How metabolism is tested on Step 1

Start from the presentation: hypoglycemia, organomegaly, neurologic regression, or an odor.

PathwayRate-limiting enzymeKey regulator
GlycolysisPhosphofructokinase-1↑ AMP, fructose-2,6-bisphosphate; ↓ ATP, citrate
GluconeogenesisFructose-1,6-bisphosphatase↓ by AMP and fructose-2,6-bisphosphate
TCA cycleIsocitrate dehydrogenase↑ ADP; ↓ ATP, NADH
Glycogen synthesis / breakdownGlycogen synthase / glycogen phosphorylaseInsulin / glucagon and epinephrine
Fatty acid synthesis / β-oxidationAcetyl-CoA carboxylase / carnitine acyltransferase IMalonyl-CoA inhibits β-oxidation
Cholesterol synthesisHMG-CoA reductaseInhibited by statins
Urea cycleCarbamoyl phosphate synthetase IN-acetylglutamate

Insulin favors storage (glycolysis, glycogen and fat synthesis); glucagon favors release (gluconeogenesis, glycogenolysis, β-oxidation).

Glycogen storage diseases

Location of the enzyme predicts liver versus muscle disease.

I · Von GierkeGlucose-6-phosphatase; fasting hypoglycemia, lacticacidosis, gout, big liverII · PompeLysosomal acid α-glucosidase; cardiomegaly,hypotoniaIII · CoriDebranching enzyme; milder hypoglycemia, normallactateV · McArdleMuscle glycogen phosphorylase; cramps,myoglobinuria, "second wind"
Glycogen storage diseases. Memory aid: Very Poor Carbohydrate Metabolism (types I, II, III, V).

Lysosomal storage diseases

Undegraded substrate accumulates inside lysosomes.

DiseaseDeficient enzymeClassic features
Tay-SachsHexosaminidase ANeurodegeneration, cherry-red macula, no hepatosplenomegaly
Niemann-PickSphingomyelinaseNeurodegeneration, cherry-red macula, hepatosplenomegaly, foam cells
Gaucher (most common)GlucocerebrosidaseHepatosplenomegaly, pancytopenia, bone crises, "crumpled tissue paper" macrophages
Fabry (X-linked)α-Galactosidase ABurning neuropathic pain, angiokeratomas, kidney and heart disease
KrabbeGalactocerebrosidaseNeuropathy, optic atrophy, globoid cells
Metachromatic leukodystrophyArylsulfatase ACentral and peripheral demyelination
Hurlerα-L-IduronidaseCorneal clouding, coarse facies, developmental delay
Hunter (X-linked)Iduronate-2-sulfataseLike Hurler but no corneal clouding; aggressive behavior

Enzyme replacement therapy is available for several, including Gaucher, Fabry, and Pompe disease.

Amino acid, urea cycle, and sugar disorders

Many present in newborns after feeding begins.

Amino acid disordersPKUPhe hydroxylase;musty odorMSUDBCKD; sweet urineHomocystinuriaLens dislocation,clotsOTC deficiencyHyperammonemia,orotic acid ↑
Amino acid disorders. OTC deficiency (X-linked) raises orotic acid without megaloblastic anemia, unlike orotic aciduria.
GalactoseClassic galactosemia: GALT deficiencyJaundice, liver failure, cataractsE. coli sepsis in newbornsRemove galactose and lactoseGalactokinase deficiency: cataracts onlyFructoseHereditary fructose intolerance:aldolase BHypoglycemia, vomiting after fruit orsucroseRemove fructose and sucroseEssential fructosuria: fructokinaseFructosuria is benignvs
Sugar disorders. Trapped phosphorylated sugars deplete phosphate and inhibit glycogenolysis, causing hypoglycemia.

Worked example

Use fasting tolerance and labs.

functions Worked example — the doll-faced infant

A 4-month-old has a round face, a very large liver, and seizures when feeds are delayed. Labs show glucose 30 mg/dL, high lactate, high uric acid, and high triglycerides. Glucagon does not raise glucose. Which enzyme is deficient?

  1. Severe fasting hypoglycemia that does not respond to glucagon means glucose cannot leave the liver.
  2. Glucose-6-phosphate accumulates and is shunted into lactate, triglycerides, and purines (uric acid).
  3. Glycogen builds up, enlarging the liver.
  4. This is von Gierke disease (glycogen storage disease type I).

Answer. Glucose-6-phosphatase (von Gierke disease); treat with frequent feeds and cornstarch.