IEM Flashcards
3d old in ER
PooR feeding, lethargic, RR 80
tachypnea, respiratory alkalosis
hyper ammonemia
OTC deficiency is most common
1’ Urea cycle defect
- resp alkalosis, low bun
2’ urea cycle defect
-Metabolic acidosis, high bun
If you suspect a metabolic disorder. What tests should you send?
You send diagnostic labs • Plasma amino acids • Urine organic acids • Urine orotic acid • Plasma acylcarnitine profile • Plasma total and free carnitine
What’s the differential of hyperammonemia?
Primary urea cycle defects: • Respiratory alkalosis, low BUN, hyperNH3 • NAGS deficiency, CPS deficiency, OTC deficiency, citrullinemia, argininosuccinic aciduria (ASAuria)
• Secondary urea cycle defects:
• Metabolic acidosis, high anion gap, normal/high BUN
• Organic acidemias: propionic acidemia, methylmalonic acidemia, etc.
• Sometimes: Mitochondrial disorders (severe lactic acidosis when crisis), Fatty
acid oxidation defect (often severe hypoglycemia on presentation), etc.
Lethargic tachypneic hypothermia and vomiting with suspected sepsis. What testing should you send besides sepsis workup?
Ammonia
Duration of ammonia is more important than peak level
What is the key management of hyperammonemia?
Energy
high dextrose and intralipids to turn catabolic state into anabolic state
What is the management of Neonatal Hyperammonenia (Acute)?
• Central line - always
• For frequent blood draws, high dextrose IVF, etc.
Umbilical site often available for UVC as infants typically < 7 days old
- Hydration
- Often dehydrated and need more than maintenance IVF
- Energy - THE KEY to management (turn catabolism into anabolic state)
- Dextrose (e.g. 10-25 %) +/- insulin
- Intralipids (unless strong suspicion of fatty acid oxidation defect)
• Ammonia scavengers
• IV Na-benzoate - Na-phenylacetate 250 mg/kg load (90mins) > 250 mg/kg/d
Central line recommended but peripheral line has been used
• Cofactors / downstream metabolites
• For UCDs: Arginine HCI load > maintenance infusion
• Dialysis (CVVH, HD)
• For hyperNH3 not responsive to above measurements, or NH3 already very high
Why does OTC have low BUn?
They don’t produce urea
Most common etiologies of neonatal hyperammonemia
- Urea cycle defects
- Organic acidemias
- Fatty acid oxidation defects (sometimes)
- Mitochondrial disorders (sometimes, typically with prominent lactic acidosis)
- Urea cycle defects:
- Typically primary respiratory alkalosis, no (or minimal) acidosis, low BUN
• Organic acidemias (MMA, propionic acidemia, etc.)
• Primary metabolic acidosis, high anion gap, secondary respiratory alkalosis
(compensation & NH3 being CNS stimulant), normal/high BUN
- Many detected via NBS, but may present before NBS back
- Send NH3 (STAT, ICED), send confirmatory labs, start treatment (energy!)
Alert baby tachypneic with severe metabolic acidosis and severe lactitemia. Dx?
Mitochondrial disorder
Term male, NSVD, Apgars 8/9. Alert, persistent tachypnea, metabolic
acidosis, lactic acidosis. A mitochondrial disorder is in your differential. You sent biochemical testing (PAA, UOA, etc.). Which Plasma amino acid is elevated?
Alanine
Term male, NSVD, Agars 8/9. Alert, tachypnea, metabolic/lactic acidosis.
Plasma amino acids with elevated alanine. Brain MRI with MRS shows
lactate peaks in basal ganglia. Which test has the highest likelihood of
diagnosing a mitochondrial disorder?
Nuclear mitochondrial gene panel
Most are AR. WES or WGS also can be done
Mitochondrial disorders presentation
• Mitochondrial respiratory chain produces ATP (energy) for cellular demands via oxidative phosphorylation (OXPHOS) • Deficient OXPHOS > anaerobic glycolysis > lactic acidosis • Symptoms can appear in any organ but typically from organs with high energy demand: • brain, liver, heart
Brain MRI with MRS: lactate peaks in basal ganglia • Tissue (often skin) biopsy foor respiratory chain enzyme activity mtDNA testing • Nuclear mitochondrial genes • Whole exome/genome sequencing
• Mitochondrial respiratory chain produces ATP (energy) for cellular demands via oxidative phosphorylation (OXPHOS) • Deficient OXPHOS > anaerobic glycolysis > lactic acidosis • Symptoms can appear in any organ but typically from organs with high energy demand: • brain, liver, heart
How do mitochondrial disorder present in neonate?
• Severe lactic acidosis • Seizures • Cardiomyopathy (often fatal hypertrophic obstructive) • Liver failure • Hypotonia • Hyperammonemia (can happen!) • Renal tubulopathy
Treatment for mitochondrial disorder
• Supportive management:
• Feeding tube, hearing aids, developmental therapies, etc.
• Diet:
• Regular infant formulas OK.
• Healthy “Mediterranean diet” for adults
• Avoid very high dextrose in IVF (can worsen lactic acidosis)
• Supplements (theoretical benefit, may help some patients):
• Coenzyme Q10, carnitine, vitamin C, vitamin E, alpha-lipoic,
thiamine, riboflavin, niacin, folic acid, arginine, citrulline
Avoid valproic acid
What drug should you avoid with mitochondrial dusordrs
Valproate
Newborns produce ketones T/F
False
Think maple syrup urine disease if encephalopathy normal lytes
Plasma amino acids Diagnostic marker (also higher branched aminos Leu, Ile, Val)
Alli-isoleucine
4 day Lethargic + poor feeding NH3 normal Jerking movements Ketones on UA
MSUD (ketones, encéphalopathic)
Management of MSUD?
MAPLE SYRUP URINE DISEASE (MSUD)
• Goal of management:
• Leucine toxic to brain, competes for transporter with lle and Val > control
leucine levels, supplement valine+isoleucine
• Management of acute crisis
• Energy - reverse catabolism!
• High dextrose +/- insulin, lipids, non-leucine amino acids
• Monitor for cerebral edema: keep Na normal, hypertonic saline, mannitol
• Chronic management (parts pertinent to NICU):
• Close monitoring of plasma leucine
• Special formula (free of branched chain amino acids)
• Supplement valine, isoleucine
• Liver transplantation (curative)
Which diagnosis should you think of in an atypical HIE?
• If you have an encephalopathic neonate, remember :
• Maple syrup urine disease (ketones, no acidosis/hyperNH3)
• Neonatal seizures (multiple metabolic etiologies, see other talk)
• Hyperammonemia (UCDs, organic acidemias, etc.)
• Mitochondrial disorders, disorders of pyruvate metabolism (lactic acidosis)
• Send:
• NH3 (STAT, ON ICE), lactate (FREE FLOWING), blood gas, lytes, transaminases
• Plasma aminos, urine organics, plasma acylcarnitines, etc.
• Above conditions typically start after a 1-3-day period of “being a
normal newborn”.
Metabolic disorders mimicking HIE (symptomatic
from the get-go) also exist: remember IEM when unusual HIe
3-day old infant with hyperammonemia. Severe anion gap metabolic acidosis with compensatory respiratory alkalosis. Normal/high BUN. No hypoglycemia. What is the most likely diagnosis?
Methylmalonic acidemia
Male, Late preterm oligo IUGR neutropenic, lactic acidosis, round facies, deep set eyes, dilated cardiomyopathy with LV noncompaction. Dx?
Barth syndrome
Taz gene, x-linked mitochondrial dx
Dx: urine organic acids or taz gene mutation
Newborn with phenylalanine>120umol/L. Which enzyme is deficient?
Phenylalanine hydroxylase
PKU
They also have increased Phe/tyrosine
Mother with PKU, infant at risk for _____?
Microcephaly (MC)
IUGR
CDH
Intellectual disability
6 day old suspected sepsis hyperbili Significantly increased left Blood and urine culture - E. coli
additional labs?
Dx?
Coags
Galactosemia (early onset liver failure + E. coli sepsis)
AR
GALT enzyme activity low (galactose 1 phosphate iridium transferase)
