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GI Block > Met 2: Disorders of AA Metabolism > Flashcards

Met 2: Disorders of AA Metabolism Flashcards

1
Q

Name 4 criteria for which diseases should be on Newborn Screen

A
  1. Cost of screen and tx is much less than the cost of not treating (society-wide cost)
  2. Disease is well understood and there is a benefit to identifying it before symptoms appear
  3. There are established, effective treatments
  4. Testing is not super invasive (accepted by public)
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2
Q

Is Newborn Screen federal or state-based?

A

Newborn Screen is state-based

*federal HHS creates recommendations for which conditions should be on NBS, but states ultimately determine what to put on their NBS

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3
Q

Describe the relationship between the prevalence and PPV in Newborn Screenings

A
  • Metabolic disorders are VERY RARE
  • So, even with a very good test,
  • # false positives >>> # true positives
    • B/c there are just so many more kids in the no disease category (remember, you test ALL kids)
  • So, the Positive Predictive Value is low
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4
Q

Compare the pre-test and pos-test probability in NBS

A
  • Pre-test probability is tiny
    • Metabolic disorders are rare
  • Post-test probability is higher, but still quite low
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5
Q

What happens next after a positive NBS?

A

A positive NBS -> more testing

*Remember, most positive NBS are FALSE positive due to rarity of metabolic disorders!

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6
Q

Describe the negative predictive value of NBS.

How does this relate to the “abnormal” threshold?

A

The negative predictive value of the NBS is 100% (there are no false negatives, so all true disease kids will have a positive test)

To accomplish this, the “abnormal” threshold is set so high that you also end up getting a lot of false positives

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7
Q

Compare the PPV and NPV of newborn screens

A

High NPV, Low PPV

This ensures that you catch all true cases of disease

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8
Q

What is the inheritance of PKU?

Name 2 underlying defects that can cause PKU

A
  • Autosomal recessive
  • Defect in phenylalanine hydroxylase OR tetrahydrobiopterin (cofactor)
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9
Q

What reaction is defective in PKU?
What metabolites build up and what is deficient?

A

PKU cannot convert phenylalanine to tyrosine

This causes a buildup of Phe and a deficiency of Tyr

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10
Q

Which PKU defect is worse: Phenylalanine hydroxylase or THB?

A

THB b/c it’s used in other pathways too

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11
Q

Name 3 symptoms of untreated PKU

A
  • Intellectual disability
  • Hypopigmentation (Phe is precursor for melanin)
  • Eczema
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12
Q

What is the dietary treatment for PKU? (2)

How long do you treat?

A
  • Restrict dietary protein
  • Supplement all non-Phe amino acids to prevent malnutrition
  • Tx is LIFELONG
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13
Q

What is an alternative to dietary treatment of PKU?

Does it work in all patients?

A
  • Give synthetic THB, Sapropterin
  • This increases the activity of phe hydroxylase
  • This tx does NOT work if you have a totally nonfunctional Phenylalanine Hydroxylase (mutation must be partial or must be in THB)
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14
Q

What is Maternal PKU?

A
  • Maternal PKU is damage to the embryo due to the mom having PKU
  • Mom’s high phe levels are teratogenic
  • This was worse when we only treated through age 6
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15
Q

What is the defect in Maple Syrup Urine Disease?

What metabolite causes sx?

A
  • Defect in branched chain ketoacid dehydrogenase
  • Can’t digest branched chain AA’s
  • Sx due to Leucine accumulation
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16
Q

Name the 3 branched amino acids

A

Isoleucine, leucine, Valine

17
Q

A child is irritable, lethargic, displays opisthotonus, and becomes apneic. Which metabolic syndrome is responsible?

When would these symptoms show up?

A

This is Maple Syrup Urine Disease

(*Opisthotonus is evidence of encephalopathy)

Onset at 48 hours because long enough to build up Leucine

18
Q

What is one adult consequence of MSUD?

A

Psychiatric disorders

19
Q

Which syndrome is an emergency: PKU or MSUD?

A

Only MSUD has acute problems.

PKU has chronic problems.

20
Q

Name 3 lab findings in MSUD

A
  • Elevated Leucine
  • Presence of allo-isoleucine (should never be present)
  • Presence of urine ketones in neonate (should not be present in neonates)
21
Q

What is chronic tx of MSUD? (3)

A
  • Limit dietary protein
  • Supplement protein without Leucine
  • Supplement thiamine
    • Cofactor for enzyme
22
Q

What cures MSUD?

A

Liver transplant

23
Q

What is the presenting symptom of tyrosinemia type I?

What are 4 other signs/symptoms?

A
  • Presents as acute liver failure in infancy
  • Other sx: Secondary porphyria, neuropathy, hepatocellular carcinoma, rickets
24
Q

What is the diagnostic metabolic in tyrosinemia type I?

A

succinylacetone in urine

25
Q

What is the defect in tyrosinemia Type I?

A

Fuarylacetoacetate hydrolase deficiency

26
Q

Name 2 signs of tyrosinemia Type II

Is this primarily chronic or acute?

A

Corneal crystals

hyperkeratosis of palms/soles

No acute complications (chronic condition)

27
Q

Compare the Tyrosine elevations in tyrosinemia type I and type II.

Which form is more severe dz?

A

Only Type II has really high Tyr

BUT, Type I is more severe disease

28
Q

Describe the tx for tyrosinemia type I and its rationale

A
  • Tyrosinemia I has a block in DISTAL part of Tyr metabolism pathway
  • Build-up of one of distal metabolites is toxic
  • Tx: NTBC blocks an upstream enzyme
  • This induces Tyrosinemia III
    • can be treated with diet
    • don’t get build-up of distal metabolite
29
Q

What is the defect in Homocystinuria?

What metabolite is responsible for sx?

A
  • Defect in cystathionine beta synthase
  • Symptoms due to toxic elevations of homocysteine
30
Q

Name 4 signs/symptoms of homocystinuria

A
  • Lens dislocation
  • Scoliosis
  • Pectus carinatum
  • Thrombotic risk
31
Q

Tx of homocystinuria (4)

A
  • Supplement cofactor B6 (pyridoxine) used by defective enzyme
  • Supplement with Betaine, which induces homocystein breakdown into Methionine
  • Methionine free diet (allow Homocysteine to be degraded into Met)
  • Anticoagulation, avoid smoking, no oral contraceptives
32
Q

symptoms of acute hyperammonemia (4 CNS)

symptoms of chronic hyperammonemia (3 CNS, 2 GI)

A

Acute: encephalopathy, ataxia, hallucinations, visual loss

Chronic: developmental delay, migraines, psychiatric disorders, nausea/failure to thrive, hepatomegaly

33
Q

Mild urea cycle enzyme disorders will become symptomatic with what 4 conditions?

A
  • Fever, illness, surgery,
    • Catabolic state
  • Post-partum
    • Breaking down pregnancy structures
  • Exces dietary protein
    • weight lifters
  • Valproate
34
Q

What is the most common urea cycle disorder?

Describe the gene and its inheritance

A
  • Ornithine transcarbamylase deficiency
  • X-linked, but females are symptomatic
  • OTC gene (only in liver)
35
Q

Why does liver transplant cure ornithine transcarbamylase deficiency?

A

Liver transplant is curative b/c enzyme is only expressed in liver

36
Q

What is the diagnostic metabolic in ornithine transcarbamylase deficiency?

A

Orotic acid

Also see elevated glutamine

37
Q

Which metabolic disorder discussed is NOT on newborn screen?

A

Ornithine transcarbamylase deficiency

38
Q

Management of ornithine transcarbamylase deficiency (3)

A
  • Low protein diet
  • Ammonia scavengers
  • Supplement citrulline/arginine (upregulate urea cycle)

GI Block (77 decks)

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