Inborn Errors in Metabolism Flashcards
what is the general mechanism in IEM and three possible consequences?
block an enzyme
- substrate accumulates
- secondary metabolite accumulates
- decrease in product
what are the two categories of IEM and how is their Rx different?
- defects in energy sources (treat w/ diet)
2. defects in cellular organelles (difficult to treat)
why do IEMs typically present about a week after birth?
placenta allows for exchange of metabolites, but when neonate starts feeding toxic metabolites accumulate
what are the two main (general) presentations in IEM
acute decompensation
neurologic deterioration
what are common symptoms in neonates? (7)
poor feeding vomiting lethargy seizures liver dysfunction apnea abnormal odor
what are some common symptoms in infant/child? (8)
failure to grow recurrent vomiting seizures developmental delay developmental regression liver dysfunction abnormal odor yet...afebrile
when should you suspect IEM in neonates? children?
neonates w/ unexplained illness and normal pregnancy/delivery
children w/ acute unexplained deterioration with an illness
what are telltale clinical sign of IEM?
high ammonia, metabolic acidosis, hypoglycemia
There are ten lab tests that help. Name them
electrolyte panel blood glucose ammonia lactate liver function urine ketones plasma AA urine organic acids plasma acylcarinitines plasma carnitine
what does electrolyte panel tell you and what are possible disorders if abnormal?
acid base status, anion gap
organic acidemias
what does blood glucose tell you and what are possible disorders if abnormal?
can lead to change in mental status and acute illness
FA ox disorder
what does ammonia tell you and what are possible disorders if abnormal?
causes acute encaphalopathy
urea cycle disorders
organic acidemias
what does lactate tell you and what are possible disorders if abnormal?
errors in aerobic metabolism and gluconeogenesis
what does liver fxn test tell you and what are possible disorders if abnormal?
galactosemia can cause acute liver dmg
what does urine ketones tell you and what are possible disorders if abnormal?
organic acidemias = ketosis
FA ox disorder = hypoketotic
what does plasma AA tell you and what are possible disorders if abnormal?
diagnostic of aminoacidopathies
what does urine organic acids tell you and what are possible disorders if abnormal?
diagnostic of organic academies, FA ox, aminoacidopathies
what does plasma acylcarnitines tell you and what are possible disorders if abnormal?
organic acidemias, FA ox
what does plasma carnitine tell you and what are possible disorders if abnormal?
organic acidemias, fatty acid ox
What are some of the criteria for a disease to be included in newborn screening? (7)
- important health problem
- accepted treatment
- recognizable pre-symptomatic
- integrated program of education, testing, diagnostic confirmation, treatment, evaluation of outcome
- suitable test
- natural history of disease understood
- cost-benefit analysis
how are IEM typically inherited?
autosomal recessive
what are some of the characteristics of IEM inheritance? (5)
allelic heterogeneity locus heterogeneity modifier genes environmental factors NBS -> early intervention -> changes natural history
Give two main aminoacidopathies and the enzyme that is deficient.
1 PKU. phenylalanine hydroxylase
2. MSUD. alpha-KB dehydrogenase
what is elevated/low in PKU?
Phe, phenylacetate, phenyl pyruvate elevated
Tyr low
what are the symptoms of PKU if untreated in children (5)
severe MR seizures autistic like eczema light hair and complexion
what are symptoms of PKU if untreated in adults? (5)
lower cognitive skills executive function deficits increase psychological problems white matter injury maternal PKU syndrome
what are symptoms if PKU is treated?
normal growth and development
How do you treat PKU
Phe restriction w/ AA formula
Biopterin cofactor therapy
how does biopterin cofactor therapy work in PKU?
60% respond
Must have to have residual enzyme activity
how is MSUD inherited, and what is elevated?
autosomal recessive
Leu
what are the symptoms of MSUD
presents in first week of life
poor feeding –> lethargy –> coma
stroke, cerebral edema
maple syrup smell
how do you diagnose MSUD
plasma AA show elevated BCAA and alloleucine
how do you treat acute MSUD
promote anabolic state stop Leu intake give Ile, Val IV dex/lipids prevent cerebral edema
how do you treat chronic MSUD
low Leu diet w/ formula supplement Ile, Val monitor BCAA illness -- reduce Leu intake liver transplant curative
how do organic acidemias present?
metabolic acidosis with ketosis and elevated anion gap
how do you diagnose organic acidemias?
metabolic acidosis with ketosis and elevated anion gap
urine organic acids
urine ketones
secondary hyperammonemia in neonates from inhibition of urea cycle
How do you treat organic acidemias
low protein diet w/ formula
carnitine supp. to bind organic acids
relevant vitamin supp (i.e. biotin/B12)
monitor ketones
how do you treat acidemias during acute decompensation
stop protein intake
IV dex/lipids + insulin
biocarbonate
carnitine
how is propionic acidemia treated, what enzyme is defective, what is the metabolic defect?
autosomal recessive
propionylCoa carboxylase defective
defect in Val, Ile, Thr, Val, Met, odd chain FA metabolism
symptoms of propionic academia?
early onset encephalopathy = poor feeding –> lethargy, vomiting –> coma
poor weight gain, chronic vomiting
propionic acidemia natural history?
recurrent episodes w/ fasting, illness, p intake
illness = ketoacidosis, hyperammonemia
late cardiomyopathy, movement disorder, stroke
80% mortality by adulthood
treatment for propionic academia?
low protein diet
carnitine, biotin supp
avoid fasting
what is the primary feature of urea cycle disorders?
hyperammonemia without acidosis
main symptom of urea cycle
poor feeding –> lethargy, vomiting –> coma
how do you approach an encephalopathic neonate/infant?
check ammonia!
what is diagnostic of urea cycle disorders?
plasma AA
What is the treatment for urea cycle disorders
limit protein intake special formula supp w/ arginine or citrulline give ammonia scavenger sick day management
how is OTC inherited, what is the enzyme deficiency, and what is elevated/low?
X linked
ornithine transcarbamoylase
low citrulline, elevated orotic acid
what is the natural history of OTC?
15% of females have severe hyperammonemia from random X inactivation in liver
classically affected males die w/o liver transplant
how do you treat OTC?
major emergency: no protein intake glucose infusion IV arginine, sodium benzoate, sodium phenylacetate hemodialysis monitor cerebral edema
what is the primary feature of fatty acid oxidation?
hypoketotic hypoglycemia
at what age does FA ox disorder present?
once the age is reached when fasting is allowed (3-18 months)
what if FA ox disorder left untreated?
lethargy, coma, seizures, vomiting, SIDS
what are unique symptoms in long chain disorders?
cardiomyopathy and muscle weakness
how is FA ox disorder inherited?
AR
how do you diagnose FA ox disorder?
hypoketotic hypoglycemia
elevated acylcarnitine
urine organic acids
how do you treat FA ox
prevent hypoglycemia carnitine supp avoid fasts immunize cardiac eval
what is MCADD? primary feature?
medium acyl CoA dehydrogenase deficiency
hypoketotic hypoglycemia
