IEM Flashcards

1
Q

3d old in ER
PooR feeding, lethargic, RR 80
tachypnea, respiratory alkalosis
hyper ammonemia

A

OTC deficiency is most common

1’ Urea cycle defect
- resp alkalosis, low bun

2’ urea cycle defect
-Metabolic acidosis, high bun

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2
Q

If you suspect a metabolic disorder. What tests should you send?

A
You send diagnostic labs
• Plasma amino acids
• Urine organic acids
• Urine orotic acid
• Plasma acylcarnitine profile
• Plasma total and free carnitine
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3
Q

What’s the differential of hyperammonemia?

A
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.

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4
Q

Lethargic tachypneic hypothermia and vomiting with suspected sepsis. What testing should you send besides sepsis workup?

A

Ammonia

Duration of ammonia is more important than peak level

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5
Q

What is the key management of hyperammonemia?

A

Energy

high dextrose and intralipids to turn catabolic state into anabolic state

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6
Q

What is the management of Neonatal Hyperammonenia (Acute)?

A

• 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

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7
Q

Why does OTC have low BUn?

A

They don’t produce urea

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8
Q

Most common etiologies of neonatal hyperammonemia

A
  • 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!)
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9
Q

Alert baby tachypneic with severe metabolic acidosis and severe lactitemia. Dx?

A

Mitochondrial disorder

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10
Q

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?

A

Alanine

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11
Q

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?

A

Nuclear mitochondrial gene panel

Most are AR. WES or WGS also can be done

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12
Q

Mitochondrial disorders presentation

A
• 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
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13
Q

How do mitochondrial disorder present in neonate?

A
• Severe lactic acidosis
• Seizures
• Cardiomyopathy (often fatal
hypertrophic obstructive)
• Liver failure
• Hypotonia
• Hyperammonemia (can happen!)
• Renal tubulopathy
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14
Q

Treatment for mitochondrial disorder

A

• 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

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15
Q

What drug should you avoid with mitochondrial dusordrs

A

Valproate

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16
Q

Newborns produce ketones T/F

A

False

Think maple syrup urine disease if encephalopathy normal lytes

Plasma amino acids Diagnostic marker (also higher branched aminos Leu, Ile, Val)
Alli-isoleucine

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17
Q
4 day 
Lethargic + poor feeding 
NH3  normal 
Jerking movements 
Ketones on UA
A

MSUD (ketones, encéphalopathic)

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18
Q

Management of MSUD?

A

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)

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19
Q

Which diagnosis should you think of in an atypical HIE?

A

• 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

20
Q

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?

A

Methylmalonic acidemia

21
Q

Male, Late preterm oligo IUGR neutropenic, lactic acidosis, round facies, deep set eyes, dilated cardiomyopathy with LV noncompaction. Dx?

A

Barth syndrome

Taz gene, x-linked mitochondrial dx

Dx: urine organic acids or taz gene mutation

22
Q

Newborn with phenylalanine>120umol/L. Which enzyme is deficient?

A

Phenylalanine hydroxylase

PKU
They also have increased Phe/tyrosine

23
Q

Mother with PKU, infant at risk for _____?

A

Microcephaly (MC)

IUGR
CDH
Intellectual disability

24
Q
6 day old
suspected sepsis 
hyperbili 
Significantly increased left
Blood and urine culture  - E. coli 

additional labs?
Dx?

A

Coags
Galactosemia (early onset liver failure + E. coli sepsis)

AR
GALT enzyme activity low (galactose 1 phosphate iridium transferase)

25
Q

Low GAA on NBS, what disease?

A

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

26
Q

1 week old with metabolic acidosis, ketosis and hyperammonemia. Dx?

A

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

27
Q

Most common neonatal effect of maternal PKU?

A

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

28
Q

Steps in oxidative phosphorylation in mitochondria

A

Oxidation of glucose, aa, fatty avids —-> acetyl CoA—-> enters krebbs cycke —> electrons generated —-> in electron transport change —-> ATP

29
Q

2 d old newborn male
Seizure
Hyper ammonemia

How to differentiate transient hyper ammonemia from urea cycle defect ?

A

Normal plasma aa in transient hyper ammonemia

Urea cycle defects with HIGHLY ABNORMAL plasma aa

30
Q

What is the inheritance pattern of prader willi ?

A
  1. Deletions (MC) 65-75%
  2. Maternal uniparental disomy (20-30%)
  3. Imprinting 1-3%

15q11.2 - q13

31
Q

Name syndromes caused by deletion of genetic mateials?

A

Cru du chat
Williams (7q11)
Rubinstein Taybi
Wolf Hirschhorn

32
Q

When is Whole Exome Sequencing used?

A

T/C in neonates with a constellation of findings not suggestive of a specific syndrome with unrevealing initial testing

33
Q

Describe Monosomy X presentation in the neonatal

Period

A

Turners syndrome:

LBW
Webbed nexk
Edema hands / feet
Coarctation of aorta

34
Q

Most common causes of lactic acidosis

A
  1. Capillary sample (usually <4)
  2. Hypoxia (MCC <5mmol)
  3. Secondary lactic acidosis 2/2 IEM (5-10)
    - Methymalonic acidemia (metabolic acidosis out of proportion to lactate level)
    - LCFA oxidation disorders
  4. Primary lactic acidosis (>10)
    electron chain transport
    Pyruvate dehydrogenase complex deficiency (encephalopathy and
35
Q
What is the diagnosis?
High lactate level
Hypoglycemia 
Increased creatinine kinase 
Dilated cardiomyopathy 
♥️ arrhythmia
A

Long chain fatty acid oxidation

Acylcarnitine profile is diagnostic

36
Q

Ketoacidosis, hyperammonemia, hypoglycemia. Dx?

A

Methymalonic acidemia

Dx: urine organic acids

Tx: Vitamin B 12

37
Q

Skeletal dysplasua associated with wide sutures, large fontanelle, clavicle hypoplasia, drooping shoulders

A

Cleidocranial dysplasia

38
Q

What condition has macrocepgaly and abnormal posturing (dystonia, opisthotonos, athetosis)

A

Glutaric acidemia type 1

AR

39
Q

Name the disease with this classic triad presenting at 2-3 d of life
Hyper ammonemia
Encephalopathy
Respiratory alkalosis

A

OTC

X link rec

40
Q

Mom with PKU -

Infant is at risk for _____?

A

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

41
Q

Why can you see transient hyperammonemia in preterm infants?

A

Immature n acetylglutamate synthetase (NAGS) activity

42
Q

Neonate with hypoglycemia, metabolic acidosis and hyperammonemia with polycystic kidney disease. What will the urine smell like?

A

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.

43
Q

What is the diagnosis a neonate with the smell of maple syrup in urine (or ear wax) and why?

A

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

44
Q

Musty urine odor. Dx?

A

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

45
Q

Rotten fish smell

A

Trimethylaminuria

46
Q

Seizures, alopecia, developmental delay and hearing deficits. Which enzyme deficiency?

A

Biotinidase deficiency