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Clinical Genetics > Inborn Errors in Metabolism > Flashcards

Inborn Errors in Metabolism Flashcards

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1
Q

what is the general mechanism in IEM and three possible consequences?

A

block an enzyme

  1. substrate accumulates
  2. secondary metabolite accumulates
  3. decrease in product
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2
Q

what are the two categories of IEM and how is their Rx different?

A
  1. defects in energy sources (treat w/ diet)

2. defects in cellular organelles (difficult to treat)

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3
Q

why do IEMs typically present about a week after birth?

A

placenta allows for exchange of metabolites, but when neonate starts feeding toxic metabolites accumulate

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4
Q

what are the two main (general) presentations in IEM

A

acute decompensation

neurologic deterioration

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5
Q

what are common symptoms in neonates? (7)

A 
poor feeding
vomiting
lethargy
seizures
liver dysfunction
apnea 
abnormal odor
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6
Q

what are some common symptoms in infant/child? (8)

A 
failure to grow
recurrent vomiting
seizures
developmental delay
developmental regression
liver dysfunction
abnormal odor
yet...afebrile
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7
Q

when should you suspect IEM in neonates? children?

A

neonates w/ unexplained illness and normal pregnancy/delivery

children w/ acute unexplained deterioration with an illness

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8
Q

what are telltale clinical sign of IEM?

A

high ammonia, metabolic acidosis, hypoglycemia

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9
Q

There are ten lab tests that help. Name them

A 
electrolyte panel
blood glucose
ammonia
lactate
liver function
urine ketones
plasma AA
urine organic acids
plasma acylcarinitines
plasma carnitine
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10
Q

what does electrolyte panel tell you and what are possible disorders if abnormal?

A

acid base status, anion gap

organic acidemias

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11
Q

what does blood glucose tell you and what are possible disorders if abnormal?

A

can lead to change in mental status and acute illness

FA ox disorder

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12
Q

what does ammonia tell you and what are possible disorders if abnormal?

A

causes acute encaphalopathy

urea cycle disorders
organic acidemias

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13
Q

what does lactate tell you and what are possible disorders if abnormal?

A

errors in aerobic metabolism and gluconeogenesis

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14
Q

what does liver fxn test tell you and what are possible disorders if abnormal?

A

galactosemia can cause acute liver dmg

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15
Q

what does urine ketones tell you and what are possible disorders if abnormal?

A

organic acidemias = ketosis

FA ox disorder = hypoketotic

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16
Q

what does plasma AA tell you and what are possible disorders if abnormal?

A

diagnostic of aminoacidopathies

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17
Q

what does urine organic acids tell you and what are possible disorders if abnormal?

A

diagnostic of organic academies, FA ox, aminoacidopathies

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18
Q

what does plasma acylcarnitines tell you and what are possible disorders if abnormal?

A

organic acidemias, FA ox

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19
Q

what does plasma carnitine tell you and what are possible disorders if abnormal?

A

organic acidemias, fatty acid ox

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20
Q

What are some of the criteria for a disease to be included in newborn screening? (7)

A
  1. important health problem
  2. accepted treatment
  3. recognizable pre-symptomatic
  4. integrated program of education, testing, diagnostic confirmation, treatment, evaluation of outcome
  5. suitable test
  6. natural history of disease understood
  7. cost-benefit analysis
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21
Q

how are IEM typically inherited?

A

autosomal recessive

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22
Q

what are some of the characteristics of IEM inheritance? (5)

A 
allelic heterogeneity
locus heterogeneity
modifier genes
environmental factors
NBS -> early intervention -> changes natural history
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23
Q

Give two main aminoacidopathies and the enzyme that is deficient.

A

1 PKU. phenylalanine hydroxylase

2. MSUD. alpha-KB dehydrogenase

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24
Q

what is elevated/low in PKU?

A

Phe, phenylacetate, phenyl pyruvate elevated

Tyr low

25
Q

what are the symptoms of PKU if untreated in children (5)

A 
severe MR
seizures
autistic like
eczema
light hair and complexion
26
Q

what are symptoms of PKU if untreated in adults? (5)

A 
lower cognitive skills
executive function deficits
increase psychological problems
white matter injury
maternal PKU syndrome
27
Q

what are symptoms if PKU is treated?

A

normal growth and development

28
Q

How do you treat PKU

A

Phe restriction w/ AA formula

Biopterin cofactor therapy

29
Q

how does biopterin cofactor therapy work in PKU?

A

60% respond

Must have to have residual enzyme activity

30
Q

how is MSUD inherited, and what is elevated?

A

autosomal recessive

Leu

31
Q

what are the symptoms of MSUD

A

presents in first week of life
poor feeding –> lethargy –> coma
stroke, cerebral edema
maple syrup smell

32
Q

how do you diagnose MSUD

A

plasma AA show elevated BCAA and alloleucine

33
Q

how do you treat acute MSUD

A 
promote anabolic state
stop Leu intake
give Ile, Val
IV dex/lipids
prevent cerebral edema
34
Q

how do you treat chronic MSUD

A 
low Leu diet w/ formula
supplement Ile, Val
monitor BCAA
illness -- reduce Leu intake
liver transplant curative
35
Q

how do organic acidemias present?

A

metabolic acidosis with ketosis and elevated anion gap

36
Q

how do you diagnose organic acidemias?

A

metabolic acidosis with ketosis and elevated anion gap
urine organic acids
urine ketones
secondary hyperammonemia in neonates from inhibition of urea cycle

37
Q

How do you treat organic acidemias

A

low protein diet w/ formula
carnitine supp. to bind organic acids
relevant vitamin supp (i.e. biotin/B12)
monitor ketones

38
Q

how do you treat acidemias during acute decompensation

A

stop protein intake
IV dex/lipids + insulin
biocarbonate
carnitine

39
Q

how is propionic acidemia treated, what enzyme is defective, what is the metabolic defect?

A

autosomal recessive

propionylCoa carboxylase defective

defect in Val, Ile, Thr, Val, Met, odd chain FA metabolism

40
Q

symptoms of propionic academia?

A

early onset encephalopathy = poor feeding –> lethargy, vomiting –> coma

poor weight gain, chronic vomiting

41
Q

propionic acidemia natural history?

A

recurrent episodes w/ fasting, illness, p intake
illness = ketoacidosis, hyperammonemia
late cardiomyopathy, movement disorder, stroke
80% mortality by adulthood

42
Q

treatment for propionic academia?

A

low protein diet
carnitine, biotin supp
avoid fasting

43
Q

what is the primary feature of urea cycle disorders?

A

hyperammonemia without acidosis

44
Q

main symptom of urea cycle

A

poor feeding –> lethargy, vomiting –> coma

45
Q

how do you approach an encephalopathic neonate/infant?

A

check ammonia!

46
Q

what is diagnostic of urea cycle disorders?

A

plasma AA

47
Q

What is the treatment for urea cycle disorders

A 
limit protein intake
special formula
supp w/ arginine or citrulline
give ammonia scavenger
sick day management
48
Q

how is OTC inherited, what is the enzyme deficiency, and what is elevated/low?

A

X linked
ornithine transcarbamoylase
low citrulline, elevated orotic acid

49
Q

what is the natural history of OTC?

A

15% of females have severe hyperammonemia from random X inactivation in liver

classically affected males die w/o liver transplant

50
Q

how do you treat OTC?

A 
major emergency:
no protein intake
glucose infusion 
IV arginine, sodium benzoate, sodium phenylacetate
hemodialysis
monitor cerebral edema
51
Q

what is the primary feature of fatty acid oxidation?

A

hypoketotic hypoglycemia

52
Q

at what age does FA ox disorder present?

A

once the age is reached when fasting is allowed (3-18 months)

53
Q

what if FA ox disorder left untreated?

A

lethargy, coma, seizures, vomiting, SIDS

54
Q

what are unique symptoms in long chain disorders?

A

cardiomyopathy and muscle weakness

55
Q

how is FA ox disorder inherited?

A

AR

56
Q

how do you diagnose FA ox disorder?

A

hypoketotic hypoglycemia
elevated acylcarnitine
urine organic acids

57
Q

how do you treat FA ox

A 
prevent hypoglycemia
carnitine supp
avoid fasts
immunize
cardiac eval
58
Q

what is MCADD? primary feature?

A

medium acyl CoA dehydrogenase deficiency

hypoketotic hypoglycemia

Clinical Genetics (6 decks)

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