Biochemical Genetics Flashcards
Defect in the synthesis of cortisol from pregnenolone via 21-hydroxylase
17-hydroxyprogesterone -x-> 11-deoxycortisol
excess 17-hydroxyprogesterone converts to androgens (testosterone) causing virilization in utero
Lack of cortisol results in salt imbalances in the kidneys
CAH (congenital adrenal hyperplasia)
What metabolic tests are commonly ordered?
amino acids organic acids acylcarnitine profiles enzyme assays gene sequencing
Phenylalanine
amino acid abnormality found on quantitative analysis associated with PKU (nl ~70 umol/L; PKU > 1200)
Leucine
amino acid abnormality found on quantitative analysis associated with MSUD (nl ~100 umol/L; MSUD > 700)
Methionine, homocysteine
amino acid abnormalities found on quantitative analysis associated with homocystinuria
Citrulline
amino acid abnormality found on quantitative analysis associated with urea cycle disorders
What is important to remember when ordering amino acid panels?
Can be done on blood OR urine
Best to do a fasting specimen (because levels go up after a meal)
Slight elevations are common, significant elevations (3-10 times normal limit) indicate concern for disease
What is important to remember when ordering organic acid panels?
Done most often on urine
Can be qualitative or quantitative
Slight elevations are common, making it occasionally difficult to interpret
Branched chain ketoacids
organic acid abnormality found on analysis associated with MSUD
What testing should be ordered for children with:
developmental delays OR
unexplained acute illnesses OR
poor growth (“failure to thrive”).
amino acid and organic acid screening
What is important to remember when ordering an acylcarnitine profile?
Can be done on blood OR urine (but blood is most common)
By detecting carnitines you can reflect intracellular acyl-CoA’s
C3 elevation (acylcarnitine profile)
propionlycarnitine (propionic or methylmalonic acidemia)
C8 elevation (acylcarnitine profile)
octanoylcarnitine (MCAD)
C14:1 elevation (acylcarnitine profile)
14 carbons, one double bond (VLCAD)
What is important to remember when ordering enzyme assays?
done on blood (enzymes that appear in WBC or serum or are stable enough for dried blood spot for NBS) or biopsy specimens (enzymes that are tissue specific such as liver or muscle or require fibroblasts which require skin biopsy and culture)
try to minimize freeze/transport because this can affect results
What is important to remember when ordering testing for inborn errors in metabolism in general?
gene sequencing is often preferred to enzyme assay (since most have known genetic loci) - since DNA is often more accessible (rather than biopsy) and there is less problems from transport artifacts
Not the possibility of VUS, though
List the causes of methylmalonic aciduria (elevated C3 on acylcarnitine profile).
Methylmalonyl-CoA mutase deficiency (most common and most severe) Cobalamin defects (Cbl A, Cbl B, Cbl C, etc.; can't activate B12) Pernicious Anemia/Vitamin B12 deficiency (because it is a cofactor of the methylmalonyl-CoA mutase reaction)
List the causes of homocystinuria.
Classical- Methionine metabolism defects (cystathionine beta-synthase)
Defects in folic acid metabolism OR vitamin B12 metabolism (homocysteinemia)
Most common cause- Folate defect (MTHFR)
NOTE- this can present very similarly to Marfan syndrome with a significant intellectual disability aspect (not seen in Marfan)
List the causes of propionic acidemia.
Defects in propionyl-CoA carboxylase enzyme (has two subunits with two different genetic loci on different chromosomes - same symptoms)
Biotin (cofactor for PCC) defects (causes different symptoms than PCC defects)
What are the general symptoms/principles that would lead you to suspect an IEM in an acutely ill infant?
Term babies Good APGARs No dysmorphic features Normal for first 24-48 hours (prodrome) Problems/distress related to feeding Lethargy Emesis Seizures Hepatomegaly Breathing pattern (hyperammonemia - rapid, shallow; acidosis - deep/Kussmaul breathing)/respiratory distress Anion gap Hypoglycemia Lactic acidemia (more common in mito) Ammonia level (high- 10-20x normal) Ketonuria/high blood ketones Blood amino acid abnormalities Urine organic acid abnormalities Carnitine/acylcarnitine profiles
Provide a genetics Ddx for the following acute illness symptoms:
emesis
lethargy
coma
Urea cycle defects
Galactosemia (with milk feedings)
Maple Syrup Urine disease (MSUD)
Organic acidemias (propionic, methylmalonic, isovaleric)
Provide a genetics Ddx for the following acute illness symptoms:
acidosis with blood pH < 7.1 (nl 7.4) and/or blood bicarb < 10 (nl 25)
Organic acidemias (propionic acidemia, methylmalonic acidemia, isovaleric acidemia) Primary lactic acidosis (electron transport chain/mito defects, pyruvate dehydrogenase deficiency)
Provide a genetics Ddx for the following acute illness symptoms:
respiratory distress
neonatal “pneumonia” (without actual infection)
Urea cycle defects (hyperpnea - rapid breathing) Organic acidemias (Kussmaul - deep breathing) Maple syrup urine disease (respiratory depression) Nonketotic hyperglycinemia (hiccuping and/or apnea)
Provide a GENETICS Ddx for the following acute illness symptoms (note that this is common in newborns and is usually not due to an enzymopathy):
hypoglycemia
Congenital adrenal hyperplasia (CAH) Fatty acid oxidation defects Galactosemia Propionic acidemia Gluconeogenic defects Glycogen storage disorders
Provide a genetics Ddx for the following acute illness symptoms:
hepatomegaly
Galactosemia (also have liver failure)
Tyrosinemia (usually later)
Fatty acid oxidation defects
Lysosomal storage disorders (usually later)
Provide a genetics Ddx for the following acute illness symptoms;
seizures
Nonketotic hyperglycinemia
Urea cycle defects (hyperammonemia)
Organic acidemias (hyperammonemia, hypoglycemia)
Gluconeogenic defects (hypoglycemia)
Lysosomal storage disorders (usually later)
acute hyperammonemia (NI ammonia ~30)
tachypnea (respiratory alkalosis), emesis, lethargy
NOT ACIDOTIC
neonatal comas (associated with ID)
Urea cycle defects
How can urea cycle defects be treated?
dialysis
medications (especially ammonia scavengers)
organ transplant
List the amino acids that carry ammonia in the urea cycle.
Ornithine Citrulline Argininosuccinate Arginine NOTE- all of these are measurable by amino acid analysis (can tell us which enzyme may be deficient)
acute, severe neonatal ketoacidosis (pH < 7.1)
emesis, hyperpnea, lethargy
Organic acidemias
How do you treat organic acidemias?
some respond to diet/vitamin treatment (B6 in homocystinuria; B12 in methylmalonic aciduria)
dialysis for acute illness
some may need kidney + liver transplant (methylmalonic acidemia)
severe ketoacidosis
sweaty feet odor
isovaleric acid in urine organic acids
elevated C5 acylcarnitine
isovaleric acidemia (isovaleryl-CoA dehydrogenase deficiency)
acute ketoacidosis with sweet smell lethargy hypotonia respiratory depression seizures emesis elevated leucine on serum amino acids branched chain acids found on urine organic acids
Maple syrup urine disease (MSUD)
How are fatty acid oxidation defects treated?
some can respond to avoidance of prolonged fasting (especially MCAD)
How can you treat MSUD?
responds well to diet
vitamin Rx (Thiamin)
treat acute illness with dialysis (removes leucine)
