Met 2: Disorders of AA Metabolism Flashcards
Name 4 criteria for which diseases should be on Newborn Screen
- Cost of screen and tx is much less than the cost of not treating (society-wide cost)
- Disease is well understood and there is a benefit to identifying it before symptoms appear
- There are established, effective treatments
- Testing is not super invasive (accepted by public)
Is Newborn Screen federal or state-based?
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
Describe the relationship between the prevalence and PPV in Newborn Screenings
- 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
Compare the pre-test and pos-test probability in NBS
- Pre-test probability is tiny
- Metabolic disorders are rare
- Post-test probability is higher, but still quite low
What happens next after a positive NBS?
A positive NBS -> more testing
*Remember, most positive NBS are FALSE positive due to rarity of metabolic disorders!
Describe the negative predictive value of NBS.
How does this relate to the “abnormal” threshold?
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
Compare the PPV and NPV of newborn screens
High NPV, Low PPV
This ensures that you catch all true cases of disease
What is the inheritance of PKU?
Name 2 underlying defects that can cause PKU
- Autosomal recessive
- Defect in phenylalanine hydroxylase OR tetrahydrobiopterin (cofactor)
What reaction is defective in PKU?
What metabolites build up and what is deficient?
PKU cannot convert phenylalanine to tyrosine
This causes a buildup of Phe and a deficiency of Tyr
Which PKU defect is worse: Phenylalanine hydroxylase or THB?
THB b/c it’s used in other pathways too
Name 3 symptoms of untreated PKU
- Intellectual disability
- Hypopigmentation (Phe is precursor for melanin)
- Eczema
What is the dietary treatment for PKU? (2)
How long do you treat?
- Restrict dietary protein
- Supplement all non-Phe amino acids to prevent malnutrition
- Tx is LIFELONG
What is an alternative to dietary treatment of PKU?
Does it work in all patients?
- 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)
What is Maternal PKU?
- 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
What is the defect in Maple Syrup Urine Disease?
What metabolite causes sx?
- Defect in branched chain ketoacid dehydrogenase
- Can’t digest branched chain AA’s
- Sx due to Leucine accumulation
Name the 3 branched amino acids
Isoleucine, leucine, Valine
A child is irritable, lethargic, displays opisthotonus, and becomes apneic. Which metabolic syndrome is responsible?
When would these symptoms show up?
This is Maple Syrup Urine Disease
(*Opisthotonus is evidence of encephalopathy)
Onset at 48 hours because long enough to build up Leucine
What is one adult consequence of MSUD?
Psychiatric disorders
Which syndrome is an emergency: PKU or MSUD?
Only MSUD has acute problems.
PKU has chronic problems.
Name 3 lab findings in MSUD
- Elevated Leucine
- Presence of allo-isoleucine (should never be present)
- Presence of urine ketones in neonate (should not be present in neonates)
What is chronic tx of MSUD? (3)
- Limit dietary protein
- Supplement protein without Leucine
- Supplement thiamine
- Cofactor for enzyme
What cures MSUD?
Liver transplant
What is the presenting symptom of tyrosinemia type I?
What are 4 other signs/symptoms?
- Presents as acute liver failure in infancy
- Other sx: Secondary porphyria, neuropathy, hepatocellular carcinoma, rickets
What is the diagnostic metabolic in tyrosinemia type I?
succinylacetone in urine
What is the defect in tyrosinemia Type I?
Fuarylacetoacetate hydrolase deficiency
Name 2 signs of tyrosinemia Type II
Is this primarily chronic or acute?
Corneal crystals
hyperkeratosis of palms/soles
No acute complications (chronic condition)
Compare the Tyrosine elevations in tyrosinemia type I and type II.
Which form is more severe dz?
Only Type II has really high Tyr
BUT, Type I is more severe disease
Describe the tx for tyrosinemia type I and its rationale
- 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
What is the defect in Homocystinuria?
What metabolite is responsible for sx?
- Defect in cystathionine beta synthase
- Symptoms due to toxic elevations of homocysteine
Name 4 signs/symptoms of homocystinuria
- Lens dislocation
- Scoliosis
- Pectus carinatum
- Thrombotic risk
Tx of homocystinuria (4)
- 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
symptoms of acute hyperammonemia (4 CNS)
symptoms of chronic hyperammonemia (3 CNS, 2 GI)
Acute: encephalopathy, ataxia, hallucinations, visual loss
Chronic: developmental delay, migraines, psychiatric disorders, nausea/failure to thrive, hepatomegaly
Mild urea cycle enzyme disorders will become symptomatic with what 4 conditions?
- Fever, illness, surgery,
- Catabolic state
- Post-partum
- Breaking down pregnancy structures
- Exces dietary protein
- weight lifters
- Valproate
What is the most common urea cycle disorder?
Describe the gene and its inheritance
- Ornithine transcarbamylase deficiency
- X-linked, but females are symptomatic
- OTC gene (only in liver)
Why does liver transplant cure ornithine transcarbamylase deficiency?
Liver transplant is curative b/c enzyme is only expressed in liver
What is the diagnostic metabolic in ornithine transcarbamylase deficiency?
Orotic acid
Also see elevated glutamine
Which metabolic disorder discussed is NOT on newborn screen?
Ornithine transcarbamylase deficiency
Management of ornithine transcarbamylase deficiency (3)
- Low protein diet
- Ammonia scavengers
- Supplement citrulline/arginine (upregulate urea cycle)
