogen Storage Disorders:
Glycogen Type 1= Von Gierke’s:
– Shortly after birth: Severe lifethreatening Hypoglycemia
Lactic acidosis –due to isolated glycolysis of G6Po
Hyper-uricemia, hyper lipidemia
Increased association with epistaxis
**Adverse response to Glucagon with worsening Lactic acidosis Management requires IV glucose, and then as outpt, close
NG corn-starch or glucose solution administration to
achieve close to nl glucose homeostasis. Frequent snacks and meals. Continuous nighttime glucose
infusions up to the age of 2. Glycogen Storage Disorders:
Glycogen Type 2- Pompe’s disease:
Do to an accumulation of glycogen in lysosomes.
Do **Ancient city of Pompeii was destroyed by Mt. Vesuvius- 79 AD** Manifested by massive Cardiomegaly,
Hepatomegaly Macroglossia Fatal If results in CHF.
Fatal Limited therapies in Neonatal Variant.
– Attempts at enzyme replacement ongoing. Mitochondrial Disorders:
Mitochondrial Emerging spectrum of diseases with life-time
variation of presentation. Infantile/Neonatal: may present with
encephalopathic picture, regressed milestones,
cerebral cortical atrophy. Generally lab findings of:
– Lactic Acidosis
Nl to low serum pyruvate, incomparison to Lactate
Nl organic acids.
*** Important to check CSF values of the above*** Leigh’s Disease
Leigh’s AKA- Subacute necrosing encephalopathy
AKA- Subacute Due to defects in the mitochondrial electron
transport May have devastating presentation with significant
developmental Unfavorable natural history. May respond to host of supplements. **Other Mitochondrial disorders for completion
– MELAS, MERRF, Leber’s HON Leukodystrophies:
Leukodystrophies: Krabbe disease: – Type 1- “Infantile”= irritability, hypertonia,
hyperesthesia, and psychomotor arrest, followed by
rapid deterioration, optic atrophy, and early death
– Type 2- Late infantile
– Type 3- Juvenile
– Type 4- Adult
Type Adult A demyelination disorder due to CNS
accumulation of galactosylceramide. Diagnosis: supported by cortical atrophy on
CT/MRI, High CSF protein and definite evidence of
deficient GALC assay in WBCs or skin fibroblasts.
in Lysosomal Disorders
Focus on key differences: Gaucher Disease:
– Infantile vs chronic
– Bone pain
– Easy bruisability
– **low Plts,
osteosclerosis, and lytic
cowboy” Tay-Sachs Disease:
– Progressive neurologic
degeneration in first
YOL and death by age
– AR inheritance with
– Increased startle reflex
– Cherry red macula
– Macrocephaly Peroxisomal Disorders
Peroxisomal Zellweger Syndrome aka: Cerebro-hepato-renal
syndrome Typical and easily
facies. Progressive degeneration
of Brain/Liver/Kidney, with
death ~6 mo after onset.
death When screening for PDs.
obtain serum Very Long
Chain Fatty AcidsChain
VLCFAs Further Evaluation in IEMs:
Further ** Head CT, MRI, Ophtho, Audio, EKG,
EEG** Genetics consultation.
Genetics Peds Neuro consultation. Random Questions for the Boards:
Amino Acids responsible for MSUD?
Valine, Leucine, Isoleucine
Name 1 of the 3 classic Metal Storage disorders?
Menke’s Kinky Hair Syndrome (X-link recessive)
Lysosomal storage disease associated with Adrenal Gland
calcifications? Wolman Disease – Fatty acid deposits, nl lipid panel
– **Mneumo= Wool Man Disease white wool deposits.
**Mneumo= Recognize that Smell:
Recognize Musty or Mousy:
maple syrup urine disease
iisovaleric acidemia or glutaric
acidemia type II
deficiencies (Biotin deficiency)
deficiencies Follow up Questions ?
Name some classic Mucopolysaccharidosis?
Hunter’s (X-linked, no corneal clouding)
Hurler’s (presence of Corneal clouding)
Morquio Syndrome (nl IQ, short, cloudy cornea) *tattoo on FI
-How are mucopolysaccharidoses Diagnosed?
Urine MPSs, definite with Skin Fibroblast Bx
How to treat Neonatal Hyperinsulinism?
Diazoxide- inhibits pancreatic B-cell insulin secretion.
DiazoxideChild Dx with PKU, now diet restricted, but with progressive
neuro deterioration. What else might be deficient?
neuro Tetrahydrobiopterin (BH4) Finally and to wet your appetite for
Sat: Name this syndrome and the associated metabolic
defect. Smith-Lemli-Opitz Syndrome: due to defect in
cholesterol For Reference:
For AAP Guidelines to IEMs.
1998;102;69- Barbara K. Burton DOI: 10.1542/peds.102.6.e69 Pediatrics Quick Algorithms:
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- Fall '11
- PKU, lactic acidosis, Inborn errors of metabolism, Hyperammonemia