BIOCHEM QUESTIONS

This child has familial hypocalciuric hypercalcemia (FHH). FHH is characterized clinically byincreased serum
calcium (hypercalcemia), relatively decreased urine calcium for the degree of hypercalcemia (relative hypocalciuria),
slight hypermagnesemia, and normal/high levels of parathyroid hormone (which are inappropriate for the degree of
hypercalcemia).
The calcium-sensing receptor (CaSR) is the product of the CaSR gene on chromosome 3q. CaSR is found in the parathyroid glands
and plays a major role in calcium metabolism by mediating feedback inhibition of the secretion of parathyroid hormone based on
blood calcium concentration. CaSR is also found in the kidney, where it mediates the feedback inhibition of parathyroid hormone
independent calcium reabsorption, again in response to blood calcium concentration.
Decreases in the sensitivity of CaSR have been implicated in several diseases, including familial hypocalciuric
hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypoparathyroidism.In familial hypocalciuric
hypercalcemia (also called familial benign hypercalcemia), which this child has, a downregulation of the receptor involving only one
gene (heterozygous downregulation) produces a relatively mild autosomal dominant condition. The condition is usually
asymptomatic and specifically does not require parathyroid surgery to decrease the mass of parathyroid tissue.
Mutation of AIRE (choice A) is a feature of autoimmune hypoparathyroidism, which is characterized bymucocutaneous
candidiasis and hypocalcemia secondary to autoimmune hypoparathyroidism. Autoimmune hypoparathyroidism is often a
component of autoimmune polyendocrinesyndrome, which may also impair function of the adrenal glands, the thyroid gland, and the
gonads.
Cyclin D1 gene (choice C) inversion is seen frequently in sporadic parathyroid adenomas, which could
causehypercalcemia and high serum parathyroid hormone. This would be uncommon in a 1-year-old, however, and would likely
cause a secondarily increased excretion of calcium in the urine.
Mutation of the epidermal growth factor receptor (EGFR)(choice D) is common in several types of cancer includinglung
cancer and glioblastoma multiforme, but it is not a major factor in endocrine neoplasias or hypercalcemia.
Mutation of GCM2 (choice E) is a feature of the autosomal recessive form of familial isolated hypoparathyroidism, which is
characterized by impaired parathyroid development leading to hypocalcemia.
Updated on 10/09/15

Orotic aciduria is associated with both a urea cycle defect and a pyrimidine nucleotide biosynthesis defect.

The urea cycle disorder is in ornithine transcarbamoylase. However, a defect in this enzyme does not result in an associated
megaloblastemia.

Orotic aciduria due to a defect in pyrimidine biosynthesis is associated with a defect in either of the 2 activities of the
bifunctional UMP synthase enzyme. These activities are identified as orotate phosphoribosyltransferase and OMP
decarboxylase.

The lack of pyrimidines impairs nucleic acid synthesis needed for hematopoiesis resulting in enlarged blast cells.

Orotic acid accumulates and spills into urine where, at high enough concentration, forms whitish needle shaped crysta

Short-acting physiologic messenger

NO is released, diffuses to smooth muscle cells, enters the cells, and activates guanylate cyclase.

Soluble guanylate cyclase makes cGMP, which triggers smooth-muscle relaxation.

Examples of NO signal transduction include relaxation of smooth muscle and dilation of blood vessels (vasodilation).

Vasodilation in the corpus cavernosum of the penis causes erection.

Short-acting physiologic messenger

NO is released, diffuses to smooth muscle cells, enters the cells, and activates guanylate cyclase.

Soluble guanylate cyclase makes cGMP, which triggers smooth-muscle relaxation.

Examples of NO signal transduction include relaxation of smooth muscle and dilation of blood vessels (vasodilation).

Vasodilation in the corpus cavernosum of the penis causes erection.

he correct answer is E. In general, you should associate primary hemolytic

anemia with defects in glycolysis or the hexose monophosphate shunt (pentose
phosphate pathway) because those are pathways of energy generation and antioxidant
defense in the red cell. A salient feature of the patients presentation is that the disorder
appears to be hereditary and that it is not X-linked, because there is not a male-bias in
the inheritance. Only one enzyme of those listed in the answer choices specifically involves
these pathways, causes hemolytic anemia when deficient and is inherited in an autosomal
fashion: pyruvate kinase (PK).
PK is a glycolytic enzyme; PK deficiency is an autosomal recessive disorder,
affecting males and females approximately equally. Consanguinity increases the
incidence of any autosomal recessive condition. Deficiency ofglucose 6-phosphate
dehydrogenase (G6PDH), which may be related to hemolytic anemia, is X-linked. A
hemolytic anemia from inherited deficiency of G6PDH in a woman is expected to be very rare.
If this enzyme is deficient, red cells are defective in their ability to produce sufficient
ATP to maintain the Na+/K+pump on the plasma membrane, secondarily causing swelling
and lysis. Severe forms of PK deficiency are usually symptomatic in newborns and may
be life-threatening. Milder cases of PK deficiency are often missed earlier in life and may or
may not produce symptoms later in life. Increased concentrations of glycolytic
intermediates in red blood cells occur. 2 to 3 times the normal levels of 2,3bisphosphoglycerate (2,3-BPG or 2,3,-DPG) in red cells are present, leading to a lower
affinity of Hb for O2.
Debranching enzyme (-1,4, -14 transferase) (choice A) deficiency is characterized by mild
fasting hypoglycemia and hepatomegaly.
Defects in glucose-6-phosphatase (choice B) produce profound fasting hypoglycemia,
lactic acidosis, hepatomegaly, hypertriglyceridemia, and hyperuricemia.
Glucose 6-phosphate dehydrogenase (choice C) deficiency decreases NADPH production
in the red cell and decreases the red cell antioxidant defense. G6PDH deficiency can
produce a hemolytic anemia during oxidant stress or during infections. G6PDH is an Xlinked gene and hemolytic anemia in the womans sister and herself make that gene defect
unlikely.
Deficiency of muscle phosphorylase (myophosphorylase) (choice D) produces weakness
and cramping during the initial phase of exercise, especially if the exercise is strenuous.
During this period glycogen normally supplies much of the glucose used by the muscle.
Updated on 02/28/16

Fructose-1-phosphate aldolase (aldolase B) deficiency is an autosomal recessivedisorder of fructose metabolism resulting

in accumulation of fructose-1-phosphate because of the inability to cleave it to glyceraldehyde and dihydroxyacetone phosphate.
The accumulated fructose-1-phosphate inhibits glycogenolysis and gluconeogenesis, causing severe hypoglycemia after
ingestion of fructose. These processes are inhibited because free inorganic phosphate (Pi) levels are reduced. Pi is required for
glycogen phosphorylase of glycogenolysis. Pi is also required for ATP production, and ATP is needed for gluconeogenesis.

As ATP levels fall, AMP levels rise. AMP is degraded to uric acid and hyperuricemia may be seen. Because urate and lactate
compete for the same transporters in the kidneys, lactic acidosis may occur.
Prolonged fructose ingestion in infants leads ultimately to hepatic failure and death. This condition is known ashereditary fructose
intolerance (HFI). Treatmentisremoval of fructose (and sucrose, a disaccharide of glucose and fructose) from the diet.
Freefructose is found fruits, honey, and high-fructose corn syrup.

Aldose reductase (choice A) reduces glucose to sorbitol and galactose to galactitol. In patients with recurring
hyperglycemia (as in diabetes) or galactosemia (as in galactokinase deficiency or UDP-galactosyltransferase deficiency),
increased concentrations of sorbitol or galactitol in the lens of the eye lead to cataracts.
Essential fructosuria involves a defect in fructokinase (choice B) and is a benign, asymptomatic condition.
Hexokinase (choice D) catalyzes the first step in glycolysis.
Lactase (choice E) breaks down lactose into glucose and galactose. Primary or secondary intestinal lactase deficiency results
in diarrhea, bloating, flatulence, and cramping after the ingestion of lactose. The majority of the worlds population is lactase
deficient.

20-year-old primigravid woman who is 2 months pregnant comes to the physician for her first routine prenatal examination. She states that she had a
congenital deficiency of phenylalanine metabolism as a child and was required to be on a special diet in which she was not able to ingest anything
sweetened with aspartame. Laboratory studies show markedly elevated maternal serum levels of phenylalanine. Genetic studies have not been performed on
the patient's husband. Which of the following is the most appropriate response by the physician?

The correct answer is E. This patient has phenylketonuria (PKU),

whose clinical effects depend upon the levels of phenylalanine, an
essential amino acid. Aspartame (N-aspartyl-phenylalanine methyl
ester), which is widely used as an artificial sweetener, must be strictly
avoided by phenylketonurics. Phenylalanine crosses the placenta
and, if maternal serum levels are elevated, acts as a teratogen to
the developing fetus. This condition is known asmaternal PKU
syndrome. Although the mother can stay well with substantial elevations
in serum phenylalanine concentration, the children born to such women
are usually profoundly retarded and may have multiple birth defects.

Although dietary modifications (choice A) can prevent the neurologic and

dermatologic manifestations of PKU in a child, the fetus is still at risk from
maternal PKU.
Further information regarding the cause of this woman's
hyperphenylalaninemia (choice B) is not needed, since the fetus is
exposed to teratogenic levels of phenylalanine.
Children born to mothers with untreated PKU present at birth
with symptoms of PKU even if they are heterozygous for the PKU
gene (choice C). Fetal phenylalanine hydroxylase cannot compensate for
the high maternal levels of phenylalanine.
The critical period in development during which teratogenic material
affects the growing organs is between the third and eighth weeks of
gestation. By the end of the second month, the damage caused by the
maternal PKU has already occurred (choice D).
Updated on 08/04/15
ReKaps

Women with PKU who become pregnant must be especially careful about the phenylalanine level in their blood to avoid
adversely affecting neurologic development in the fetus.

Infants whose phenylketonuric mothers have not maintained adequate metabolic control during pregnancy have a high risk for
mental retardation, microcephaly, and low birth weight.

This question introduces maternal PKU syndrome. Even if the fetus is heterozygote for this autosomal recessive
disorder, the fetus is still at risk for mental retardation if the PKUic mother does not maintain low levels of plasma
phenylalanine.

There are several variants of G6PD deficiency (X-linked recessive) in Africa. The most common clinically significant variant is the so-called
A-type, which produces an unstable G6PD enzyme. This variant is found in up to 11% of African-American males. In red cells, NADPH from
the HMP shunt is essential for detoxifying reactive oxygen species that otherwise would damage proteins and lipids in the RBC.
Glutathione reductase and glutathione peroxidase are involved in the normal detoxification process. The A-variant renders the individual's
red cells susceptible to oxidative stresses, such as those that occur with administration of the antimalarial drug primaquine. Sulfonamides
and dapsone are other agents that can trigger hemolytic episodes. Infections (bacterial or viral) are another important trigger for
hemolysis in these individuals. Rarely, G6PD deficiency presents as neonatal jaundice or with chronic hemolysis. In Mediterranean
populations, G6PD deficiency-associated hemolysis may occur in individuals who eat a meal of fava beans (Vicia fava) and several hours
later develop hemoglobinuria and peripheral vascular collapse secondary to intravascular hemolysis as a result of the oxidant injury
initiated by the fava beans.
Fanconi anemia (choice A) is caused by a mutation in one of several genes encoding a multiprotein nuclear complex that functions in
the BRCA pathway, which repairs damage to DNA caused by cross-linking agents. All bone marrow elements are affected. In addition to
the often-fatal leukemia, pigmentary changes in the skin and malformations of the heart, kidney, and limbs (aplasia of the radius, thumb
deformity) are associated features.
Myoglobinuria following strenuous exercise, especially in the initial phase (choice B) is characteristic of myophosphorylase deficiency
(McArdle disease) a defect in muscle glycogenolysis.
A neonate with an enlarged spleen and chronic hemolysis (choice C) is consistent with pyruvate kinase deficiency, the neonatal form of
which is often fatal. Transfusions coupled with splenectomy often lessen the symptoms.
An adult who suffers shortness of breath during an airplane ride (choice E) (or any activity at low pO2) is consistent with a person who is
heterozygous or homozygous for the S allele of the hemoglobin -chain locus and is either a carrier (heterozygous) or a person with
sickle cell anemia (homozygous).
Reviewed on 02/14/15

A 45-year-old woman comes to the physician because of headaches and palpitations. Her blood pressure in the office is 120/70 mm Hg, but when she is
symptomatic her pulse is 105/min and blood pressure is 190/140 mm Hg. A CT scan of the abdomen shows an adrenal mass. The hormones secreted by the
adrenal mass are derived from which of the following amino acids

The patient has an adrenal pheochromocytoma that is causing episodic hypertension(leading to headache)
and arrhythmia (leading to palpitations). The tumor arises from the sympathetic chromaffin cells in the adrenal
gland. Catecholamines secreted by the tumor include epinephrine, norepinephrine, anddopamine. All three of these are derived
from tyrosine (which is, in turn, derived from phenylalanine). Catecholamine synthesis is shown below.

Arginine (choice A) is the amino acid precursor of the biological messenger nitric oxide (NO). Arginine is also an intermediate in the
urea cycle.
Glutamate (choice B) is the amino acid precursor of gamma-amino butyric acid(GABA).
Glycine (choice C) is itself an amino acid and a neurotransmitter, not a precursor of hormones.
Tryptophan (choice D) is the amino acid precursor of 5-hydroxytryptophan, serotonin, and melatonin.
The table below lists some important products formed from amino acids:

Updated on 10/07/15
The patient has an adrenal pheochromocytoma that is causing episodic hypertension(leading to headache)
and arrhythmia (leading to palpitations). The tumor arises from the sympathetic chromaffin cells in the adrenal
gland. Catecholamines secreted by the tumor include epinephrine, norepinephrine, anddopamine. All three of these are derived
from tyrosine (which is, in turn, derived from phenylalanine). Catecholamine synthesis is shown below.

Arginine (choice A) is the amino acid precursor of the biological messenger nitric oxide (NO). Arginine is also an intermediate in the
urea cycle.
Glutamate (choice B) is the amino acid precursor of gamma-amino butyric acid(GABA).
Glycine (choice C) is itself an amino acid and a neurotransmitter, not a precursor of hormones.
Tryptophan (choice D) is the amino acid precursor of 5-hydroxytryptophan, serotonin, and melatonin.
The table below lists some important products formed from amino acids:

Updated on 10/07/15

The correct answer is E. Carnitine is a methylated derivative of lysine

that is used by the enzyme carnitine palmitoyltransferase (CPT/CAT). This
enzyme catalyzes the movement of a long-chain fatty acyl group from CoA
to carnitine, and then the fatty acid attached to carnitine is carried across
the inner mitochondrial membrane and into the mitochondrial matrix.
Within the mitochondrion, fatty acyl-CoA is regenerated and undergoes
beta-oxidation. Carnitine is obtained to some degree from the diet and to
a greater degree by endogenous synthesis. Carnitine deficiency can result
either from increased demand (e.g., ketosis) coupled with inadequate diet
or from defects in the carnitine metabolic pathways. In addition to
features noted in the question stem, carnitine deficiency may cause fatty
liver, lipid storage myopathy, and confusion.

Serum albumin carries free fatty acids in the blood (choice A) for
distribution to tissues that can oxidize them, such as liver and muscle.
An N-terminal hydrophobic signal sequence is required to import nascent
proteins into the lumen of the rough endoplasmic reticulum (choice B).
Targeting misfolded proteins to proteasomes (choice C) requires
ubiquitin.
Transfer of digestive enzymes from the Golgi apparatus to
lysosomes (choice D) requires phosphorylation of mannose in the
glycosylated enzyme to form mannose-P.
Reviewed on 02/19/15
ReKaps

Carnitine is a derivative of the amino acid lysine.

Carnitine is used by the enzyme carnitine palmitoyltransferase, which transfers a fatty acid (most commonly palmitate) onto
carnitine.

The fatty-acyl carnitine is transported across the mitochondrial membrane, where it is transferred from carnitine back to CoA
to undergo beta-oxidation.

A 6-month-old girl is brought to the physician because of persistent weakness. Laboratory studies show hypoglycemia, hyperammonemia, and
myoglobinuria. A diagnosis of defective carnitine biosynthesis is made. This molecule is necessary for which of the following biochemical functions?

A. Carrier of free fatty acids in the blood

B. Importing nascent proteins into the endoplasmic reticulum

C. Targeting proteins to proteasomes

D. Transfer of digestive enzymes from the Golgi apparatus to lysosomes

E. Transport of long-chain fatty acids into mitochondriapart

Part 2
The principal route of metabolism of ethanol is via alcohol dehydrogenase and acetaldehyde dehydrogenase, both of
which reduce NAD+ to NADH, markedly increasing the ratio of NADH to NAD+.

Pyruvate + NADH Lactate + NAD+. The higher-than-normal ratio of [NADH]/[NAD+] would increase conversion of pyruvate to
lactate.
The higher-than-normal [NADH]/[NAD+] favors the formation of glycerol-3-phosphate from dihydroxyacetone
phosphate (compare with choice A) and would decrease the conversion of malate to oxaloacetate rather than stimulating
it (choice B).
The relative excess of NADH has a number of effects, including decreasing, rather than increasing, fatty acid oxidation (choice E).
This effect on fatty acid oxidation would decrease rather than increase conversion to ketone bodies (choice C). Choice C is also
incorrect because the patient is presumed to be a long term alcoholic and likely has alcoholic cirrhosis of the liver. Therefore, any
pathway normally conducted by the liver will be impaired, such as gluconeogenesis. And, in this case, there would be decreased
production of ketone bodies.
The borderline fasting hypoglycemia is likely due to impaired gluconeogenesis, which is a consequence of decreased pyruvate,
decreased dihydroxyacetone phosphate, and decreased oxaloacetate from the higher-than-normal ratio of [NADH]/[NAD +]. In each
instance, those gluconeogenic precursors are being shunted away from gluconeogenesis rather than shunted into the pathway of
glucose synthesis.

NADH + DHAP Glycerol-3P + NAD

NADH + Pyruvate Lactate + NAD

NADH + Oxaloacetate Malate + NAD

When [NADH] increases and [NAD] decreases, the equilibrium of the reactions above are shifted to the right.

In order to promote gluconeogenesis, the equilibrium of these reactions must favor the formation of oxaloacetate,
dihydroxyacetone phosphate, and pyruvate so these substrates can be converted to glucose

The graph shows that protein tyrosine phosphatase 1B (PTP 1B) decreases the tyrosine kinase activity of the insulin receptor. In the
knockout mice, this tyrosine kinase activity would be increased, because of the lack of PT1B action, leading to increased insulin effects.
The relationships are summarized below:

Insulin binding to the insulin receptor activates the cytoplasmic tyrosine kinase domain, causing autophosphorylation of the
receptor. These phosphotyrosine residues initiate the signal transmission pathways associated with insulin.

PTP 1B opposes insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor, blocking further
signal transmission.

A mouse lacking PTP 1B activity would show an increased hepatic response to insulin.

The question now becomes "Which of the following enzyme activities is increased by insulin?" Acetyl-CoA carboxylase, which
catalyzes the rate-limiting step in fatty acid biosynthesis, is the only enzyme among the answer choices that is activated by insulin
and would therefore have increased activity in PTP 1B knockout mice compared with normal mice.
This figure below shows activation of acetyl CoA carboxylate by insulin (and citrate). Insulin stimulates the liver to store glucose in the
form of glycogen. However, as glycogen accumulates to high levels, glycogen synthesis is suppressed and additional glucose is shunted
into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. Lipoproteins are broken down in the
circulation, providing free fatty acids for other tissues. This includes adipocytes, which will then synthesize triglycerides.

Hexokinase (choice B) is not regulated by insulin. This enzyme activity would be similar in the PTP 1B knockout mice and in normal mice.
In addition, the experiment is carried out in liver cell cultures; liver does not have hexokinase, but instead has glucokinase.
Glycogen phosphorylase (choice C) is phosphorylated and activated by glycogen phosphorylase kinase. This enzyme in liver would be
less active in response to insulin.
Glycogen phosphorylase kinase (choice D) is phosphorylated and activated by protein kinase A (PKA), an enzyme activated by glucagon,
not insulin, in the liver.
Protein kinase A (PKA) (choice E) is activated by cAMP. Insulin does not increase cAMP concentration in the liver, but rather decreases it.
The figure below shows the opposing actions of insulin and glucagon on glycogen metabolism.

Cocaine blocks the reuptake of norepinephrine, resulting in tachycardia as well

asexcessive vasoconstriction of coronary vessels, leading to ischemia and infarction

of heart tissue known ascontraction band necrosis. Under these pathologic conditions,
myocardial cells switch to anaerobic metabolismand therefore, glycolysis becomes the
major source of ATP via substrate-level phosphorylations by phosphoglycerate kinase and
pyruvate kinase. Phosphofructokinase-1 (PFK-1) is the rate-limiting enzyme of
glycolysis, and its activity would therefore be increased.
Glyceraldehyde 3-phosphate dehydrogenase (choice A) is an enzyme of glycolysis that
produces 1,3-bisphosphoglycerate, a substrate for the ATP-producing enzyme
phosphoglycerate kinase. Glyceraldehyde 3-phosphate dehydrogenase is not a
regulated enzyme of glycolysis and is not expected to increase in activity under hypoxic
conditions or under a shift from aerobic to anaerobic metabolism.
Phosphoenolpyruvate carboxykinase (choice B) is a regulatory enzyme in
gluconeogenesis, which is induced by cortisol, epinephrine, and glucagon. It functions in the
hepatic synthesis of glucose when energy levels from beta-oxidation of fatty acids are
adequate.
Pyruvate dehydrogenase (choice D) produces acetyl-CoA from pyruvate and coenzyme A,
bridging glycolysis and the tricarboxylic acid (TCA) cycle. It requires 5 cofactors, including
NAD and FAD, which would no longer be produced by the electron transport under
hypoxic conditions, decreasing its activity.
Succinate dehydrogenase (choice E) is a key enzyme of the TCA cycle, producing a reduced
equivalent of FAD to feed into the electron transport chain. It is also known as Complex II. The
TCA cycle only functions if oxygen is in appropriate concentrations since it is regulated by the
levels of NADH, which is only consumed by the electron transport chain if there is enough
oxygen. The absence of oxygen leads to an accumulation of NADH and a subsequent
decrease in the enzyme activities of the TCA cycle.
Updated on 01/27/16

Hyperuricemia may progress to acute and chronic gouty arthritis if monosodium urate is deposited in joints and surrounding
soft tissue.

Chronic hyperuricemia may also lead to repeated episodes of renal calculi.

Chronic gout and overproduction of uric acid are treated with allopurinol.

Allopurinol is an inhibitor of xanthine oxidase, the enzyme of purine catabolism that produces uric acid from hypoxanthine and
xanthin

There are two types of beriberi: (1) Dry beriberi causes progressive polyneuropathy with myelin degeneration, leading to foot
drop and wrist drop. (2) Wet beriberi is associated with high-output cardiac failure.

Thiamine is required for two TCA cycle enzymes and thus a deficiency of thiamine may lead to a deficiency of energy
metabolism from carbohydrate, fatty acid or amino acids as fuel

ay-Sachs disease:

Deficiency of lysosomal hexosaminidase A

Accumulation of ganglioside GM2 in lysosomes of CNS and retina

Common in Ashkenazi Jews

Cherry-red spot in macular region of retina

Dilated neurons with lipid-filled vacuoles in CNS

Normal at birth, onset by 3-6 months

Intellectual disability and motor incoordination

No hepatosplenomegaly

Death by 45 years of age

he correct answer is D. Neonatal jaundice is a very common condition that may require medical attention in
newborns. Accumulation of unconjugated bilirubin (UCB) causes the yellow coloration (jaundice or icterus) of theskin and
sclera. In many cases, this is a physiologic rather than a pathologic occurrence. It is observed in approximately 60% of term neonates
and 80% of preterm neonates. There is great cause for concern, however, if serum UCB levels increase too much (for example, with Rh
incompatibility) because UCB is neurotoxic. It can causekernicterus (deposition of lipid-soluble UCB in the basal ganglia), which
can produce lifelong neurologic complications in neonates who survive. Neonatal hyperbilirubinemia occurs more frequently in
boys and those ofEast Asian and Native American descent. Breast milk jaundice is a type of neonatal jaundice associated with
breastfeeding.
Neonatal jaundice develops for two reasons.First, bilirubin production is increased because of hemolysis of fetal red
blood cells (RBCs) as they are replaced with newly-formed hemoglobin Acontaining RBCs. The porphyrin ring of the heme
prosthetic group of hemoglobin liberated by hemolysis is converted by NADPH-requiring heme oxygenase to linear biliverdin as carbon
monoxide and iron are released. Biliverdin is reduced to bilirubin by NADPH-requiring biliverdin reductase. Bilirubin is conjugated with two
molecules of glucuronic acid by bilirubin UDP-glucuronosyl transferase (bilirubin UGT), a hepatic enzyme, and ultimately secreted into the
bile. If more bilirubin is made than can be conjugated, UCB accumulates. Second, the hepatic excretory capacity for bilirubin is
low at birth, in part because of low bilirubin UGT levels in the perinatal period. Genetic deficiencies in bilirubin UGT are the cause
of Gilberts and Crigler-Najjar I and II.

Phototherapy is routinely used to treat neonatal jaundice because light converts bilirubin into water-soluble isomers that are
excreted into urine. Another molecule that absorbs light is the water-soluble vitamin riboflavin (vitamin B2), which degrades with
phototherapy (but not heat). Riboflavin supplementation is required to prevent deficiency of the vitamin.
Ascorbate (choice A), folate (choice B), and niacin (choice C) are water-soluble vitamins that do not appreciablydegrade under
the conditions of phototherapy and do not have to be supplemented.
Vitamin D (choice E) is a fat-soluble vitamin generated in a UV-requiring pathway that leads from 7-dehydrocholesterol to
calcitriol (1,25-dihydroxycholecalciferol, vitamin D). Vitamin D is not typically depleted with phototherapy and actually may
be increased by exposure to some forms of light.
Updated on 08/31/15
he correct answer is C. In addition to decreasing the availability of essential amino acids, prolonged starvation and protein deficits
tend to reduce the body's ability to synthesize even the "non-essential" amino acids. However, for purposes of the USMLE, you should
pick out one of the essential amino acids, which include phenylalanine, valine, tryptophan, threonine, isoleucine,
methionine, histidine, arginine, lysine, and leucine. (mnemonic: PVT TIM HALL). Not all authors include arginine, which is not
usually required by the adult unless there is an increased demand for protein synthesis (pregnancy or recovery from negative nitrogen
balance, as in the case of these individuals). Arginine is essential in children because they are growing and adding extra protein to their
bodies.
In response to dietary deficiency of essential amino acids, skeletal protein is degraded, leading to the thin phenotype of the
children. As the protein malnutrition progresses, synthesis of albumin in the liverdecreases, leading to osmotic imbalance
and fluid accumulation in extravascular tissues, leading to the distended abdomens of the children.

he correct answer is C.Citrate is produced by citrate synthase from acetyl CoA and oxaloacetate. This is a reaction of
the mitochondrialcitric acid cycle (see figure), but citrate can move freely from the mitochondria into the cytosol using the citrate
shuttle. When the citric acid cycle slows down, citrate accumulates and enters into the cytosol. In the cytosol, it acts as a negative
allosteric regulator of phosphofructokinase I (PFK 1), the enzyme that catalyzes the committed step of glycolysis. This prevents
excess substrate from entering the cycle. Citrate is a positive allosteric effector of cytosolic acetyl CoA carboxylase, the ratelimiting and regulated enzyme of fatty acid synthesis.

Fructose-2,6-bisphosphatase (choice A) is an activity of

the bifunctional enzyme PFK 2. It breaks down fructose-2,6bisphosphate (synthesized by the kinase domain of PFK 2), which is a
potent allosteric activator ofphosphofructokinase I (PFK 1) in glycolysis and
an inhibitor of fructose-1,6-bisphosphatase in gluconeogenesis. This results
in inhibition of glycolysis and activation of gluconeogenesis. Fructose-2,6-

bisphosphatase is regulated covalently. In the liver,phosphorylation of PFK 2

by PKAactivates the phosphatase activity (and inactivates the kinase), whereas
in cardiac muscle, phosphorylation by AMPKinactivates the
phosphatase activity (and activates the kinase).
Isocitrate dehydrogenase (choice B) converts isocitrate to alphaketoglutarate in the citric acid cycle. It isallosterically
stimulated by ADP and calcium and inhibited by ATP and NADH. This reaction
produces NADH and CO2.
Pyruvate carboxylase (choice D) is a mitochondrial enzyme that
converts pyruvate to oxaloacetate in a biotin and ATP-dependent reaction. It is
important in gluconeogenesis and replenishes the oxaloacetate in the citric acid
cycle. Acetyl-CoA is a required allostericactivator of pyruvate carboxylase.
6-Phosphogluconate dehydrogenase (choice E) converts 6-phosphogluconate to
ribulose 5-phosphate in thepentose phosphate shunt (pathway), and in the
process reduces NADP to NADPH for biosynthesis (liver), for generating superoxide
to kill bacteria (neutrophil), and for protecting erythrocyte membranes from
oxidative damage and hemolysis.
Updated on 09/09/15

This patient has a classic case of Lesch-Nyhan syndrome, an X-linked

recessive disorder due to near-complete deficiency of the purine
salvage enzyme hypoxanthine-guanine phosphoribosyl transferase(HPRT, or
sometimes referred to as HGPRT). This enzyme recycles purine bases back into
nucleotide synthesis and thereby prevents their degradation to uric acid. The
deficiency of HPRT is associated with excessive de novo purine
synthesis, hyperuricemia (elevated levels of uric acid in the blood), and the
clinical signs and symptoms described in the question stem. The biochemical basis of
the often striking self-mutilation, which may require restraints and even tooth
extraction, has never been established.
Treatment with allopurinol inhibits xanthine oxidase and its production of uric
acid, and reduces the gouty arthritis, urate crystal formation, urate
nephropathyand subcutaneous deposits of urate crystals (tophi) associated with
hyperuricemia. It does not, however, modify the neurologic/psychiatric presentation.

Galactosemia is an autosomal recessive trait that results from a defective gene

encoding galactokinase, galactose 1-P uridyltransferase, or galactose 6-phosphate
epimerase. When galactose accumulates, it is metabolized by the enzyme aldose
reductase to galactitol(choice A) in the lens. Galactitol in the lens causes swelling and
cataracts.
Glucocerebroside (choice B) is the sphingoglycolipid substrate accumulating in inclusion
bodies of individuals withglucocerebrosidase deficiency (Gaucher disease). The disease
is characterized by hepatosplenomegaly, erosion and fractures of bones,
thrombocytopenia or pancytopenia, and characteristic macrophages (crumpledpaper inclusions).
Orotic aciduria is an autosomal recessive disorder caused by a defect in the pyrimidine
synthesis pathway. Orotic acid (choice D) accumulates and spills into the urine, resulting
in orotic acid crystals. Infants with some forms of this disorder can present with
severe megaloblastic anemia that does not respond to supplementation with
vitamin B12 or folic acid.
Phenylalanine hydroxylase deficiency results in phenylketonuria (PKU), in which the
accumulation of phenylalanine (choice E) results in slow development, severe
intellectual disability, autistic symptoms, and loss of motor control. There is
mandatory newborn screening for PKU in all states in the U.S. because early diagnosis and
treatment (dietary restriction) prevent pathology.
Updated on 10/07/15
This child presents with hepatomegaly, cardiomegaly, and heart failure secondary to
cardiomyopathy,all characteristic features of Pompe disease, one of the glycogen storage
diseases. In this condition, glycogen accumulates in organs due to a deficiency of
lysosomal -1,4- glucosidase. This disease differs from many other glycogen storage
diseases (notably von Gierke disease) by the relative prominence of skeletal and cardiac
muscle symptoms (weakness) and the relative lack of hypoglycemic and acidotic
episodes. In contrast to Von Gierke disease (Type 1 glycogen storage disease), patients
with Pompe disease do not show a severefastinghypoglycemia.
Von Gierke disease (glucose-6-phosphatase deficiency; choice A) is characterized
by severe hypoglycemia, lactic acidosis, hepatomegaly, renomegaly,
hyperlipidemia, and hyperuricemia.

Andersen disease (branching enzyme deficiency; choice B) is characterized by hypotonia,

cirrhosis, and early death (by age 2 years).
Lysosomal sphingomyelinase deficiency (choice D), also known as Niemann-Pick disease,
is a disorder of sphingolipid catabolism characterized by hepatosplenomegaly, microcephaly,
severe mental retardation, zebra bodies in inclusions, characteristic foamy macrophages, and
early death.
Individuals with the glycogen storage disease due to a myophosphorylase
deficiency(McArdle disease; choice E) present with muscle cramps and weakness on
exercise.