Inborn Errors of Metabolism B&B

Question 1

which glycogen storage diseases do NOT present with hypoglycemia? (2)

Answer 1

1. McArdle’s Disease (Type V)
2. Pompe’s Disease (Type II)

only affect muscles!

Question 2

what are the two main lab finding of Von Gierke’s disease and why do these occur?

Answer 2

aka Type 1 glycogen storage disease

1. Severe fasting hypoglycemia - gluconeogenesis is not able to occur
2. Lactic acidosis - Cori cycle is disrupted, and lactate backs up because glucose cannot be exported from the liver.

Question 3

how does the presentation of Cori’s disease (Type III glycogen storage disease) different from that of Von Gierke’s (Type I) disease and why?

Answer 3

Von Gierke’s/ Type I: ineffective gluconeogenesis —> severe hypoglycemia + lactic acidosis (back up of Cori cycle)

Cori’s/ Type III: gluconeogenesis is intact, but glycogen cannot be broken down —> mild hypoglycemia with no lactic acidosis

Question 4

hereditary fructose intolerance leads to disruption of which two biochemical pathways? Why?

Answer 4

Deficiency of aldolase B —> buildup of fructose 1–phosphate, which depletes ATP

Loss of gluconeogenesis and glycogenolysis because these require ATP —> hypoglycemia, lactic acidosis, ketosis, hepatomegaly (glycogen build up)

Question 5

how is hereditary fructose intolerance diagnosed in clinical practice?

Answer 5

Deficiency of aldolase B —> buildup of fructose 1–phosphate, which depletes ATP —> loss of gluconeogenesis and glycogenolysis

diagnosed via reducing sugars (glucose, fructose, galactose) in the urine + hypoglycemia

Question 6

newborn baby with unexplained academia + hyperammonemia —> what is on your differential? (2)

Answer 6

presenting with an organic acidemia - should consider abnormal metabolism of
1. propionic acid
2. methylmalonic acid

recall these are the intermediates by which amino acids/ cholesterol/ odd chain FA are converted to succinyl-CoA to enter TCA

dx with elevated urine/plasma organic acids

Question 7

what are the basic steps (3) by which amino acids (isoleucine, valine, threonine, methionine), cholesterol, and all chain fatty acids are funneled into the TCA cycle? Include the cofactors that are required (2)

Answer 7

1. amino acids, cholesterol, odd chain FA are converted to propionyl-CoA
2. propionyl-CoA is converted to methylmalonyl-CoA, which requires biotin
3. methylmalonyl-CoA is converted to succinyl-CoA, which requires B12
4. succinyl-CoA enters the TCA cycle

Question 8

which enzyme is deficient in propionic acidemia vs methylmalonic acidemia? which cofactors are required for each of these enzymes to function?

Answer 8

propionic acidemia: deficiency of propionyl-CoA carboxylase (requires biotin), which converts propinyl-CoA to methylmalonyl-CoA

methylmalonic acidemia: deficiency of methylmalonyl-CoA mutase (requires B12), which converts methylmalonyl-CoA to succinyl-CoA (—> TCA)

recall this is the pathway by which amino acids/ cholesterol/ odd chain FA are funneled into TCA

Question 9

what is the cause of maple syrup urine disease? what causes the urine to smell sweet?

Answer 9

deficiency of alpha-ketoacid dehydrogenase, which is required to metabolize branched chain amino acids (valine, leucine, isoleucine)

branched amino acids + alpha-ketoacids (first step of their metabolism) build up in plasma/urine —> alpha-ketoacid of isoleucine gives urine sweet smell

Question 10

which two cofactors are required for the enzyme that is deficient in maple syrup urine disease?

Answer 10

deficiency of alpha-ketoacid dehydrogenase, which is required to metabolize branched chain amino acids (valine, leucine, isoleucine)

multi-subunit complex with 2 cofactors: thiamine + lipoic acid

Question 11

what is the key lab finding of the fatty acid disorders such as carnitine deficiency and MCAD deficiency? why does this occur?

Answer 11

hypoketotic hypoglycemia when fasting

lack of FA breakdown —> low ketone bodies —> over-utilization of glucose —> hypoglycemia

lack of FA breakdown —> lack of acetyl-CoA for gluconeogenesis —> hypoglycemia

Question 12

how do urea cycle disorders present?

Answer 12

onset in newborn period (24-48 hours) with poor feeding, vomiting, lethargy —> seizures

labs shows isolated severe hyperammonemia (urea >1000)

Question 13

what is the consequence of a ornithine transcarbamylase (OTC) deficiency? (lab findings - 3)

Answer 13

most common urea cycle disorder

OTC required to funnel both NH4+ and carbamoyl phosphate into urea cycle; deficiency —>

1. high NH4+
2. high carbamoyl phosphate
3. high orotic acid (in pyrimidine synthesis, carbamoyl phosphate is converted to orotic acid —> pyrimidines)

Question 14

what is the cause of orotic aciduria? what are the 2 major features?

Answer 14

in pyrimidine synthesis, glutamine —> carbamoyl phosphate —> orotic acid —> pyrimidines

orotic aciduria: disorder of pyrimidine synthesis —> megaloblastic anemia, poor growth

[note, normal ammonia levels, differentiating it from OTC deficiency]

Question 15

elevated alanine level suggests…

Answer 15

mitochondrial disorder - loss of ability to metabolize pyruvate to acetyl CoA

pyruvate consequently shunted to alanine and lactate —> severe lactic acidosis

most common is pyruvate dehydrogenase complex deficiency