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)
Low GAA on NBS, what disease?
Pompe disease
Deficiency of acid-alpha glucosidase enzyme
Next best test is echo yo looks for hypertrophic cardiomyopathy
EkG short PR interval
CK elevated
Tx:early enzyme replacement
1 week old with metabolic acidosis, ketosis and hyperammonemia. Dx?
Organic acidemia (B hydroxybutyrate, propionic acidemia and methylmalonic acidemia)
Think in setting of anion gap acidosis with normal lactate. If metabolic acidosis with lactatemia think disorders of pyruvate metabolism
Most common neonatal effect of maternal PKU?
Microcephaly 73%
Less common:
IUGR 40%
Congenital heart defect 12%
Dont forget PKU is AR deficiency of phenylalanine hydroxylase (converts Phe to tyrosine). Phe accumulates.
Control of maternal Phe <360 for 3 mo before conception is recommended to minimize rusk kf CHD and facial dysmorphism. Then 120-360 dueing pregancy to prevent IUGR, microcephaly and developmental delay
Steps in oxidative phosphorylation in mitochondria
Oxidation of glucose, aa, fatty avids —-> acetyl CoA—-> enters krebbs cycke —> electrons generated —-> in electron transport change —-> ATP
2 d old newborn male
Seizure
Hyper ammonemia
How to differentiate transient hyper ammonemia from urea cycle defect ?
Normal plasma aa in transient hyper ammonemia
Urea cycle defects with HIGHLY ABNORMAL plasma aa
What is the inheritance pattern of prader willi ?
- Deletions (MC) 65-75%
- Maternal uniparental disomy (20-30%)
- Imprinting 1-3%
15q11.2 - q13
Name syndromes caused by deletion of genetic mateials?
Cru du chat
Williams (7q11)
Rubinstein Taybi
Wolf Hirschhorn
When is Whole Exome Sequencing used?
T/C in neonates with a constellation of findings not suggestive of a specific syndrome with unrevealing initial testing
Describe Monosomy X presentation in the neonatal
Period
Turners syndrome:
LBW
Webbed nexk
Edema hands / feet
Coarctation of aorta
Most common causes of lactic acidosis
- Capillary sample (usually <4)
- Hypoxia (MCC <5mmol)
- Secondary lactic acidosis 2/2 IEM (5-10)
- Methymalonic acidemia (metabolic acidosis out of proportion to lactate level)
- LCFA oxidation disorders - Primary lactic acidosis (>10)
electron chain transport
Pyruvate dehydrogenase complex deficiency (encephalopathy and
What is the diagnosis? High lactate level Hypoglycemia Increased creatinine kinase Dilated cardiomyopathy ♥️ arrhythmia
Long chain fatty acid oxidation
Acylcarnitine profile is diagnostic
Ketoacidosis, hyperammonemia, hypoglycemia. Dx?
Methymalonic acidemia
Dx: urine organic acids
Tx: Vitamin B 12
Skeletal dysplasua associated with wide sutures, large fontanelle, clavicle hypoplasia, drooping shoulders
Cleidocranial dysplasia
What condition has macrocepgaly and abnormal posturing (dystonia, opisthotonos, athetosis)
Glutaric acidemia type 1
AR
Name the disease with this classic triad presenting at 2-3 d of life
Hyper ammonemia
Encephalopathy
Respiratory alkalosis
OTC
X link rec
Mom with PKU -
Infant is at risk for _____?
If not compliant throughout pregnancy- at risk for microcephaly
- mat Phe goal 120-360 to minimize iugr, microcephaly, dev delay
If not compliant in early part if pregnancy (< 8 weeks) - at risk for congenital ♥️ defects and facial dysmorphism
- control of mat Phe <360 mmol for 3 months prior to conception
Why can you see transient hyperammonemia in preterm infants?
Immature n acetylglutamate synthetase (NAGS) activity
Neonate with hypoglycemia, metabolic acidosis and hyperammonemia with polycystic kidney disease. What will the urine smell like?
Sweaty feet
Diagnosis is Glutaric Acidemia Type II (multiple acyl CoA dehydrogenase deficiency). Rare AR disorder.
Mutations in enzymes needed un the mutochondrial electron transfer chain
Neonatal onset form is fatal
Tx until diagnosis is confirmed includes IV glucose, carnitine, riboflavin, Na phenyl acetate/Na benzoate/arginine. May also need hemodialysis.
What is the diagnosis a neonate with the smell of maple syrup in urine (or ear wax) and why?
Maple syrup urine disease
Enzymatic deficiency leading to inability to metabolize 3 branched Aa (leucine, isoleucine, valine)
Neonates present with lethargy, poor feeding and irritability
Musty urine odor. Dx?
PKU
Deficiency un phenylalanine hydroxylase causing accumulation of Phe.
Leads to intellectual disabiltuy and seizures
The phenylacetic acid in sweat and urine leads to musty or mousy smell
Rotten fish smell
Trimethylaminuria
Seizures, alopecia, developmental delay and hearing deficits. Which enzyme deficiency?
Biotinidase deficiency
